Course on Recent Advances in Oncologic Surgical Pathology - Siapec

PATHOLOGICA 2005;97:23-64
<strong>Course</strong> on Recent Advances
in Oncologic Surgical Pathology
Presented conjointly by:
“Società Medica del Friuli”, Udine, Italy
The Department of Pathology, Division of Anatomic Pathology
General Hospital “S. Maria della Misericordia”, Udine, Italy
The Department of Pathology
M.D. Anderson Cancer Center
Houston, Texas, USA
Under the patronage of SIAPEC-IAP
23-25 September 2004
<strong>Course</strong> Venue
Hotel Là di Moret, Udine, Italy
<strong>Course</strong> director
Stefano Pizzolitto, M.D.
Chief, Anatomic Pathology Services
General Hospital “S.M. Misericordia”, Udine, Italy
President, Società Medica del Friuli
Associate director
Cesar A. Moran, M.D.
Department of Pathology
M.D. Anderson Cancer Center, Houston, Texas, USA
<strong>Course</strong> lecturers
Department of Pathology
M.D. Anderson Cancer Center
University of Texas School of Medicine
Houston, Texas, USA
Elvio G. Silva, M.D.
Chief, Gynecologic Pathology Section
Cesar A. Moran, M.D.
Pulmonary Pathology Section
Janet M. Bruner, M.D.
Neuropathology Section, Chairman
Victor G. Prieto, M.D.
Director of Dermatology
and
Mario A. Luna, M.D
Section Chief, Autopsy Services
Guest Faculty
Michal Michal, M.D.
Director, Sikl’s Department of Pathology Charles University, Medical Faculty Hospital, Pilsen, Czech Republic
Home of the 2nd Arkadi M. Rywlin
International Pathology Slide Seminar
9-10 June 2005
<strong>Course</strong> coordinator
Giovanni Falconieri, M.D.
Anatomic Pathology Services
General Hospital “S.M. Misericordia”, Udine, Italy

24
ATTI CONGRESSUALI
La Società Medica del Friuli, unitamente alla Struttura
Operativa Complessa di Anatomia Patologica dell’Azienda
Ospedaliera “S. Maria della Misericordia” di
Udine, ha recentemente organizzato il Congresso Internazionale
“<strong>Course</strong> on Recent Advances in Oncologic
Surgical Pathology” a Udine dal 23 al 25 settembre
2004. Hanno partecipato in qualità di relatori autorevoli
patologi dell’M.D. Anderson Cancer Center di Houston
(USA), una delle più note istituzioni mondiali all’avanguardia
nella diagnosi, cura e ricerca nel settore
oncologico. Tali relatori sono anche professori di Anatomia
Patologica presso il locale ateneo, la University
of Texas School of Medicine.
Gli obiettivi prefissati dell’iniziativa erano di affrontare
aree controverse in diagnostica oncologica valutate in
chiave clinicopatologica. La ricaduta di beneficio è stata
considerevole per tutti gli operatori medici che hanno
preso parte al congresso. Per i molteplici argomenti trattati
(patologia neoplastica di polmone, laringe, pleura,
encefalo, cute ed apparato genitale femminile) si può
certamente affermare che notevole è stato l’arricchimento
del bagaglio culturale teorico dei partecipanti. Di notevole
rilievo, inoltre, il feedback derivante dalle sessioni
pratiche (ben 6) con cui i relatori hanno integrato le 10
lezioni tradizionali frontali, utilizzando allo scopo i set
di preparati istologici che in precedenza erano stati inviati
a mezzo posta ai partecipanti.
Dei partecipanti, oltre la metà ha raggiunto Udine da
paesi stranieri dell’Europa. Hanno partecipato inoltre
medici provenienti da Stati Uniti e dal Venezuela. Numerosi
gli specializzandi affluiti soprattutto dall’Ateneo
di Trieste e da quello di Udine.
L’indice di gradimento espresso dai partecipanti è stato
particolarmente elevato, sia per quanto ha riguardato la
tipologia delle attività didattiche (conferenze e seminari)
sia per lo specifico ritorno in termini di apprendimento,
grazie al formato interattivo del corso che ha
permesso approfondimenti e la discussione di aspetti
controversi. La disponibilità in sede di apposita strumentazione
ha infine consentito di revisionare direttamente
al microscopio con i docenti sia casi personali
dei partecipanti, che analizzare nello specifico il materiale
didattico del corso. L’apprezzamento all’iniziativa
è anche emerso dalle schede di rilevazione compilate
dai partecipanti ai fini del riconoscimento dei crediti
ECM.
I lavori congressuali si sono tenuti, come previsto, nel
Centro Congressi dell’Hotel Là di Moret, ed hanno seguito
il calendario previsto per un impegno totale di 18
ore. Tutte le sessioni sono state tenute in lingua Inglese.
Rilevante anche l’affluenza di pubblico alla serata
inaugurale di mercoledì 22 settembre 2004, nel Salone
del Parlamento Friulano del Castello di Udine, dove si
è svolta l’inaugurazione ufficiale del Congresso, anche
alla presenza di varie autorità locali, seguita, come previsto,
dalla lettura magistrale del professor Michal Michal
di Pilsen (Repubblica Ceca) su “Mixed Epithelial
and Stromal Tumors of the Kidney”.
Contents
Mixed Epithelial and Stromal Tumors of the Kidney (Michal Michal, M.D.) p. 25
Update in GYN Pathology, part I (Elvio G. Silva, M.D.) p. 28
Update in GYN Pathology, part II (Elvio G. Silva, M.D.) p. 34
Soft tissue tumors of the skin (Victor G. Prieto, M.D.) p. 37
Surgical Pathology of the Larynx: a Practical Overview (Mario A. Luna, M.D.) p. 41
Adnexal Tumors of the Skin: Diagnostic Pitfalls (Victor G. Prieto, M.D.) p. 46
Neuroendocrine Tumors of the Lung (Cesar A. Moran, M.D.) p. 52
Pleural Mesothelioma and its Mimickers (Cesar A. Moran, M.D.) p. 55
Controversial Salivary Gland Lesions (Mario A. Luna, M.D.) p. 61

ATTI CONGRESSUALI
25
Mixed Epithelial and Stromal Tumors of the Kidney
MICHAL MICHAL, M.D.
A distinctive benign renal neoplasm was recently recognized
by Michal and Syrucek 43 . The descriptive name
mixed epithelial and stromal tumor of the kidney (ME-
STK), suggested by these authors 43 , is currently the favored
terminology 3 9 11 21 44 48 . Several tumors reported
under various names in the earlier literature appear identical
to MESTK. Despite the difficulty in assessing critically
published illustrations and sometimes poorly documented
histological features in earlier case reports, it is
our impression that MESTKs have been published under
the following names in the older literature: leiomyomatous
renal hamartoma 1 , congenital type of mesoblastic
nephroma in an adult 12 14 15 22 24 25 27 28 30 32 38 39 41 46 49 51 54 56-59 ,
cystic hamartoma of renal pelvis (when they bulged into
the renal pelvis) 31 42 47 , solitary muitilocular cyst of the
kidney 10 23 , multilocular renal cyst with Müllerian-like
stroma 52 , and adult metanephric stromal tumor 13 . Grossly
and histologically MESTKs are dimorphic tumors
composed of solid and cystic areas, consisting of a mesenchymal
component in the form of a solid septal
growth of spindle cell stroma, morphologically and immunohistochemically
indistinguishable from ovarian
stroma as well as an epithelial component composed of
tubules or cystically dilated glands which are often lined
by hobnail eosinophilic cells. MESTKs occur almost exclusively
in middle aged perimenopausal to older women.
The age and sex of the patients points to the importance
of hormonal factors in the pathogenesis. There
is only one reported case of a MESTK in a male: Case 9
in the series of Adsay et al. 3 was a 71 year old man, with
prostatic carcinoma treated hormonally with diethylstilbestrol
for 7 years, followed by lupron therapy for 4
years, before a 11.5 cm MESTK was detected and surgically
excised. Interestingly the nuclei of the ovarian-like
stroma in most of the MESTKs express estrogen receptors
including the single male case 3 .
MESTK usually displays a benign morphology and generally
behaves in a benign fashion without recurrence
or metastasis 3 . There are a few recorded cases developing
a malignancy in the background of MESTK. Svec
et al. recently described a MESTK which underwent
malignant change in the stromal component, resembling
a poorly differentiated variant of synovial sarcoma
53 . Another case of MESTK with malignant stroma
was published by Bisceglia and Bacchi 11 . Other similar
cases may have previously been reported under the designation
of sarcomatous transformation of cystic
nephromas in adults 5 . Therefore, it may be possible
that at least some so-called primary synovial sarcomas
of the kidney in females develop as a sarcomatous transformation
in MESTK 6 37 .
The relationship of MESTK and cystic nephroma is interesting.
Eble and Bonsib 26 suggested that cystic
nephroma is not one but two diseases, and this position
seems well-substantiated. Cystic nephroma in adults is
said to occur with an 8:1 predominance in women, while
in children it occurs more often in boys 40 . Cystic
nephroma in children forms a continuous spectrum
with cystic partially differentiated nephroblastoma 35 .
The adult type hardly occurs before the age of 30, whereas
cystic partially differentiated nephroblastoma is
exceptional beyond the age of 2 years. Furthermore
skeletal muscle fibers are common in cystic partially
differentiated nephroblastoma but are not present in cystic
nephroma. Therefore, if adult type cystic nephroma
was a terminally differentiated variant of cystic partially
differentiated nephroblastoma, it would be remarkable
that the skeletal muscle should disappear along with
the immature elements.
In order to see what proportion of cystic nephromas
diagnosed in the past might represent MESTKs. I searched
for, and retrieved all cases diagnosed as such in
our files. Interestingly all cases in females were more
or less cystic, well circumscribed, unencapsulated tumors
with an ovarian-like stroma. I found only two cases
diagnosed previously as cystic nephromas or ME-
STK in males in our files. Both of these lacked the ovarian-like
stroma and the distinctive hobnail epithelium
seen in the female cases. These two male tumors might
therefore represent examples of true cystic nephromas.
Most if not all cases diagnosed as cystic nephromas in
the past arising in middle aged to elderly females are
probably examples of MESTKs. No case of cystic
nephroma occurring in childhood was found in our files.
This may be explained by the fact that childhood
tumors are usually treated in specialized pediatric oncology
centers, and none of our hospitals would routinely
receive these tumors. I suspect however, that most
cases diagnosed as cystic nephromas in children represent
examples of cystic partially differentiated
nephroblastoma. Therefore, I suggest that cystic renal
neoplasms diagnosed as cystic nephromas in the past
contain at least three different entities: 1) most of the
tumors in adult middle aged to elderly females represent
MESTK; 2) a minority of cystic tumors lacking
ovarian-like stroma represents genuine cystic nephromas,
and most of these probably occur in males; 3) most
benign looking cystic tumors in children are probably
examples of cystic partly differentiated nephroblastomas
35 .
It is important to note that similar cystic tumors containing
an ovarian-like stroma occur not only in the kidney,
but are also described in the biliary tract and
pancreas 16 19 20 60 63 . There is on record even one case of
mucinous cystadenoma with ovarian-like stroma, which
arose in pancreatic heterotopia in the spleen 45 . Similar to
MESTK, these tumors are almost exclusively in middle
aged and elderly females, and they represent a distinct

26
ATTI CONGRESSUALI
entity. In the pancreas, tumors with a mesenchymal ovarian-like
stroma are called “mucinous cystic tumors of
pancreas” 4 55 64 and must be distinguished from pancreatic
intraductal papillary mucinous neoplasms, because
the latter are often accompanied by an invasive ductal
component and consequently, they have a much worse
prognosis. In contrast, mucinous cystic tumors with ovarian-like
stroma of the pancreas only rarely have a fatal
outcome 2 4 61 . Like their renal counterparts, these biliary
tract and pancreatic tumors show immunohistochemical
expression of estrogen receptors and the stroma reveals
widespread smooth muscle actin and focally desmin positivity
60 . I therefore think that MESTKs represent the
renal counterpart of the cystic tumors in the biliary tract
and pancreas with an ovarian-like stroma 16 19 20 60 63 . Interestingly,
the pancreatic tumor sometimes contains inhibin
positive luteinized cells in the ovarian-like stroma 33
64
, which are identical to similar cells of the ovarian medulla
and cortex 18 50 . However, no such steroidogenic
cells could be demonstrated by inhibin immunostaining
in our cases of MESTKs.
Müllerian differentiation has never been described in
biliary and pancreatic tumors with ovarian-like stroma,
and I am aware of only one case report briefly alluding
to endometroid differentiation in MESTK 9 . Beiko et al.
described a case of MESTK with columnar and ciliated
serous epithelium. They hypothesized that their case
may possibly have arisen from paramesonephric remnants,
which may be closely related to the kidney and
upper urothelial tract 9 . I can confirm that such Müllerian
differentiation occurs in MESTK. Several cases in
our files contained various types of Müllerian epithelium
including endometroid, tubal, squamous and clear
cell epithelia. In addition, one MESTK in our files contained
large areas with leaflet-like structures rimmed
by an endometroid glandular epithelium bearing a remarkable
similarity to Müllerian adenofibroma or adenosarcomas
of the female genital tract 34 36 . Even the lipomatous
differentiation seen around these leaflet-like
structures is well known to occur sometimes in Müllerian
adenofibromas and adenosarcomas of the female
genital tract.
Typical stromal hyalinization resembling corpora albicantia
is an interesting, but, nonspecific feature in our
cases. I think that they are not real corpora albicantia,
because I did not observe any primordial follicles in
MESTKs, but rather that they represent a type of nonspecific
pattern of scarring with hyalinization charactenistic
of ovarian stroma. Identical corpus albicans-like
scarring was recently described by Cenilli in a mucinous
tumor of the pancreas with ovarian stroma 17 .
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ATTI CONGRESSUALI
Update in GYN Pathology – Part I
ELVIO G. SILVA, M.D.
WT-1
Many years ago we found an association between surface
peritoneal papillary serous carcinoma and endometrial
serous carcinoma. The endometrial tumors
always involved endometrial polyps. All patients were
post-menopausal. We started the study reviewing serous
carcinoma and endometrial polyps and we found
that even the stage I patients that were followed-up for
more than 24 months had a high recurrence rate. Sixty
percent recurred in the peritoneum as surface papillary
carcinoma, high-grade. Most pathologists were familiar
with the aggressive prognosis of serous carcinoma
of the endometrium; however, the prognosis of stage I
lesions was unknown and the presence and significance
of serous carcinoma in polyps was not recognized.
Serous carcinoma in the polyps can be seen involving
the surface epithelium or the glands that are inside the
polyps. Invasion of the stroma is not necessary to render
this diagnosis. The tumor cells are strongly positive
for p53 and if the tumor involves other areas beyond
the endometrial polyp, usually it involves the epithelium
of the fallopian tube, the peritoneal surface of the
ovary, and different areas of the peritoneum. It is very
important to remember that the involvement of the fallopian
tube and ovary can be extremely focal and microscopic.
Therefore, if the pathologist does not include
the entire ovary or fallopian tube, these areas can be
totally missed. Since the endometrial tumor frequently
does not even have invasion of the stroma of the endometrium,
we thought that the tumors in the endometrial
polyp and the peritoneal surface were synchronous serous
tumors of the female genital tract involving multiple
areas of the peritoneum, fallopian tube, ovarian surface,
and endometrial polyps. It is very interesting that
in most of these areas the tumors can be very superficial.
We refer to these tumors as surface papillary serous
carcinoma of the peritoneum; however, some
pathologists prefer to use the term peritoneal serous
carcinoma because in some cases it is difficult to see
the papillary areas.
Recent studies with WT-1 in serous carcinoma seem to
confirm our findings. WT-1 or Wilms’ tumor gene is a
suppressor gene that is present in normal tissues including
kidney, ovary, mesothelium, testis, spleen, and hematopoietic
precursors. Therefore, WT-1 has been
found positive in Wilms’ tumor, leukemia, and mesothelioma.
It is interesting that WT-1 has a different
reaction in serous carcinoma of the ovary and of the
uterus. It is almost always positive in serous carcinoma
of the ovary; however, it is usually negative in serous
carcinoma of the uterus. We have completed a study of
WT-1 in serous carcinoma involving the peritoneum
where we reached several important conclusions. It is
possible to see peritoneal surface carcinoma by itself
and also associated with serous carcinoma in endometrial
polyps. We have found that if the serous carcinoma
in the peritoneum is associated with an endometrial
polyp, then it reacts as the endometrial lesions which is
negative for WT-1. However, if the serous carcinoma of
the peritoneum is not associated with an endometrial
polyp, then it reacts as serous carcinoma of the ovary.
It is extremely important to be aware of this different
reactivity because WT-1 is frequently used to differentiate
serous carcinoma from metastatic lesions. It is important
to remember that if the patient has serous carcinoma
in the polyp, the peritoneal lesion can be negative
and therefore, the stain is not going to be useful in
the differential diagnosis.
A possible explanation for the different reaction of the
WT-1 ovary and endometrium might be that both, the
ovarian surface epithelium and the uterine glands, are
from the mesoderm; the ovarian surface epithelium is
from the lateral plate or coelomie area and they develop
earlier, the uterine glands are from the inner plate
and develop later. Therefore, this may explain the different
reaction of the WT-1 which is found in normal
tissues that develop very early.
References
Dupont J, Marshall DS, Leitao M, Hummer A, Thaler H, Soslow
RA. WT1 Expression in Ovarian and Endometrial Carcinomas
Using Tissue Microarrays. Mod Pathol 2003;16:213A.
Egan JA, Ionescu MC, Eapen E, Jones JG, Marshall DS. Can Immunohistochemical
Analysis of p53 and WT1 Assist in Distinguishing
Uterine Serous Carcinoma from Uterine Endometrioid Carcinoma.
Mod Pathol 2003;16:188A.
Euscher ED, Malpica A, Deavers MT, Silva EG. Differential Expression
of WT-1 Antibody in Serous Carcinomas Based on Primary
Site. Mod Pathol 2003;16:189A.
Silva EG, Jenkins R. Serous Carcinoma in Endometrial Polyps. Mod
Pathol 1990;3:120-8.
Zhang PJ, Williams E, Pasha T, Acs G. WT1 is Expressed in Serous,
but Not in Endometrioid, Clear Cell or Mucinous Carcinomas of the
Peritoneum, Fallopian Tube, Ovaries and Endometrium. Mod
Pathol 2003;16:216A.
Uterine Adenomyosis
Adenomyosis is a very common finding in hysterectomy
specimens. This common diagnosis implies the
presence of endometrial glands and endometrial stroma
within the myometrium. However, in cases of marked
adenomyosis, in addition to the typical glands with the
stroma around them, we will find glands that do not have
any stroma around them or groups of stromal cells
within the myometrium without any glands. We designate
these areas as uterine adenomyosis complete and

ATTI CONGRESSUALI
29
incomplete. Lets review first the presence of stroma
without glands. This is a fairly common finding that
can create diagnostic problems mainly when the groups
of stromal cells are large and intravascular. The presence
of endometrioid tissue within vessels was the basis
of one of the theories on the origin of endometriosis
that was explained as the result of endometrial tissue
getting inside vessels during the menstrual period. We
did a study on intravascular endometrial tissue and in
275 hysterectomy specimens we found intravascular
endometrial tissue in 14 cases, all of them associated
with diffuse adenomyosis. There was no intravascular
endometrial tissue in patients without adenomyosis.
There is a very important differential diagnosis in this
situation which is endometrial stromal sarcoma with intravascular
tumor. The difference between this neoplasm
and the benign process is that in the neoplasm there
is a mass, there are many areas of tumor infiltrating
the myometrium and many vessels and adenomyosis is
not always present. We will review now the opposite
problem which is the presence of glands without stroma
in the myometrium. We started the study of these
cases because of a fairly common problem which is to
separate invasive endometrial adenocarcinoma from
adenocarcinoma in adenomyosis. Different authors have
proposed using CD10 for this diagnosis. Usually it is
difficult to determine the depth of invasion of an adenocarcinoma
of the endometrium in cases of uterine
adenomyosis because single glands can be identified in
the myometrium and, in cases of well differentiated
adenocarcinoma, it is difficult to determine if they represent
invasive adenocarcinoma or adenomyosis. The
presence of a desmoplastic reaction in the stroma is
seen in a small percentage of cases and mainly in moderate
to poorly differentiated cases. That is why some
authors have proposed using CD10 to determine if the
glands in the myometrium are related to adenomyosis
or if they represent invasive adenocarcinoma. CD10 is
a very good marker for endometrial stroma; however, it
is not a perfect marker and in cases of uncomplicated
adenomyosis, there are areas of endometrial stroma
which can be totally negative for CD10. In addition, the
glands that on H&E appear to have no stroma around
do not have any positive cells with the CD10 marker
around them. It is interesting that in some of these cases
when we looked at the overlying endometrial tissue,
there were patchy areas of CD10 negative stroma.
CD10 has been described in acute lymphoblastic leukemia
and originally was described as positive in 100% of
endometrial stromal cells. With immunostaining we
know that it is very unusual for a marker to be positive
in 100% of the cases of a given entity. There are different
studies on CD10 in uterine stromal tumors and some
of them show 87% positive of endometrial stromal
sarcoma but what is very important also is that in cases
in leiomyosarcomas, there are smooth muscle cells positive
for CD10 in approximately 60% of the cases. Some
authors have concluded that the absence of CD10
confirms myometrial invasion; however, in invasive
carcinoma, CD10 can be positive around the glands infiltrating
the stroma. Our review shows that in approximately
30% of cases of adenomyosis, only stroma is
seen and in most cases of adenomyosis, there are one or
few glands without stroma. In 5 of the 40 cases that we
studied, C10 was patchy and in three cases, it was absent
around a few normal glands. It is interesting to note
that of the three negative cases around glands, two
were patients over 70 years old. We believe it is necessary
to be very cautious before using CD10 as a marker
to determine if an adenocarcinoma of the endometrium
is invasive or not. The presence of adenomyosis in the
uterus that we are reviewing can be important in determining
the interpretation of the results of the stain.
Reference
Black M, Ali R, Stringer A, Deavers MT, Malpica A, Silva EG. Uterine
Adenomyosis, Complete and Incomplete. Mod Pathol
2003;16:182A.
Paget’s Disease of the Vulva
The diagnosis of Paget’s disease of the vulva is not difficult
in the typical cases. There are single cells or
groups of cells in the lower part of the squamous
epithelium sometimes containing mucin or even forming
glands. For example, mucin can be seen with the
mucicarmine stain or alcian blue and the glands are not
frequently seen; however, they are diagnostic of Paget’s
disease. Many years ago at our institution, Drs.
Gunn and Gallagher did a study showing that Paget’s
disease of the vulva is a multicentric disease with very
irregular borders and therefore, it is extremely difficult
to obtain negative margins by frozen section. I think
that it is very important to remember that there are three
different types of Paget’s disease in the vulvar and
perineal area. The primary disease could be in the vulva
or in the perianus without special distribution. There
is a secondary disease which is associated with bladder
cancer or with rectal cancer. If it is associated with
bladder cancer, it is always in the area of the vestibule
and the clitoris and if it is associated with rectal cancer,
it is always in the perianal skin. The importance of these
different distributions of Paget’s disease is that they
have a different immunophenotype
according to the type of lesion. Sometimes it is
difficult to see the cells of Paget’s disease and in the past
we used to depend on the CEA stain to identify these
cells. However, keratin 7 has been shown to be a much
better marker than CEA in identifying Paget’s cells.
In cases of periurethral Paget’s disease, it is important
to know that keratin 7 still identifies the cells; however,
if the tumor is secondary to a bladder cancer, CEA
could be completely negative and also in cases secondary
to rectal cancer, keratin 7 can be completely negative
but in that case, CEA is strongly positive. The primary
cutaneous Paget’s disease seems to be the only type
positive for cystic disease fluid protein. Cases se-

30
ATTI CONGRESSUALI
condary to bladder cancer may also be positive for uroplakian.
Keratin 7 is not specific for Paget’s disease because
it also stains other cells including Toker cells,
Merkel cells, and even some pagetoid Bowen cells. The
difference with the other cells is that Merkel cells are
strongly positive for keratin 20 and weakly positive for
keratin 7. Paget’s cells are strongly positive for keratin
7 and negative for keratin 20. CEA and Her-2-neu are
positive in Paget’s cells and negative in Toker cells. Finally,
sometimes it is necessary to differentiate Paget’s
cells from pagetoid Bowen’s because both are positive
for keratin 7. The difference is that Paget’s cells are positive
for CEA and mucin and pagetoid Bowen’s are
positive for keratins 903 and 5/6.
References
Wilkinson EJ, Brown HM. Vulvar pagetoid urothelial, intraepithelial
neoplasia: differentiation from Paget disease of cutaneous or
ano-rectal origin. Mod Pathol 2001;14:174A.
Toker C. Clear cells of the nipple epidermis. Cancer 1970;25:601-
10.
Van de Putte SCJ, Toonstra J, Hennipman A. Mammary Paget’s disease
confined to the areola and associated with multifocal Toker
cell hyperplasia. Am J Dermatopathol 1995;17:487-93.
Lundquist K, Kohler S, Rouse RV. Intrapidermal cytokeratin 7 expression
is not restricted to Paget cells but is also seen in Toker cells
and Merkel cells. Am J Surg Pathol 1999;23:212-9.
Grossing of Omentum
in Serous Neoplasms of the Ovary
It is easy to gross the omentum when there are macroscopic
areas of tumor; however, with the frequent early
detection of tumors, omentum specimens that are grossly
negative are seen more frequently now and the role
of the pathologist in these cases is extremely important.
One of the problems that the pathologist encounters is
the presence of small microscopic foci of tumor detached
from the tissue. In this situation we usually review
many sections and request many deeper sections trying
to figure out if the detached fragments were really metastases
or contaminants. Our conclusion has almost
always been that if the fragment of tumor is on the surface
of the omentum, most probably it is a contaminant;
however, if it is inside of the omentum with an intimate
relationship with the space in the adipose tissue,
it represents a real metastasis and deeper sections will
prove adhesion to the surface of the omentum. Therefore,
whenever we see groups of tumor cells within
the omentum, and an intimate relationship with the adipose
tissue, we designate these areas as foci of metastases.
When the omentum is grossly negative, we submit
one section for every 2 cm of negative omentum.
Approximately 15% of the grossly negative omentum
specimen will show foci of metastases when numerous
sections are submitted. This will radically change the
stage of the patient because it will go from a I or II to
a very aggressive stage III disease.
PTEN in Endometrium
There are different classifications of endometrial hyperplasia.
For many years we used the terms simplex
and complex hyperplasia with and without atypia. Recently,
it has been proposed to change this classification
and refer to the proliferative or secretory endometria
as endometrium, simplex and complex hyperplasia
as hyperplasia, and the atypical hyperplasia and the
well differentiated adenocarcinoma as endometrial
neoplasia. This has created a new term for atypical endometrial
hyperplasia which is endometrial intraepithelial
neoplasia or EIN. The definition of endometrial intraepithelial
neoplasia is a glandular proliferation of the
endometrium that contains a volume percentage stroma
less than 55% and cytologic atypia. I think that we all
should admit that it is extremely difficult to diagnose a
volume percentage stroma of 55%. I believe it is extremely
difficult to differentiate between 40 and 50% or
50 and 60%. In my opinion, this volume percentage
stroma is the equivalent of glands back-to-back; but instead
of concentrating on the distance between glands,
the authors prefer to evaluate the amount of stroma
between the glands. The current classification proposed
by the endometrial collaborative group allows more
stroma between glands than the one proposed by Drs.
Hendrickson and Kempson several years ago. In the
evaluation of the amount of stroma, we need to avoid
including cases of secretory endometrium. In order to
render the diagnosis of hyperplasia, the endometrial
glands should be in a proliferative phase. There is a
group of pathologists working with Dr. Mutter who have
proposed an interesting concept. This group believes
that the diagnosis of endometrial intraepithelial neoplasia
should be based on the recognition of a monoclonal
proliferation in the endometrium. This monoclonal proliferation
can be diagnosed based on the volume percentage
stroma less than 55%, the presence of atypia,
and the absence of PTEN and MLH1. PTEN is a suppressor
gene that is normally positive in the gland and
becomes negative in most cases of complex hyperplasia
and endometrial carcinoma. It appears that the inactivation
of PTEN is the most common genetic defect in
endometrial carcinoma. PTEN suppresses cell division
and enables apoptosis. There are some PTEN knockout
human syndrome like the Cowden syndrome where
the patient develops cancer of breast, thyroid, and
endometrium and there are some PTEN knock-out mice
where all the mice developed endometrial hyperplasia.
MLH and MSH are mismatched repair genes that
may some structural defects. They are found in hereditary
colon cancer and a good percentage of these cases
also have endometrial cancer. In a smaller proportion
of cases, it can also be seen in sporadic cancer. The
authors who are using the new terminology say that
there are less false negatives using the EIN terminology
than using the WHO terminology. In addition, there are
less false positive cases. Most of the patients that have
a positive PTEN and/or positive MLH1 do not develop

ATTI CONGRESSUALI
31
carcinoma but most of the ones that have negative
PTEN or MLH1 develop carcinoma. We believe there
will be a significant change in the classification of endometrial
hyperplasia in how we recognize adenocarcinoma
of the endometrium. Currently, until this new
proposal is completely accepted, the presence of a diagnosis
of endometrial glandular hyperplasia rather than
carcinoma should be rendered when the glands are
back-to-back in an area smaller than 2 x 2 mm and
when there is no stromal fibrosis. In addition, we do not
use cribriform pattern to diagnose carcinoma because
have seen several cases of hyperplasia with cribriform
areas that responded to the treatment with progesterone,
especially in obese patients.
References
Faquin WC, Fitzgerald JF, Lin MC, Boynton KA, Muto MG, Mutter
GL. Sporadic Microsatellite Instability is Specific to Neoplastic and
Preneoplastic Endometrial Tissues. Am J Clin Pathol 2000;113:576-
82.
Hampel H, Yearsley MM, Nakagawa H, Lehman A, de la Chapelle
A, Frankel WL. Histologic Features in Microsatellite Unstable and
Stable Endometrial Carcinomas. Mod Pathol 2003;16:191A.
Hardisson D, Moreno-Bueno G, Sanchez L, Farre X, Sarrio D, Suarez
A, et al. HMLH1 and hMSH2 Protein Expression in Endometrial
Carcinoma with Atypical endometrial Hyperplasia on Tissue Microarray.
Relationship with Microsatellite Instability. Mod Pathol
2003;16:191A.
Hecht JL, Ince TA, Baker HE, Mutter GL. Concordance of WHO
Hyperplasia and EIN Classification of Endometrial Precancers.
Mod Pathol 2003;16:191A.
Horowitz N, Pinta K, Mutch DG, Herzog TJ, Rader JS, Gibb R, et
al. Gyn Oncol 2002;86:62-8.
Ince TA, Baker HE, Kust GA, Mutter GL. Molecular Classification
of Endometrial Cancer. Mod Pathol 2003;16:193A.
Mutter G, Ince TA, Baak JPA, Kust GA, Zhou X-P, Eng C. Molecular
Identification of Latent Precancers in Histologically Normal Endometrium.
Cancer Res 2001;61:4311-4.
Rush DS, Wang H, Douglas W, Ellenson LH. Association of Altered
PTEN Expression and Upregulation of Phospho Akt in Uterine Endometrioid
Adenocarcinoma. Mod Pathol 2003;16:209A.
Sun H, Enomoto T, Fujita M, Wada H, Yoshino K, Ozaki K, et al.
Mutational Analysis of the PTEN Gene in Endometrial Carcinoma
and Hyperplasia. Am J Clin Pathol 2001;115:32-8.
Zheng W, Senturk BZ, Baker HE, Parkash V, Mutter GL. Involution
of PTEN-Null Endometrial Glands with Progestin Theraphy. Mod
Pathol 2003;16:217A.
Cox-2
Cox-2 is a prostaglandin H-synthase. It is an inflammatory
mediator important in cancer because it is associated
with increased cellular proliferative activity and
it is an apoptosis inhibitor that stimulates angiogenesis.
Cyclo-oxygenase is the enzyme involved in the transformation
of amino acids to prostaglandin. Cox-1 has
a housekeeping type of function in the stomach and
kidney. Cox-2 is the one that is related to time of stress
and it is related to fever, pain, and inflammation. Cox-
2 can be studied by immunocytochemistry. We have reviewed
several endometrioid lesions and found that it is
positive in the majority of the carcinomas in endometriosis
while it is positive in only 17% of the endometriosis.
In serous carcinoma, Cox-2 is also positive in
all cases that we reviewed; 125 cases, with low expression
in 32%, and high expression in 68%. The significance
of Cox-2 in ovarian epithelial neoplasms is that
cases which are positive for Cox-2 might respond to
treatment with a Cox-2 inhibitor which in reality is an
anti-inflammatory agent but since it inhibits Cox-2, it
might have a role in ovarian carcinomas. The drug that
has an effect against Cox-2 is Celebrex.
References
Adegboyega PA, Ololade O. Expression of Prostaglandin H-Synthase
(COX2) in Normal Endometrium and Endometrial Lesions. Mod
Pathol 2003;16:178A.
Ali-Fehmi R, Bandyopadhyay S, Munkarah AR, Morris R, Lawrence
WD, Silva E. Agiogenesis and the Expression of COX-2, BCL2
and p53 in Ovarian Endometriosis, Atypical Endometriosis and
Epithelial Carcinoma Arising in a Background of Endometriosis.
Mod Pathol 2003;16:180A.
Ali-Fehmi R, Munkarah AR, Che M, Bandyopadhyay S, Malone
JM, Lawrence WD. Prognostic Tumor Markers in Ovarian Serous
Carcinoma (SOC): A study of One Hundred and Twenty Five Advanced
Stage Cases. Mod Pathol 2003;16:179A.
Hickey KL, Cao QJ, Marconi S, Naber SP, Otis CN. The Expression
of COX-2 in High Grade Endometrial Neoplasms. Mod Pathol
2003;16:192A.
Imkie M, Tawfik OW, Davis MD, Kirchoff J, Fabian C, Montgomery-Rice
V, et al. Cyclooxygenase-2 and MIB-1 in Normal and
Pathologic Ovaries: Correlations with Ovulation, Follicular Cysts
and Cancer. Mod Pathol 2003;16:192A.
Khalifeh I, Ali-Fehmi R, Bandynopadhyay S, Munkarah AR, Morris
R, Lawrence WD. Expression of Cox-2, CD34, bcl-2 and P-53 and
Survival in Patients with Primary Peritoneal Serous Carcinoma
(PPC) in Comparison to Primary Ovarian Serous Carcinoma
(OSC). Mod Pathol 2003;16:195A.
Pansare V, Ali-Fehmi R, Lawerence WD, Morris R, Munkarah AR.
Angiogenesis, Cyclooxygenase-2 and p53 Expression in Borderline,
Low Grade and High Grade Ovarian Epithelial Neoplasms. Mod
Pathol 2003;16:204A.
Immuno in GYN Epithelial Tumors
We discussed the results of WT-1 serous tumors. In endometrioid
tumors, WT-1 is negative in tumors from
the endometrium but it can be positive in up to 30% of
ovarian endometrioid tumors. This can probably be explained
in the same way as the different reaction of
WT-1 in serous tumors of the endometrium and ovary.
p53 is positive in all serous tumors of the ovary except
in those of low malignant potential or borderline;
however, it appears that in approximately 30% of serous
borderline tumors, p53 can be positive and this
seems to be associated with a higher recurrence rate.
We use keratin 7 and 20 to separate primary from metastatic
lesions in the ovary. In general, in a primary
ovarian carcinoma, keratin 7 is positive and keratin 20
is negative. However, 30% of serous carcinoma can be

32
ATTI CONGRESSUALI
positive with keratin 20, the difference is that the percentage
of positive cells with keratin 20 is smaller than
the percentage of positive cells with keratin 7.
The differential diagnosis of mesothelial proliferation
and serous neoplasm involving the peritoneum can be
extremely difficult on hematoxylin and eosin. Different
immunocytochemistry stains have been proposed to aid
in this difficult differential diagnosis. All mesothelial
proliferations are positive for calretinin; however, 30%
of serous neoplasms, especially the ones that are of
very low grade, can also be positive. All serous neoplasms
are positive for Ber-EP4, 90% for B72.3 and 80%
for Leu-M1. Mesotheliomas are positive for these
stains in 8%, 8%, and 0%, respectively.
References
Cathro HP, Stoler MH. The Utility of Inhibin, Calretinin and WT1
Immunohistochemical Staining in Ovarian Tumors. Mod Pathol
2003;16:185A.
Egan JA, Ionescu MC, Eapen E, Jones JG, Marshall DS. Can Immunohistochemical
Analysis of p53 and WT1 Assist in Distinguishing
Uterine Serous Carcinoma from Uterine Endometrioid Carcinoma.
Mod Pathol 2003;16:188A.
Gupta A, Bhan AK, Bell DA. Can the Implants of Serous Borderline
Tumors of the Ovary Be Distinguished from Mesothelial Proliferations
by Use of Immunohistochemistry Mod Path 2003;16:190A.
Liang SX, Yu HH, Senturk BZ, Parkash V, Rimm D, Zheng W. Overexpresion
of p53 Predicts Recurrence of Ovarian Cancer: A Tissue
Microarray Study. Mod Pathol 2003;16:197A.
Ramalingam P, Malpica A, Silva EG, Liu JL, Gershenson DM, Deavers
MT. The Use of Cytokeratin 7 in Differentiating Yolk Sac Tumors
from Endometrioid and Clear Cell Carcinomas of the Ovary.
Mod Pathol 2003;16:207A.
Serous Carcinoma of the Ovary, Fallopian
Tube or Peritoneum with Initial
Presentation as a Lymph Node Metastasis
We recently completed a study of 22 cases of serous
carcinoma that presented with lymph node metastasis.
Twenty cases were high grade carcinomas and one was
a low grade carcinoma. Most of the lymph nodes involved
by serous carcinoma were in the inguinal area;
however, there were 5 supraclavicular nodes, 1 axillary,
1 cervical, and 1 retroperitoneal. Thirteen of the 22 carcinomas
were primary in the ovary, 4 in the peritoneum,
1 in the fallopian tube, and 2 had an unknown
primary. When the papillary carcinoma presented in an
unusual lymph node, for example supraclavicular, immunostains
were performed for keratin 7 and WT-1, all
with a positive reaction. The most interesting part of
this study is that even when the patients presented with
a lymph node, only 11 patients died of disease. Five patients
are alive with disease and 3 patients are with no
evidence of disease, one of them had a cervical lymph
node involved at presentation. The median survival for
all of the patients with inguinal lymph nodes was 36
months and those with supraclavicular nodes, 29
months. Ten patients had positive omentums and the
median survival was not different from the survival of
the high stage patients. However, if the omentum was
not involved, the median survival was 166 months. In
our opinion, serous carcinomas that present with lymph
node metastases do not have a different survival than
those cases without lymph node metastases. In addition,
patients with lymph node metastasis and minimal
peritoneal disease have a long survival time. In cases
where a primary abdominal serous carcinoma is not
found, it is possible that a tumor arose in areas of endosalpingiosis.
References
Chen CA, Huang SH, How SW, Hsieh CY. Case Report. Systemic
Lymphadenopathy as the Primary Symptom of Serous Surface Papillary
Carcinoma of the Ovary. Gynecol Oncol 1995;58:251-4.
Euscher ED, Elishaev E, Silva EG, Deavers MT, Gershenson DM,
Malpica A. Serous Carcinoma of the Ovary, Fallopian Tube or Peritoneum
with Initial Presentation as a Lymph Node Metastasis. Mod
Pathol 2003;16:188A.
Orris BG, Geisler JP, Geisler HE. Ovarian Cacinoma Metastatic to
Bilateral Axillary Lymph Nodes. A Case Report. Eur J Gynaecol Oncol
1999;20:189-90.
Tan LK, Flynn SD, Carcangiu ML. Ovarian Serous Borderline Tumors
with Lymph Node Involvement. Clinicopathologic and DNA
Content Study of Seven Cases and Review of the Literature. Am J
Surg Pathol 1994;18:904-12.
PEComas
The term PEComas has been used to designate a group
of tumors of perivascular epithelioid cells. Originally,
this group included angiomyolipomas of the kidney,
lymphangioleiomyomatosis of the lung, clear cell “sugar”
tumor of the lung and more recently, uterine
epithelioid smooth muscle tumors. We reviewed our
cases of epithelioid leiomyosarcomas and from a
group of 13 cases, we selected 5 that had a clear cell
component. We also selected areas with spindle cells
that were present in all of the cases. We selected
blocks with spindle areas and with epithelioid areas
with clear cells and we performed immunostains for
smooth muscle markers including SMA, desmin, caldesmon,
and also HMB-45. We found smooth muscle
markers positive in the spindle cell areas and very focally
positive in the epithelioid areas. In 4 of the 5 cases
in the epithelioid areas of the clear cell components,
there were cells positive for HMB-45. Because
of the presence of the positive smooth muscle markers,
we believe this type of lesion should be designated as
a leiomyosarcoma; but we agree that they are positive
for HMB-45 and because of this, they might belong to
the group of PEComas. However, in my opinion, the
epithelioid smooth muscle tumors of the uterus positive
for HMB-45 should not be designated as PEComas
because this term has been proposed to designate a
group of tumors and not single entities. An angiomyolipoma
of the kidney is still designated angiomyolipoma
even when it belongs to the PEComa group. There

ATTI CONGRESSUALI
33
are still some questions that need to be clarified regarding
the designation of PEComas. The definition is not
clear. Some authors use the definition of a tumor with
HMB-45 expression by at least some epithelioid cells;
however, other authors use the definition of a tumor
with co-expression of melanocytic and muscle
markers. However, 20% of angiomyolipomas are negative
for HMB-45 and the clear cell “sugar” tumor is
usually negative for muscle markers. Also, all the lesions
included in the concept of PEComas have significant
clinical and pathological differences. Probably
the most important fact of PEComa is that it is seen in
patients with tuberous sclerosis. However, the prototype
of the PEComa which is a clear cell “sugar” tumor
is usually not associated with tuberous sclerosis. PEC
means perivascular epithelioid cells; however, some
lesions did not have a perivascular distribution and in
some cases the cells positive for HMB-45 were not
epithelioid. Finally, it is difficult to understand a group
of tumors that were named based on a cell that has not
been found in normal tissues. Currently there are
major and minor features to diagnose tuberous sclerosis
complex, but in the major features, angiofibroma,
lymphangioleiomyomatosis, renal angiomyolipoma,
cardiorhabdomyoma, subependymal giant cell astrocytoma
are included. It is possible that epithelioid
smooth muscle tumors of the uterus with clear cells
will soon be included as one of the diagnostic criteria
of tuberous sclerosis complex. It appears that the explanation
for the presence of melanin in these tumors
can be related to an abnormality in the metabolism of
the phenylalinine going to melanin. Most probably the
perivascular epithelioid cell described by Bonetti is a
modified smooth muscle cell that can be found in different
lesions which becomes positive for HMB-45.
Currently the significance of this is that the identification
of this type of tumor in a patient warrants the investigation
of tuberous sclerosis complex.
References
Bonetti F, Pea M, Martignoni G. Review article: new unifying concept.
The perivascular epithelioid cell and related lesions. Adv Anat
Pathol 1997;4:343-58.
Pea M, Martignoni G, Zamboni G. Perivascular epitheioid cell.
[Letters to the editor]. Am J Surg Pathol 1996;20:1149-55.
Silva EG, Deavers MT, Dodurka D, Malpica A. Uterine Epithelioid
Leiomyosarcomas with Clear Cells or Malignant PE Comas Mod
Pathol 2003;16:211A.
Silva EG, Tornos C, Ordonez N, Morris M. Uterine leiomyosarcoma
with clear cell areas. Int J Gynecol Pathol 1995;14:174-178.
Smolarek TA, Bejarano PA, Heffelfinger S. HMB-45 immunoreactivity
is present in both uterine leiomyomas and normal myometrium.
[Abstr] Mod Pathol 1999;12:125A.
Vang R, Kempson RL. Perivascular epithelioid cell tumor (“PEComa”)
of the uterus. A Subset of HMB-45 positive epithelioid mesenchymal
neoplasms with an uncertain relationship to pure smooth
muscle tumors. Am J Surg Pathol 2002;26:1-13.

34
ATTI CONGRESSUALI
Update in GYN Pathology
Part II
ELVIO SILVA, M.D.
Adenocarcinoma in Omentum
Pancreas vs Ovary
The differential diagnosis of an adenocarcinoma with
focal mucinous differentiation involving the ovary is
frequently between a mucinous carcinoma of pancreas
and a mucinous carcinoma of the ovary. However, mucinous
carcinomas of the ovary are rare lesions and
they can be a low stage disease. The differential diagnosis
of an adenocarcinoma in omentum includes metastasis
from pancreas and ovary; however, the ovarian
tumors are usually non-mucinous because as previously
stated, mucinous tumors are rare and can be low
stage lesions.
The differential diagnosis of adenocarcinoma of the
pancreas with adenocarcinoma of the ovary can be extremely
difficult. In most cases pancreatic tumors have
significant fibrosis with open glands, marked nuclear
atypia, similar size glands, at least focal mucinous differentiation.
Most ovarian carcinomas are papillary serous carcinoma
and it is very easy to recognize ovarian tumors because
the papillae in serous carcinoma consist of pure
cells and the papillae are very regular. However, there
are some cases where this differential diagnosis is not
so easy. In a recent study that we did, we found that it
is difficult sometimes to separate pancreas from ovary
in the omentum even when the tumors are not pure mucinous
tumors. The following cases are samples of this
difficult differential diagnosis.
Case 1 is a predominantly glandular tumor that could
be from the pancreas or from the ovary. There were
only very focally, very small but irregular papillae that
made the diagnosis of ovarian cancer easier.
Case 2, this is an adenocarcinoma with irregular glands
and also some papillary formations; however, the papillae
in this case are very regular and because of this particular
architecture, there are no groups of cells in the lumen;
therefore, this favors the diagnosis of pancreatic
adenocarcinoma. We need to be careful evaluating the
papillae in areas of invasion because adenocarcinoma of
the pancreas may have some papillae in the stroma creating
the clear spaces around them similar to the papillae
of serous carcinoma. Probably the main difference with
serous carcinoma is that in the pancreatic tumors there is
still a mucinous background in some of the cells. Usually
in these cases of pancreatic lesions, we might find
areas of mucinous differentiation focally.
Case 3 was a difficult case in the study because it is a
tumor composed of clear cells which can be seen in the
pancreas and also in the ovaries; however, clear cell
carcinoma of the ovary usually has four different patterns
including glandular, papillary, microcystic, and
solid. The papillae are very typical because of the hyaline
stroma. In this clear cell carcinoma, we do not see
the type of papillae of mullerian clear cell carcinoma
and we do not see the hobnail appearance of the mullerian
clear cell carcinoma. In addition, the papillary area
infiltrating the stroma with clear spaces around the papillae
were also present in this tumor and focally there
were open glands. The diagnosis of this case was pancreatic
adenocarcinoma.
Finally, Case 4 is a tumor with a very solid pattern and
signet-ring cells which contain mucin. We used to consider
a tumor with signet-ring cells with mucin as a metastasis
to the ovary; however, there is a pattern from
the ovary that we have recently reported which is the
microcystic high grade ovarian cancer that is characterized
by the presence of microcysts and also signet-ring
cells with mucin which are always within epithelial
groups of cells. Individual signet-ring cells are never
seen in the stroma.
In summary, the glands in ovarian tumors are large,
anastomosing with rare foamy cytoplasm, the papillae
are multiple and irregular, it is common to see sheetlike
formations, and if the tumor is a clear cell neoplasm
it shows different patterns; psammoma bodies can
be present and cytologic atypia is common. In contrast,
pancreatic tumors usually have small glands with mucin,
foamy cytoplasm is common, papillae are rare, but
when they are present, are very uniform; it is unusual
to see sheet-like formations. Clear cell neoplasms have
only one pattern, psammoma bodies are rare, and high
grade cytologic atypia is also rare.
References
Ali-Fehmi R, Silva E, Sakr W, Lucas D, Che M, Dey J, et al. The
Challenge in Distinguishing Metastatic Ovarian and Pancreatobiliary
Carcinomas in the Abdomen and the Morphologic Criteria for
Their Distinction. Mod Pathol 2003;16:180A.
Small Cell Carcinoma
The diagnosis of small cell carcinoma of the ovary, hypercalcemic
type is not difficult when the histology is
typical because these tumors are characterized by cords
of highly atypical cells and in areas they form the typical
follicles of the small cell carcinoma. There are th-

ATTI CONGRESSUALI
35
ree tumors with follicles in the ovary including small
cell carcinoma, juvenile granulosa cell tumor, and metastatic
melanoma. In juvenile granulosa, the follicles
have a very smooth border, in metastatic melanoma and
in small cell carcinoma, they have an irregular border;
however, usually in metastatic melanomas there is serum-like
material in the lumen while in the small cell
carcinoma the follicles are usually empty. The tumor is
a high grade neoplasm and it is frequently associated
with hypercalcemia. Although we call it small cell carcinoma,
the large cell variant is more common. Frequently,
foci of rhabdoid cells are present and many
sections may be necessary to demonstrate their follicular
pattern that sometimes may be confused with areas
of edema. We have completed a study on the immunophenotype
of small cell carcinoma. We did this study
because sometimes it is extremely difficult to find the
follicles and therefore we might not be able to recognize
this type of tumor. Keratin, calretinin, synaptophysin,
CD56 and EMA could be positive; however, they
are always focal. The main differential diagnosis is
with an unclassified stromal tumor of the ovary. We
need to remember that calretinin can be positive in both
tumors; however, in our experience, inhibin has always
been negative in small cell carcinoma.
References
Neto AG, Deavers MT, Silva EG, Malpica A. Immunohistochemical
Profile of Ovarian Small Cell Carcinoma, Hypercalcemic Type. Mod
Pathol 2003;16:202A.
Taraszewski R, Rosman PM, Knight CA, Cloney DJ. Small Cell
Carcinoma of the Ovary. Gynecol Oncol 1991;41:149-51.
Aguirre P, Thor AD, Scully RE. Ovarian Small Cell Carcinoma. Histogenetic
Considerations Based on Immunohistochemical and
Other Findings. Am J Clin Pathol 1989;92:140-9.
C-kit
The gastrointestinal stromal tumors have been the classical
neoplasm where the significant discovery of the
C-kit protein has shown that new therapeutic agents
can be used in tumors having this protein. The gastrointestinal
tumors are characterized by cords and
groups of very uniform cells with focal palisading and
concentric arrangements. These tumors are strongly
and diffusely positive for C-kit. The mesenchymal cell
that is positive for C-kit is a cell that is a hybrid
between a mesenchymal cell related to neuroblasts and
a smooth muscle cell. This has been designated as the
interstitial cell of Cajal. It is an intermediary cell
between the neuroblasts and the smooth muscle cell in
the intestinal wall. The C-kit has also been found in hematopoietic
progenitor cells, mast cells, and in germ
cells. This is important because we should look for this
protein in tumors related to these cells. What is extremely
important today is a drug called Gleevec that inhibits
protein tyrosine kinases and one of them is the C-
kit protein. The other two are Abl and platelet-derived
GFR. We have currently investigated these proteins by
immunocytochemistry in different ovarian lesions and
have found that PDGFR is positive in most of the cases
and most probably has no clinical significance. Abl is
positive in some cases and the clinical significance is
currently being reviewed. C-kit seems to be the most
important of the three kinases and it is positive in only
25% of high grade ovarian cancer; however, it is positive
in most cases of dysgerminoma (70%) and also in
many cases of small cell carcinoma of the cervix, neuroendocrine
type (65%). It appears that the kit protein
can be activated with a paracrine effect in the receptor
and that could be the mechanism of the small cell carcinoma
or it could be activated through mutations, and
this apparently is the mechanism in the gastrointestinal
stromal tumor, mastocytosis, seminoma or dysgerminoma,
and acute myelogenous leukemia. In a preliminary
study of different cases in the gyn tract, we have
found more positive cases in low grade lesions than in
high grade tumors. However, it is positive in most cases
of dysgerminomas and small cell carcinoma of cervix.
The positive immuno-reaction of C-kit in a case
does not mean that the tumor is going to respond to
Gleevec. Tumors that are positive by immunocytochemistry
for C-kit may have mutations in exon 11 and
17. Only tumors with mutations in exon 11 respond to
this treatment.
References
Broaddus RR, Gershenson DM, Schmandt RE. Immunohistochemical
Expression of Gleevec-Sensitive Protein Tyrosine Kinases in
Ovarian High Grade Serous Carcinoma. Mod Pathol 2003;16:183A.
Chen SC, Sabbatini P, Marshall DS, Leitao M, Soslow RA. Expression
of PDGF-R in Epithelial Ovarian Tumors. Mod Pathol
2003;16:185A.
Constantinescu M, Turbat-Herrera EA, Nordberg ML, Daley W, Jones
L, Mansour R, et al. CD117 and CD34 Expression by Immunohistochemistry
in Uterine Malignant Mixed Mullerian Tumors.
Mod Pathol 2003;16:186A.
Malpica A, Broaddus R, Deavers MT, Kavanagh J, Silva EG. Tyrosine
Kinases in Ovarian Dysgerminoma. Mod Pathol 2003;16:200A.
Przygodzki RM, Moran C, Hubbs AE, Malpica A, O’Leary T. Ovarian
Dysgerminoma: Evidence of Unique Single and Multiple KIT
Mutations. Mod Pathol 2003;16:206A.
Total Abdominal Hysterectomy
and Bilateral Salpingo-oophorectomy
for BRCA
Frequently we receive specimens of uteri and ovaries
resected because of prophylactic treatment in patients
that have tested positive for BRCA. The usual diagnosis
in these specimens is leiomyoma and adenomyosis
without any malignant diagnosis. However, in cases
that have been very well studied, dysplastic changes of
the fallopian tube have been found. Areas of carcinoma
in situ and moderate dysplasia have been important in
this type of specimen. Up to 20% of the cases may
show foci of carcinoma, predominantly in situ and dy-

36
ATTI CONGRESSUALI
splastic changes. Any type of tumor can be found except
that there have been no reports of mucinous lesions.
Most of the tumors are incidental and very small
which cannot be seen by the naked eye. Therefore, the
recommendation is that ovaries and fallopian tubes in
patients who have a strong family history of breast or
ovarian cancer or have a BRCA mutation, should be entirely
submitted for microscopic examination.
References
Carcangiu ML, Radice P, Spatti G, Manoukian S, Pasini B. Histopathology
of Ovarian Tumors in Women with BRCA1 and 2 Mutations.
Mod Pathol 2003;16:184A.
Carcangiu ML, Radice P, Spatti G, Manoukian S, Pasini B. Incidental
Tumors in Prophylactic Oophorectomy Specimens from BRCA
Mutation Carriers. Mod Pathol 2003;16:184A.
Parker RL, Lee CH, Brown LA, Makretsov N, Gilks CB, Robb D, et
al. Disruption of BRCA1 or BRCA2 by Allelic Deletion is an Uncommon
Event in Ovarian Carcinogenesis. Mod Pathol
2003;16:205A.
Changes in Epithelial Ovarian Tumors
After Chemotherapy
The diagnosis of surface papillary carcinoma of the peritoneum
is based on the presence of a very small area
with tumor measuring < 5 mm in largest dimension.
Usually these tumors have an omental cake but it can
be difficult to see the tumor on the ovarian cortex if the
entire ovary is not submitted. Originally this diagnosis
was based on the presence of grossly normal size ovaries,
then it was changed to the presence of tumor only
on the ovarian surface cortex, and then it was changed
to a tumor that invaded the ovarian parenchyma < 3
mm. In order to be consistent with the diagnosis, the
Gynecologic Oncology Group accepted the definition
of an epithelial tumor in the ovary smaller than 5 mm
in largest dimension.
The diagnosis of psammocarcinoma is based on the
presence of multiple psammoma bodies with a few
epithelial areas, usually having very few cells. The
groups of cells in this type of lesion should have less
than 15 cells.
It is important for pathologists to remember that the
diagnosis of surface papillary carcinoma of the peritoneum
and psammocarcinoma should be made with extreme
caution if a patient has been treated with chemotherapy
before the operation because the main changes
seen after chemotherapy treatment are marked reduction
in the size of the tumor, the presence of cystic
changes, more fibrosis in the omentum, reduction of
the number of mitotic figures, significant atypia, and
more calcifications.
P. Effects of Pre-Operative Chemotherapy on Pathological Assessment
of Ovarian Surface Epithelial Carcinomas. Mod Pathol
2003;16:200A.
Intermediate Trophoblastic Tumors
The current classification of intermediate trophoblastic
tumors includes the placental site trophoblastic tumor
and the epithelioid trophoblastic tumor. The so-called
epithelioid trophoblastic tumor is characterized by
groups of tumors cells in nodules with a hyaline center
and fairly uniform cells. This is usually different in placental
site trophoblastic tumors that form groups of tumor
cells infiltrating the myometrium without necrosis.
However, this differential is not as easy and there are
some cases that are extremely difficult to subclassify
into one or the other group. We prefer to designate these
lesions as intermediate trophoblastic tumors because
in our experience they behave similarly and the treatment
is similar also. There is a maker called p57 which
is a negative regulator of cell cycle expressed from the
maternal allele. Since there is no maternal component
in the complete mole, this marker will be negative;
however, in partial mole, abortion, and normal pregnancy,
since there is a maternal component, it will be
positive in extravillous trophoblast, cytotrophoblast,
and also mesenchymal cells. In complete hyaditidiform
moles, there are usually groups of decidual cells which
are positive for p57. The stain is positive in the nuclei
of the cells. In a recent study we have found that choriocarcinomas
are positive for p57 in all of the cases;
however, intermediate trophoblastic tumors are rarely
positive. It is also interesting to remark that placental
site nodules are usually positive; therefore, it is possible
that intermediate trophoblastic tumors are not related
to placental site nodules. Another interesting issue
in intermediate trophoblastic tumors is that in all cases
where the karyotype had been studied, all had a Y chromosome;
therefore, they are from female conceptus
and cannot follow a complete mole. We believe that based
on the p57 stain we could say that intermediate
trophoblastic tumors are of most probably of paternal
origin and most probably they are not related to placental
site nodules.
References
Jalali M, Malpica A, Deavers MT, Burke T, Silva EG. Immunohistochemical
Study of p57 in Intermediate Trophoblastic Lesions. Mod
Pathol 2003;16:193A.
Oldt III RJ, Kurman RJ, Shih IM. Molecular Evidence of Trophoblastic
Origin in Plancental Site Trophoblastic Tumors and Epithelioid
Trophoblastic Tumors. Mod Pathol 2003;16:203A.
References
Martens MB, Beauchamp A, Gilks B, Ehlen T, Miller DM, Hoskins

ATTI CONGRESSUALI
37
Soft tissue tumors of the skin
VICTOR G. PRIETO, M.D.
Soft tissue tumors occurring in the skin comprise a full
spectrum from completely benign lesions, such as dermatofibroma,
to full-blown malignancies capable of
metastasizing to distant organs. It is important to note
that most lesions described in the deep soft tissues also
occur in the subcutaneous or underfascial tissues of the
skin. Therefore, even though some purists may consider
such lesions not as “cutaneous” tumors, the surgeons
may submit them as “skin biopsies”. This talk is
oriented to discuss the most important histologic and
clinical features described within the last years.
Perineurioma
These usually benign lesions occur preferentially in
children and young adults, as dermal or subcutaneous,
circumscribed nodules in the trunk and hands or palms.
There are two main subtypes: intraneural perineurioma
(“hypertrophic neuropathy”) and storiform perineurial
fibroma/sclerosing perineurioma. Of these two, the later
is the one that can occasionally be seen in the skin.
These are circumscribed, richly vascular, with small
round cells and spindle cells forming elongated bundles
and interdigitating weaving fascicles, and in a vague
storiform arrangement (whorl formation). Some lesions
have myxoid background, calcification, osseous
metaplasia, or keloidal collagen.
Perineuriomas appear to derive from the perineural cells.
These are flat, spindle cells that surround bundles of
nerve fascicles and express EMA, CD99, laminin, type
IV collagen, and VE cadherin. The latter is a calciumdependent
adhesion molecule and may play a role in
maintaining the structure and function of the perineurial
junctions. S100 protein and neurofilaments can be
seen in residual nerves in the center of the lesion, thus
supporting the concept of a tumor composed of perineural
cells. Isolated reports indicate focal expression
of CD34, cytokeratin, and actin; it is unknown the significance
of these observations.
In very rare instances, some tumors with these features
show malignant cytology and aggressive
(recurrent/metastatic behavior), i.e., malignant perineuriomas.
A few cases have shown abnormalities on chr 10 and
22; alterations on chr 22 can be seen in patients with familial
meningioma and schwannoma.
The differential diagnosis includes giant cell tumor of
tendon sheath but the latter usually has a multinodular
pattern of growth, hemosiderin, and giant cells. Trichodiscomas
are also well-circumscribed proliferations
that resemble the fibrous myxoid stroma of hair follicles;
they also lack EMA expression. Soft tissue meningiomas
express EMA but they usually contain
psammoma bodies and focally express cytokeratin.
Sclerotic fibromas are very similar to perineuriomas
(see below).
Dermatofibroma/Fibrous histiocytoma
Within the last years there have been several reports regarding
unusual variants of dermatofibroma/fibrous histiocytic
lesions in the skin. Among them we will highlight
epithelioid cell histiocytoma, fibrohistiocytic lesions
with atypical features, and plexiform fibrohistiocytic
tumor of infancy.
A) EPITHELIOID CELL HISTIOCYTOMA
ECH is considered to be a variant of dermatofibroma.
It usually presents as a raised, non-pigmented or light
brown nodule on the extremities of adults. Histologically,
the lesion has a dermal population of epithelioid,
bland looking cells, with abundant eosinophilic cytoplasm.
Focally, there is increased vascularity. Notably,
there is no epidermal involvement.
The importance of this lesion lies in recognizing how
easily it is confused for melanocytic and vascular lesions.
ECH shares some features with dermatofibroma, including
occasional epidermal hyperplasia and keloidal
collagen. Unlike dermatofibroma, however ECH tends
to be more sharply circumscribed, lack other cell types
(such as giant cells, foamy macrophages), and prominent
vascularity.
ECH can simulate metastatic or primary melanoma.
Clues to the diagnosis are: lack of cytologic atypia
(though this may be present, especially in cases that also
have features of dermatofibroma), lack of epidermal
involvement (though this would not distinguish metastatic
melanoma from ECH), and lack of nested pattern
or pigment. Also, an epidermal collarette may be present.
In addition, anti-S-100 and antibodies to melanoma
antigens (such as gp100, MART-1 etc.) are very
useful in separating the two entities (although S-100
can be focally positive in a small minority of cases of
ECH). Factor XIIIa (positive in 50-70% of cases) and
CD68 positivity, along with lack of convincing reactivity
for melanoma antigens is useful in the diagnosis of
ECH. (Note: CD68 can be positive in melanoma; therefore,
a combination of histologic and immunohistochemical
findings are essential in establishing a diagnosis).
ECH may have abundant vascularity and thus simulate
a vascular tumor. The important difference is that the
epithelioid cells lack CD34 or CD31 expression.

38
ATTI CONGRESSUALI
Those cases of clear cell ECH may simulate metastatic
renal cell carcinoma. Both lesions can be very vascular.
However, extravasated red cells are a clue to metastatic
RCC. Immunohistochemistry will prove helpful since
renal cell carcinoma are usually cytokeratin and CD10
positive.
B) FIBROHISTIOCYTIC LESIONS WITH ATYPICAL
FEATURES AND RELATIONSHIP WITH DERMATOFIBROMA
AND DERMATOFIBROSARCOMA PROTUBERANS
Dermatofibroma (DF) is a common skin lesion composed
predominantly of fibroblast-like spindle cells, capillaries,
and macrophages within a collagenous stroma,
usually associated with hyperplasia and hyperpigmentation
of the overlying epidermis. Dermatofibrosarcoma
protuberans (DFSP) is a tumor composed of
fascicles of slender cells, frequently arranged in a storiform
pattern. DFSP is a low-grade malignant neoplasm
with a marked tendency for local recurrence and a
low rate of regional or distant metastasis, and therefore
requires complete excision. Thus, a definitive distinction
between DF and DFSP has considerable importance.
In a few circumstances, however, the histologic appearances
of these lesions can overlap significantly;
occasional cases of DF, because of cytologic atypia,
cellularity, size, location in the deep dermis or extension
into the subcutaneous tissue, may be difficult to
differentiate from DFSP.
The differential diagnosis between DF and DFSP has
been considerably aided in recent years by immunohistochemistry
with antibodies against factor XIIIa and
CD34. While factor XIIIa (FXIIIa) is expressed by most
DF, CD34 is expressed by the vast majority of DFSP.
However, the reliability of CD34 staining to distinguish
DFSP from DF is not absolute. The sensitivity of
CD34 staining in DFSP varies from 84 to 100%; conversely,
some DF can have focal staining with CD34 in
a low percentage of cells, so specificity is also incomplete.
Nevertheless, based on the fundamentally different
immunophenotypes of DF and DFSP, it has been
proposed that the two lesions are not benign/malignant
counterparts of one another, but rather represent entirely
distinct lineages. However, in the last years we have
encountered several unusual fibrohistiocytic lesions
exhibiting biphasic differentiation toward DF and DF-
SP, based on clinical, histologic, and immunophenotypic
features.
These atypical lesions occur mainly in the trunk, a distribution
more characteristic of DFSP. However, all
cases were smaller than 2 cm, favoring the diagnosis
of DF, as DFSP usually is larger than 5 cm in diameter.
The partial honeycomb pattern of infiltration of the
subcutaneous fat in all of our cases is suggestive of
DFSP, as deep DF typically infiltrates the subcutis in a
radial or bulging fashion. However, the overall appearance
of the current lesions more closely recapitulates
that of DF because all the lesions are quite sclerotic
and contain thick collagen fibers. While most DF are
usually non-reactive for CD34, these atypical lesions
have strong immunoreactivity for CD34 in 20 to 70%
of the lesional cells. This level of immunoreactivity
for CD34 in these lesions is distinctly unusual and argues
against classifying these cases simply as a variant
of DF.
Regarding follow-up and clinical management, the recurrence
in one of these atypical lesions indicates possibly
an aggressive clinical behavior and suggests that
a complete excision may be a prudent approach. Based
on all these features, we have suggested the term of Indeterminate
Cutaneous Fibrohistiocytic lesions as a
non-committal nomenclature for these unusual lesions.
Plexiform fibrohistiocytic tumor
Plexiform fibrohistiocytic tumor is a rare neoplasm of
intermediate malignancy that most commonly presents
as a dermal or subcutaneous mass of the trunk and extremities
in children or young adults. Histologically,
these are poorly circumscribed, plexiform tumors composed
of multiple small nodules, containing a distinctive
admixture of rounded mononuclear cells (likely macrophages)
and osteoclast-like giant cells. These nodules
are in turn often surrounded by short fascicles of fibroblastic
and/or myofibroblastic-appearing spindled
cells. Mitotic figures are rare. Immunohistochemically,
the spindled component may express smooth muscle
actin while the rounded cells and osteoclasts express
CD68. In a few occasions, only the fibroblastic areas
are identified in the sections.
Fibrous hamartoma of infancy
Fibrous hamartomas of infancy typically occur within
the first year of life (91% with 23% being congenital),
more commonly in boys, and usually involving the
axillary region, upper arm, upper trunk, inguinal region,
and external genital area. Most cases are solitary,
painless nodules, occasionally with rapid growth. Histologically,
these fibrohistiocytic lesions have a characteristic
triphasic morphology: fibroblastic fascicles,
fat, and nodules and whorls of primitive-appearing mesenchymal
tissue. The main differential diagnosis is
with neural neoplasms, but fibrous hamartoma lacks
any significant expression of S100 protein.
Sclerotic fibroma
Sclerotic fibroma (“plywood” fibroma) is a skin lesion
sometimes associated with Cowden syndrome. They
are well-circumscribed dermal nodules composed of
spindled cells with focal nuclear pseudo-inclusions.
There is usually extensive fibrosis with hypocellular,
storiform areas, resembling to some authors plywood.
Occasionally, the spindled cells strongly express CD34,
but not factor XIIIa or markers of melanocytic, neural,

ATTI CONGRESSUALI
39
or muscular differentiation. It has been recently reported
that some sclerotic fibromas express CD99.
Nuchal fibroma
Nuchal-type fibroma is a distinct subcutaneous and
dermal fibrous tissue proliferation associated with
Gardner syndrome and has been possibly present in
two others. Gardner syndrome is an autosomal-dominant
condition; these patients have epidermoid cysts,
fibrous tumors, osteomas, and intestinal polyposis. Nuchal-type
fibromas occur mostly around the neck area
in patients of all ages. Histologically these lesions are
paucicellular, haphazardly arranged collagen bundles
with entrapped adipose tissue. Van-Gieson stain reveals
a marked diminution of elastic fibers. The spindle cells
within the lesions express mostly CD34 while also containing
a few factor XIIIa-positive cells.
Ossifying fibromyxoid tumor
of soft parts
Ossifying fibromyxoid tumors (OFT) of soft parts are
very rare neoplasms characterized by well-circumscribed,
slow-growing, asymptomatic subcutaneous masses.
The most common locations are the trunk and
proximal extremities, with sizes ranging from 1 to 14
cm (median 4.0 cm). A characteristic finding is a fibrous
capsule and an incomplete peripheral shell of
mature bone. However, histologic slides may not contain
bone if the person grossing the lesion avoids them.
Tumors are composed of varying amounts of both
myxomatous areas with spindle tumor cells and pseudoalveolar
structures with oval tumor cells. The tumor
cells have evenly sized, oval nuclei usually without significant
atypia and slightly eosinophilic cytoplasm
with intracellular vacuoles. Mitotic figures are usually
scarce. Occasionally there are satellite micronodules,
mucinous microcysts, solid growth (with only focal presence
of myxoid stroma), chondroid differentiation with
binucleated lacunar cells, or pericytic growth pattern.
Immunohistochemical studies reveal an expected expression
of vimentin, as well as focal expression of S-
100 protein, pancytokeratin, smooth muscle actin, desmin,
collagen II, CD57, GFAP, NSE. Due to these findings
some authors have suggested that these tumors are
composed of Schwann cells. Ultrastructural examination
has revealed a few filopodia-like processes, discontinuous
basal lamina and a few primitive cell junctions.
Cytogenetic studies have shown several abnormalities.
A number of lesions (around 20%) behave in a locally
aggressive, recurrent fashion. In particular, lesions with
infiltrative borders, high cellularity, high nuclear grade,
or > 2 MF/50 HPF may have increased risk for recurrence
and metastasis. In a series with 10 such lesions, 6
of them metastasized. Overall, around 10% of the lesions
metastasize.
Hemangiopericytoma
vs solitary fibrous tumor
During the last years there has been a push to eliminate
the term hemangiopericytoma with solitary fibrous
tumor. Regardless the preferred concept, these lesions
occasionally occur in the skin.
Solitary fibrous tumor (SFT) is an uncommon mesenchymal
tumor originally described in the pleura but
currently such a diagnosis is given to lesions occurring
in the liver, lung, thymus, orbit, soft tissue, orbit and
skin. They are usually circumscribed nodules around 1-
6 cm in size, with tan and fleshy appearance and areas
of hemorrhage. Although originally characterized as
“patternless” lesions, SFT have a typical arrangement
of hyper and hypocellular areas with bland spindle cells
usually lacking nuclear pleomorphism, prominent
nucleoli, or significant mitotic figures. The cells are
usually associated with a fibrous stroma containing
dense/ keloidal collagen. There are usually numerous
vascular channels with a pericytomatous arrangement,
hence the term hemangiopericytoma. These lesions express
CD34, CD99, and bcl-2 while usually failing to
express factor XIIIa, cytokeratin, S100 protein, or actin.
According to the morphologic and immunophenotypic
findings, the potential cell of origin should possess a
spindled morphology, be ubiquitous, and express CD-
34. Therefore it seems likely that, at least in the skin,
SFT are composed of cells closely resembling dermal
dendrocytes.
SFT resembles dermatofibroma and dermatofibrosarcoma
protuberans (also see below). In contrast with the
former, SFT strongly expresses CD34 and lacks factor
XIIIa. DFSP is a poorly circumscribed neoplasm that
involves the subcutaneous tissue in a “honeycomb”
pattern. Synovial sarcoma shares many features with
SFT; both are composed of predominantly spindle cells,
with a fibromyxoid background and expression of
CD34, bcl-2 and CD99. However, the large majority of
synovial sarcomas shows a very uniform pattern of
densely cellular fascicles with small spindle cells and
express at least focally cytokeratins and EMA.
Another lesion expressing CD34 is the pleomorphic
hyalinizing angiectatic tumor (see below).
Pleomorphic hyalinizing angiectatic
tumor of soft parts (PHAT)
This is a grossly lobulated, firm, yellow-tan, focally hemorrhagic
tumor, of up to several cm in size, usually
located in the lower extremity middle-aged individuals.
Most lesions are infiltrative involving the deep dermis
and subcutaneous tissue. The tumors consist of infiltrating
sheets of spindled and pleomorphic cells with frequent
intranuclear pseudoinclusions, within a loose
connective stroma containing clusters of ectatic vessels
surrounded by a characteristic, prominent hyaline ma-

40
ATTI CONGRESSUALI
terial. Other areas, predominantly at the periphery of
the lesions, show numerous, non-hyalinized vessels.
Although some of the cells display large, pleomorphic
nuclei suggesting a diagnosis of sarcoma, mitotic figures
are very rare. In the series reported in the literature,
up to 50% of the patients with follow-up develop local
recurrence so a complete excision should be accomplished
when feasible. Distant metastases appear distinctly
rare.
Tumor cells express at least focally CD34, CD99, and
factor XIIIa, so some authors have suggested that these
lesions develop along the lines of perivascular and dermal
dendritic cells.
The differential diagnosis includes malignant fibrous
histiocytoma but PHAT has prominent intranuclear cytoplasmic
inclusions, lacks significant numbers of mitotic
figures, and shows focal CD-34 expression. Despite
the similarities with neurilemomas (dilated vessels
with hyaline material and intranuclear cytoplasmic
inclusions) PHAT are infiltrative rather than well circumscribed
and lack S100 expression. The lack of vascular
markers other than CD34 is against a diagnosis
of hemangioma/hemangioendothelioma.
Acral myxoinflammatory tumor
with atypical bizarre giant cells
Also called inflammatory myxohyaline tumor of distal
extremities with virocyte or Reed-Sternberg-like cells,
and inflammatory myxoid tumor of soft parts with bizarre
giant cells. This is a rare malignant neoplasm that
occurs in the distal extremities (around the hands and
feet), from young adults to elderly individuals, and has
a propensity to recur locally. The lesions are between 1
and 6 cm and are clinically suspected to be ganglion
cysts, tenosynovitis, or giant cell tumors of tendon
sheath. On microscopy, these are multinodular, poorly
circumscribed tumor, with a prominent fibromyxoid
matrix containing numerous inflammatory cells (neutrophils,
eosinophils, lymphocytes, and plasma cells).
Intermixed in the lesion are large, bizarre tumor cells
with vesicular nuclei, prominent inclusion-like nucleoli,
and abundant eosinophilic cytoplasm, mimicking
ganglion and Reed-Sternberg cells. Ultrastructurally,
the bizarre tumor cells had features of modified fibroblasts,
including an abundance of intermediate filaments
and dilated rough endoplasmic reticulum. A
number of the tumor cells express CD68 and CD34, but
not neuroectodermal, epithelial, or lymphoid markers.
Along with the rare number of mitotic figures, these lesions
have a very low Ki67 labeling. In the initial series,
10 of 44 required amputation due to repeated local
recurrences. Distant metastases (lymph node and lung)
were seen in two patients.
The differential diagnosis includes a reactive process
(due to the prominent inflammatory infiltrate and fibrosis)
but the presence of the large, bizarre cells
should be a clue to the diagnosis of acral myxoinflammatory
fibroblastic sarcoma (AMFS). Malignant fibrous
histiocytoma is very similar to AMFS. A diagnosis
of the latter should be favored on acral lesions
showing the characteristic Reed-Sternberg-like cells.
Hodgkin lymphoma can be ruled out by the lack of expression
of lymphocyte markers such as CD30.
References
Billings SD, Folpe AL. Cutaneous and subcutaneous fibrohistiocytic
tumors of intermediate malignancy: an update. Am J Dermatopathol
2004;26:141-55.
Canales-Ibarra C, Magarinos G, Olsoff-Pagovich P, Ortiz-Hidalgo
C. Cutaneous sclerosing perineurioma of the digits: an uncommon
soft-tissue neoplasm. Report of two cases with immunohistochemical
analysis. J Cutan Pathol 2003;30:577-81.
Diwan AH, Graves ED, King JA, Horenstein MG. Nuchal-type fibroma
in two related patients with Gardner’s syndrome. Am J Surg
Pathol 2000;24:1563-7.
Folpe AL, Weiss SW. Ossifying fibromyxoid tumor of soft parts: a
clinicopathologic study of 70 cases with emphasis on atypical and
malignant variants. Am J Surg Pathol 2003;27:421-31.
Hanft VN, Shea CR, McNutt NS, Pullitzer D, Horenstein MG, Prieto
VG. Expression of CD34 in sclerotic (“plywood”) fibromas. Am
J Dermatopathol 2000;22:17-21.
McCarron K, Oriba H, Bergfeld W. The epithelioid variant of benign
fibrous histiocytoma (BFH): a clinicopathologic & immunohistochemical
analysis of 19 cases. J Cutan Pathol 2000;27:564.
Meis-Kindblom JM, Kindblom LG. Acral myxoinflammatory fibroblastic
sarcoma: a low-grade tumor of the hands and feet. Am J Surg
Pathol 1998;22:911-24.
Michal M. Inflammatory myxoid tumor of the soft parts with bizarre
giant cells. Pathol Res Pract 1998;194:529-33.
Montgomery EA, Devaney KO, Giordano TJ, Weiss SW. Inflammatory
myxohyaline tumor of distal extremities with virocyte or Reed-
Sternberg-like cells: a distinctive lesion with features simulating inflammatory
conditions, Hodgkin’s disease, and various sarcomas.
Mod Pathol 1998;11:384-91.
Morgan MB, Pitha J, Johnson S, Dunn B, Everett MA. Angiomatoid
malignant fibrous histiocytoma revisited. An immunohistochemical
and DNA ploidy analysis. Am J Dermatopathol 1997;19:223-7.
Mori O, Hashimoto T. Plexiform fibrohistiocytic tumor. Eur J Dermatol
2004;14:118-20.
Sakaki M, Hirokawa M, Wakatsuki S. Acral myxoinflammatory fibroblastic
sarcoma: a report of five cases and review of the literature.
Virchows Arch 2003;442:25-30.
Smith ME, Fisher C, Weiss SW. Pleomorphic hyalinizing angiectatic
tumor of soft parts. A low-grade neoplasm resembling neurilemoma.
Am J Surg Pathol 1996;20:21-9.
Sotelo-Avila C, Bale PM. Subdermal fibrous hamartoma of infancy:
pathology of 40 cases and differential diagnosis. Pediatr Pathol
1994;14:39-52.
Suster S, Nascimento A, Markuu M, Sickel J, Moran C. Solitary fibrous
tumors of the soft tissue: a clinicopathologic and immunohistochemical
study of 12 cases. Am J Surg Pathol 1995;19:1257.

ATTI CONGRESSUALI
41
Surgical Pathology of the Larynx: a Practical Overview
MARIO A. LUNA, M.D.
The larynx is a dynamic organ that participates in diverse
physiological functions. Three functions, however,
are the most important: air way protection, respiration
and phonation. In addition to squamous cell carcinoma
which is the most common malignant neoplasms,
many other neopalsms, benign and malignant, can occur
in the larynx causing diagnostic dilemmas. In this
syllabus we will briefly present the most important
laryngeal neoplasms.
Anatomic considerations
As is known, the larynx has a different embryological
derivation for its compartments. The supraglottic region
develops from the buccopharyngeal anlage, whereas the
glottis and subglottis derive from the tracheobronchial
anlage This different embryological origin has led to the
conclusion that the larynx is made up by two hemilarynx
superposed not only embryologically but also clinically,
particular in tumor pathology. Also, based on objective
anatomopathological and clinical elements,it has been
demonstrated that the subdivision of the larynx in three
regions-supraglottis, glottis and subglottis- is acceptable
only for descriptive purposes, but not from the point of
view of tumor pathology 1 . Histopathological studies by
well known researches have demonstrated that supraglottic
tumors may actually invade the glottic area an
spread even further to the subglottis, though clinically
the neoplasms appear to be restricted to the supraglottis
region (transglottis carcinomas) 2 . The concept
of the embryological barrier and the anatomical regions
delimiting neoplastic invasion is therefore no
longer acceptable in the light of the above data. As result,
the more malignant is the neoplasm the more atypical
is the tumor spread to the whole larynx.
Same considerations apply for the larynx and hypopharyx,
embryologically and anatomically, these
two regions are two distinct entities. Neoplasms arising
in these regions have a different biologically
behavior, even though the histological type of tumor
is the same. In practice, however, such distinction is
possible only for tumors at their initial stage, which
remain relatively limited in extension 3 . There are two
other reasons to consider the two neoplasms combinedly:
1) many authors still use the term “extrinsic”
tumors to designate neoplasms arising in the hypopharyx
and 2) from the morphologic point of view,
the histological types of tumors are the same, though
one type usually prevails in one region or another of the
larynx and hypopharynx 3 .
Potential malignant and early malignant
lesions
Since the prognosis of early malignant lesions of the
larynx is very favorable, it is important that both the
clinicians and pathologist recognize the pathologic features
of the potential malignat and early malignant
changes in the larynx. Several investigators have demonstrated
that the different degrees of atypia reflect
“steps” along the pathways to malignancy with the more
severe atypical lesions representing higher risk.
There is no universally accepted histopathologic classification
for these changes. Three systems are the most
used among pathologist and clinicians: 1) the nomenclature
developed by the WHO, 2) the Squamous intraepithelial
neoplasm system (SIN) and 3) the Ljubljana
Classification. Most pathologist are familiar with
the WHO 4 and SIP/LIP 5 systems. Therefore, I will present
briefly the Ljubljana classification 6 .
The Ljubljana classification is the most recent but it has
been tested there by pathologists and clinicians for more
than 30 years. The histologic system is divided into
four grades: 1) simple and 2) benign basal and parabasal
cell hyperplasia (abnormal hyperplasia) these two
types form a benign group, 3) atypical hyperpalsia (or
risky hyperplasia) is potentially, while 4) carcinoma in
situ (CIS) is actually a malignant lesion 6 .
The crireria are as follow: Simple hyerplasia the epithelium
is thickened as a result on an increased prickle cell
layer. The cells of the basal and parabasal region, which
comprise one to three layers, remain unchanged.
There are no cellular atypias and only scarce, regular
mitoses are seen in the basal layer. Benign basal cell
hyperplasia (abnomal hyperplasia) the thickened
epithelium consists of basal and parabasal cells augmented
so that is occupies up to one-half of the entire
epithelium. The cells do not show significant nuclear
changes and are aligned in “normal perpendicular”
orientation. The augmented basal cells contain moderately
enlarged nuclei and normal distribution of chromatin.
Normal mitoses are always located in or near the
basal layer. Dyskeratosis, with no prickles and strongly
eosinophilic cytoplasm, is seen in less than 5% of the
cells.
Atypical hyperplasia (risky epithelium) stratification
still is preserved. Augmented cells are often perpendicularly
oriented to the basement membrane, the nuclei
of many of them showing mild to moderate changes of
atypia, which are defined by the following alterations:
the nuclei are enlarged, their contours may be irregular
with marked variations in staining intensity, frequently
hyperchromatic; nucleoli, increased in number and size.
Nuclear/cytoplasmic ratio is generally increased.
This type of epithelial cells may occupy the lower half

42
ATTI CONGRESSUALI
or more of the entire epithelial thickness. Mitoses are
increased, usually found in the lower two-thirds, they
are rarely, if ever, abnormal. Dyskeratotic cells are frequent
within entire epithelium. Apoptotic cells may be
present (Civattes bodies). Two subdivision of atypical
hyperplasia are recognized: 1) “ basal cell type” with
no intercellular prickles and no cytoplasmic eosinophilia,
the cells partially aligned perpendicularly to the basement
membrane and 2) “spinous cell type “ with intercellular
prickles and increased cytoplasmic eosinophilia.
The cells may be aligned horizontally to the
basement membrane.
Carcinoma in situ. Four distinct morphologic characteristics
are usually present: 1) loss of stratification. The
surface may be covered by three to five layers of compressed,
horizontally stratified, and sometime keratinzed
cells, 2) cell alterations of the type found in atypical
hyperplasia, but as a rule of a considerably greater
degree. The epithelial cells may show all the characteristics
of invasive squamous cell carcinoma, 3) mitotic
figures are markedly increased throughout the whole
epithelium, often more than five per high power field.
Abnormal mitosis are frequently seen. Civatte bodies
and dyskeratotic cells are present in high number and
4) preservation of the basement membrane In CIS, the
lesion may fall within two categories: 1) “basal cell type”
without intercellular prickles and no eosinophilic
cytoplasm and 2) “spinous type” with intercellular
prickles and cytoplasmic eosinophilia.
The risk of progression to SCC in the subsequent 10
years for simple and basal cell hyperplasia is 1.0 and
0.9% respectively), it rises sharply for atypical hyperplasia
(10%), and may well be as high as 90% for intraepithelial
carcinoma 6 .
Malignant tumors
The incidence of malignant tumors of the larynx is
about 1.5 to 2.0% of all malignant neoplasms in all locations.
Men are more frequently affected by laryngeal
and hypopharyngeal carcinomas than women (ratio 8:1
and 13:1 respectivelly). Most malignant neoplasms of
the larynx and hypopharynx are squamous cell carcinomas;
other primary malignant neoplasms of epithelial
and mesenchymal origin are rare.
Malignant epithelial tumors
CONVENTIONAL AND VARIANTS OF LARYNGEAL
SQUAMOUS CARCINOMA
The pathogenesis of laryngeal SCC is probably influenced
by various endogenous, genetic, constitutional
and/or hormonal factors. Exogenous agents, such as
tobacco smoke, ionizing radiation and alcohol abuse,
are contributory factors. Smoking and chewing tobacco
may induce hypopharyngeal carcinoma. Consumption
of aromatic nuts in Asia or sideropenic dysphagia are
associated with higher incidence of laryngeal cancer.
Most laryngeal squamous carcinomas are of moderately
differentiated. Seevral variants of SCC have been
documented in the larynx: 1) verrucous, 2) papillary, 3)
spindle or sarcomatoid, 4) basaloid, 5) adeno-squamous,
6) lymphoepithelial or nasopharyngeal type and
7) others less well characterized.
Verrucous carcinoma (VC). A slow-growing, locally
destructive variant of well differentiated SCC; it does
not metastasize. The deceptively innocuous looking tumor
is made up of warty, exophytic, folds of well differentiated
keratinizing epithelium that lacks morphologic
signs of malignancy. Plump acanthotic, bulbous
rete ridges extend into subjacent tissue. The lesion
should be well sample to exclude a hybrid verrucousconventional
SCC. In the larynx VC represent only 4%
of all malignant neoplasms. With surgery only 2% of
the VC recur locally 7 .
Papillary carcinoma (PSCC). A variant of SCC composed
of exophytic fibrovascular cords lined by cytologically
malignant non keratinizing epithelial cells in a papillary
configuration. It predominates in the supraglottis
in males in the 6 th decade. In biopsies invasion is difficult
to demonstrate. Invasion, however, may be noted
if enough sections are reviewed. If no demonstrated
then the terms “non invasice PSCC” or “severe papillary
dysplasia” may be used. Surgery is usually curative,
laryngeal PSCCs seldom metastasize and recur
about 10% 8 .
Spindle or sarconatoid carcinoma (SSCC) a variant of
SCC with spindle cell. The biphasic type is composed
of nest of SCC with transition to spindle cells, the monophasic
type is composed exclusively of spindle cells
in the latter type is mandatory to demonstrate cytokeratin
in the neoplastic cells in order to call it SSCC. If immunonegativ
and histologically malignant the term
“sarcomatoid malignant neoplasm” is advisible. As a
general rule “Any malignant spindle neoplasm in the
mucosas of the H & N most likely represent SSCC until
proven otherwise”. SSCC may appear as a polypoid
mass or as flat infiltrating lesion, in the former usually
the SCC component is found at the base of the mass.
Surgery is the treatment of choice with a recurrence of
approximately of 45% 9 .
Basaloid carcinoma (BSCC). An aggressive variant of
SCC that predominates in the supraglottis and hypopharyx
in males in the 7 th decade, commonly present
with cervical metatases. CIS or severe dysplasia usually
found in biopsies and may be the only signs of squamous
differentiation. Histologically it is a biphasic
epithelial malignancy with conventional SCC and mostly
undifferentiated basaloid cells arranged in nests,
cords, festoons, cribriform or pseudoglands. Extracellular
eosinophilic basement membrane-like material

ATTI CONGRESSUALI
43
and comedonecrosis usually present. Surgery with radical
neck dissection and adjuvant therapy is the best
treatment. Cervical lymph node metastases 64%, distant
spread 44%, mortality 38% at 17 months 10 .
Adenosquamous carcinoma (ADSCC) A rare, aggressive
variant of SCC with histomorphologic features of conventional
SCC and adenocarcinoma. Male predominance
in 6 th and 7 th decade. SCC component originates from
the surface mucosa with gradual transition into adenocarcinoma
deeper within the tissue. CIS may be the only
evidence of squamous differentiation. Adenocarcinoma
component usually non-classifiable as any specific type,
true ductal lumina are present Surgery ideal treatment.
Frequent local recurrences and early metastasis to cervical
lymph nodes. Distant metastases in 20%, 50% reported
patients have died within 5 years 11 .
Nasopharyngeal – type carcinoma (lymphoepithelioma)
(NPC). This non keratinizing undifferentiated subtype of
carcinoma is composed of round to oval cells with clear
nuclei and prominent nucleoli arranged in nests or cords
surrounded by heavy lypho-plasmocytic infiltrate. Often
giant cells, granulomas, amyloid or heavy eoninophilic
infiltrate may be present. The epithelial nature of the
neoplasm is often demonstrated only by immunostains
(CK). Laryngeal NPC constitute less than 0.5% of all
malignant tumors of this organ. It metastasizes early to
cervical lymph nodes and approximately 25% of patients
develop distant metastasis. Radiotherapy combined with
chemotherapy gives the best results 12 13 .
NON- SQUAMOUS LARYNGEAL CARCINOMAS
Nonsquamous laryngeal carcinomas make up fewer
than 1% of all epithelial malignancies of the larynx.
Nonsquamous laryngeal carcinomas fall into two catgories:
1) neuroendocrine type and 2) sialocarcinomas.
Neuroendocrine carcinomas appear to constitute the
majority of so-called laryngeal adenocarcinomas 14 .
Neuroendocrine carcinomas (NEC). The most common
are the so-called atypical carcinoids (NEC moderately
differentiated), followed by small cell NEC, and the
less common are the carcinoids (well differentiated
NEC) 15 16 . The pathology is identical to the NEC of the
lungs and this will be discuss by Dr Cesar Moran.
Sialocarcinomas. This neoplasms are imperfectly separated
into ones that are surface and ones that are nonsurface
(seromucous gland) in origin. Adenoid cystic
carcinoma is not only the most representative of this
group, it is the most prevalent (60%). All other salivary-type
are rare. Rarer still are surface adenocarcinomas.
It is safe to presumen that except for low-grade
mucoepidermoid carcinomas, other grades of that carcinoma
in the larynx are more likley to be adenosquamos
carcinomas 17 . The pathology laryngeal sialocarcinomas
is identical to their counterpart in the salivary
glands and therefore not presented here.
Mesenchymal neoplams
Benign and malignant tumors of mesenchymal origin
of the larynx and hypopharnx are rare and make up approximately
0.3% to 1.0% of all malignancies of this
organ. The can arise in the soft tissues or in the skeletal
portions of the organ. The histologic type does not
differs from that of mesenchymal neoplasias of the soft
tissues or skeletal system (See soft tissues section). Here
we will discuss only the most common soft tissue lesions
of these organs. Also briefly we will present some
uncommon interesting mesenchymal lesions.
GRANULAR CELL TUMORS (GCT)
This benign tumor entity usually is not difficult to recognize
microscopically with a little practice. The controversy
centers about the frequent pseudoepitheliomatous
hyeperplasia (PEH) of the overlying laryngeal mucosa.
The important factor is that often GCT are diagnosed
as squamous carcinoma because the overlying
PEH, actually many patholgist recognized but ignored
the GCT component. Follow-up of all these cases called
SCC with CCT have revealed that none gave clinical
evidence of a malignant SCC. Other point of interest
is that laryngeal GCT often are incompleted excised
because, in generally, they lack encapsulation. In
spite of this the great majority of cases undergo a local
type of resection with little mutilation of the larynx
which is mostly curative 18 .
MYOFIBROBLASTOMA
Myofibroblastic tumors (MFB) are benign neoplasms
formed exclusively of mesenchymal spindle cells with
histologfically benign to low grade malignant features
and characterized by both smooth muscle and fibroblastic
features initially seen as submucosal nodules. MFBs
are are in the head and neck region, and a few cases have
been reported in the larynx 19 . Inflammatory MFBs,
benign tumors composed of myofibrobalsts and chronic
inflammatory cells, have been described at many locations
and recently in the larynx 20 . Immunohistochemical
stuies have demonstrated stronmg immunorecativity to
SMA, and negative staining for desmin, S-100 protein,
CK, and h-Caldesmon supporting their myofibroblastic
nature. The findings of enhaced cellularity, nuclear pelomorphism
and elevated mitotic activity combined with
the ill-defined infiltrative nature reflect a low-grade histologic
aggressiveness. The most relevant differencial
diagnosis is with sarcomatoid carcinoma, the wholly
submucosal presentation and the absence of epithelial
features combined with negative CK expression and positive
SMA excludes this possibility. The negative staining
for CD34 excludes solitary fibrous tumor and low
grade fibrosarcomas. And neurogenic tumors are excluded
on the basis of negative reactivity for S-100 protein.
FIBROMATOSIS
Laryngeal fibromatosis (LF) is considered to be rare 21 .
Cases have been described in pediatric patients, inclu-

44
ATTI CONGRESSUALI
ding newborns. In adults it is also rare as 2001 only 3 cases
have been reported in the English literature 21 The histopathologic
diagnosis of LF is based on the recognition
of the characteristic fibroproliferative changes associated
with dense collagen production alongside scattered
chronic inflammatory cells. Mitotic activity is usually
very low and scanty atypia, if not absent. The spindle
cells are immunoreactive for vimentin and SMA. LF appears
to be as aggressive as in soft tissues of the H&N.
Total laryngectomy appears a valid treatment in preventing
local recurrences and death. The usefulness of adjuvant
chemo radiation is questionable, additional cases of
LF are needed to draw definitive conclusios. Neck dissection
appears not to be indicated 21 .
CARTILAGENOUS TUMORS
Laryngeal lesions composed of cartilage fall into three
categories: 1) chondrometapalstic nodules, 2) chondromas
and 3) chondrosarcomas 22 .
Chondrometaplasia does no arise from hyaline cartilage
and does not have the typical lobular pattern of
hyaline cartilage, it arise from elastic cartilage 22 . It
occurs in two settings: 1) asymptomatic and found at
necropsy where they are smaller than 2 mm and preponderantly
in the region of the false cords, and 2)
larger (usually less than 1 cm), symptomatic nodules
that occur in the vocal cords, epiglottis and rarely, in
the ventricle. Patients whose age range between 14
and 98 years may have them. Chodrometaplasia has
predilection for the posterior and midportion of the
glottis where it must be distinguished from the normal
vocal process of the arytenoids. Like chondrometaplastic
nodules, the vocal process is also composed of
elastic cartilage, but unlike chondrometaplasia, it is a
well-circumscribed nodule 22 .
Both chondromas and chondrosarcomas share essentially
the same biologic course. The eventual outcome
of lesions initially labeled chondromas is not significantly
different from those identified as chondrosarcomas
at the onset 22 . The tumors arise from
hyaline cartilage and show no evidence of elastic tissue.
there is a striking predilection for chondrosarcomas
to arise in the region of the cricoid cartilage
(70% to 75%), usually in the posterior or posterolateral
areas. Origin from thyroid cartilage follows distantly
and the arytenoid origin is rare 22 , males are
affected most and the median age at onset is 63 years.
Laryngeal chondrosarcomas are nearly low-grade.
The criteria used are the same as those used in cartilaginous
lesions elsewhere in the body; increased cellularity,
presence of double-nucleated cells, and nuclear
atypia. Most condrosarcomas are removed by a
laryngofissure approach, approximately one-fourth
of patients, a total alryngectomy will be necessary. In
all cases, the oncologic principle of including margins
of normal tissue should be followed. Laryngeal
chondrosarcomas rarely metastasize and their slow
course allows conservative management if the size
and site of the tumor allow 22 .
OTHER LARYNGEAL SKELETAL LESIONS
Aneurysmal bone cysts 23 and giant cell tumors 24 are
among the benign skeletal laryngeal lesions that have
been documented in the literature. Laryngeal osteosarcomas
occur in the larynx in two forms: as a pure primary
osteosarcoma and as a component of a sarcomatoid
carcinoma 25 . These sarcomas occur in men ranging
in age from 50 to 69 years (median age 63.3 years). The
morphology is identical to their skeletal counterpart and
the differential diagnosis is with sarcomatoid carcinoma,
therefore immunostains for epithelial markers are
mandatory before this diagnosis is rendered. Pulmonary
metastasis and local recurrences are common 25 .
LARYNGEAL SOFT TISSUES SARCOMAS
Synovial sarcoma (SS) after fibrosarcoma is the most
common laryngeal sarcoma. Of 345 SS studied by Enzinger
and Weiss 26 , seven arose in the pharynx and 7 in
the larynx. The age range from 10 to 51 years (median 19
years), they arged from 1 to 12 cm and usually are polypoid.
Microscopically the neoplasms may be biphasic,
monophasic fibrous, monophasic epithelial or poorly differentiated
as seen in the soft tissues counterpart 27 28 . CK
and EMA are present in both components of SS, 62% express
CD99. Translocation between X and 18 (t) (X;18)
(p11.2;q.11.2) is seen in SS regardless of site 29 . The main
differential diagnosis is with sarcomatoid carcinoma. Of
50 patinetns with SS of the H&N, almost 33% had local
recurrences and 25% distant metastasis 26-28 . Other laryngeal
sarcomas documented in the literature are: MFH,
rabdomyosracomas and liposarcomas 30 .
MISCELLANEOUS NEOPLASMS
Extramedullary plasmacytoma has a strong tendency to
occur in the larynx, approximately 25% of all EMP of
the H&N region arose in the larynx 31 . The histology is
essentially of a diffuse monotonous infiltrate of plasma
cells with their typical immunomarkers. The differential
diagnosis is with reactive inflammatory process
(plasma cell granuloma). Experience indicates that if
there is an admixture of other inflammatory cells elements,
the diagnosis of plasma cell granuloma is most
likely. EMP of larynx seldom develop a fatal plasma
cell disorder such as multiple myeloma 31 . Only 53 cases
of primary malignant melanoma of the larynx have
reported in the medical literature as 2001 32 . Metastatic
melanoma should always be clinically excluded.
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Stasney CR, Beaver ME. Transglottic carcinoma. Ear Nose Throat
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Shanmugaratnam K. Histologic typing of tumours of the upper
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Orvidas LJ, Olsen KD, Lewis JE. Verrucous carcinoma of the
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Eryilmaz A, Gocer C, Acar A. Basaloid squamous cell carcinoma
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Lopez-Aguado D, Lopez Campos D, Perez Pinero B. Lymphoepithelial
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Narozny W, Betlejewski A, Stankiewicz C. Ventriculosaccular
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Batsakis JG, Luna MA, El Naggar AK. Non squamous carcinoma
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Soga J, Osaka M, Yakuwa Y. Laryngeal endocrinomas (carcinoids
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Mahlstedt K,Ubmuller J, Donath K. Malignant sialogenic tumours
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Pelucchi S, Amoroso C, Grandi E. Granular cell tumor of the
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MacGregor AR, Batsakis JG, El-Naggar AK. Myofibrobalstoma
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Wenig BM, Devaney K, Bisceglia M. Inflammatory myofibroblastic
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Martinez Madrigal F, Ruiz Godoy LM, Pineda Daboin K, Luna
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46
ATTI CONGRESSUALI
Adnexal Tumors of the Skin: Diagnostic Pitfalls
VICTOR G. PRIETO, M.D.
Although the field of adnexal tumors may appear as threatening
to surgical pathologists, most of the lesions
are easily classified on benign and malignant, even if a
clear cut differentiation or name cannot be provided. In
general, benign neoplasms are well differentiated, circumscribed,
and non-infiltrative, and can usually be
cured by simple excision. Malignant adnexal neoplasms
show a locally aggressive and, much less commonly,
metastatic behavior. This talk attempts to include
only those lesions that, in our opinion, are important
because they raise important differential diagnoses or
are associated with systemic diseases.
Follicular cysts
The two main ones are the infundibular and the tricholemmal
(or isthmic) types. These cysts correspond to
dilatation of the hair structure at different levels, thus
resulting in a different cyst lining and contents.
FOLLICULAR CYST, INFUNDIBULAR TYPE (ALSO KNOWN
AS “EPIDERMAL INCLUSION”, “EPIDERMOID,”
“SEBACEOUS”)
This very common lesion develops following a presumed
blockage of the opening of the follicle thus resulting
in retention of keratin and sebaceous secretion.
These cysts are most common on the head, neck, and
trunk but they may occur in almost any hair-bearing location.
Especially if they occur in younger patients or
in large numbers, infundibular cysts may be associated
with Gardner or Muir-Torre syndromes (see below). Infundibular
cysts are lined by stratified squamous
epithelium with a smooth contour and a thin granular
layer, thus resembling that of the normal infundibular
portion of the follicle. The cyst is filled with loosely
packed keratin resembling the basket weave stratum
corneum (“shreaded wheat”).
Dermoid cysts show also infundibular type of keratinization
but contain other tissue elements such as adnexal
glands. Patients with local trauma (e.g., barbers, mechanics)
may develop true epidermal inclusion cysts by
traumatic implantation of epidermis into the dermis.
FOLLICULAR CYST, ISTHMIC (TRICHOLEMMAL) TYPE
These cysts are most common on the head and neck,
especially on the scalp. They are firm, flesh-colored,
and range from several mm to several cm. Generally
they are asymptomatic. Isthmic cysts are lined by stratified
squamous epithelium with smooth contour and
lacking a granular layer. The cyst is filled with densely
packed keratin. Calcification is common. Occasionally
the epithelium is arranged in cellular clusters. In our
opinion this suggests the existence of a spectrum of tricholemmal
lesions between cysts, proliferating lesions,
and frank neoplasms (see below).
Trichoepithelioma/trichoblastoma
After the first detailed description of trichoblastoma by
Headington, some authors consider trichoepithelioma a
superficial form of trichoblastoma, thus combining adnexal
tumors with different degrees of hair follicle differentiation.
Furthermore, recently it has been proposed
that since basal cell carcinomas probably differentiate
toward the hair follicle rather than the basal cells
of the epidermis they should be considered as trichoblastic
carcinomas.
Solitary trichoepithelioma (TE) appears sporadically in
childhood or adolescence as a flesh-colored, 2-10 mm
papule or nodule, typically located on the face. Uncommonly,
multiple TEs with identical histopathology
can occur in families as an autosomal dominant condition.
Both sporadic and familial trichoepitheliomas
may show mutations of the region of the Drosophila
patched gene (9p21).
TE/trichoblastomas are composed of basaloid cells arranged
in cords and nests with focal peripheral palisade.
A common finding is the presence of papillary-mesenchymal
bodies, fibroblastic aggregations surrounded by
a cup-like extension of basaloid cells, thus recapitulating
the follicular papilla of the hair follicle. The intervening
stroma is fibrous. Mitotic figures or apoptotic bodies can
also be present. Merkel cells are commonly detected in
TE. TE have a well-formed layer of dendritic cells expressing
CD34 around the tumor cords, and a characteristic
pattern of expression of bcl-2 in the basaloid keratinocytes
located at the periphery of the cords.
TE can closely resemble basal cell carcinoma (BCC),
both clinically and histologically. The retraction artifact
between tumor parenchyma and stroma and peritumoral
myxoid stroma are the most helpful differentiating
features. Another useful criterion is the presence of
papillary-mesenchymal bodies (81% of TEs vs. 20% of
BCCs). In one series, calcification was observed only
in TE, but it was not a frequent finding (29%). Amyloid
was present in 33% of TEs and in only 13% of BCCs.
Both apoptotic cells and mitotic figures were also present
in TE (100% and 46% respectively); thus deregulation
of cell division and death is a feature common to
both TE and BCC.
Trichoadenomas show more advanced follicular differentiation
than trichoepithelioma, with keratin-filled
cysts arranged in the dermis almost equidistant one
from another.
Trichoepitheliomas are benign lesions that tend not to
recur and they usually do not require complete exci-

ATTI CONGRESSUALI
47
sion. However, while the above criteria are useful for
making a definitive diagnosis in most cases, in doubtful,
incompletely excised lesions and in the appropriate
clinical setting (e.g., lesion on sun-exposed facial
skin of an elderly patient) it is prudent to recommend
that the lesion be treated as a BCC, to reduce the risk of
recurrence.
Tricholemmoma/proliferating
tricholemmal tumor/tricholemmal
carcinoma
These three names designate a spectrum of lesions in
which there is isthmic-type keratinization, i.e., compact-packing
keratin overlying an epithelium lacking
keratohyaline granules. Thus these cells resemble those
seen in the outer root sheath of the follicle.
Tricholemmomas are solitary lesions typically present
on the face of young individuals. Patients with multiple
lesions may suffer Cowden syndrome (see below). Proliferating
tricholemmal tumors usually appear de novo
on the scalp of middle-aged individuals. Finally, tricholemmal
carcinomas are rare malignant tumors, presenting
as nodules of up to various centimeters, mostly
occurring on the trunk and extremities, with a tendency
for recurrence but no known metastatic capabilities.
All these three lesions are composed of cuboidal cells
with central, round nuclei and lightly pink or clear cytoplasm.
When keratinization occurs, these cells usually
lack keratohyaline granules. Rather bright red granules
(trichohyaline) may occasionally be seen focally
in these lesions. Many of the cells contain abundant
glycogen (positivity with PAS is removed after treatment
with diastase). Tricholemmomas are composed of
clusters of basaloid cells connected with the epidermis
and forming a peripheral palisade. Typically, the stroma
immediately outside this peripheral palisade is brightly
pink (“hyaline membrane”). Proliferating tricholemmal
tumors are nodular aggregates of basaloid cells
with only small areas containing densely packed keratin.
Lesions located outside the scalp, with rapid
growth, size greater than 5 cm, infiltrative growth, and
significant cytologic atypia with mitotic figures may
have recurrent and metastatic behavior. Tricholemmal
carcinomas are poorly circumscribed, invasive, asymmetrical
proliferations of basaloid cells focally attached
to the epidermis, sometimes with pagetoid extension.
The cells display frank pleomorphism with hyperchromatic
nuclei and mitotic figures.
Since tricholemmal carcinoma cells may infiltrate the
overlying and adjacent epidermis, the differential diagnosis
in a superficial biopsy includes melanoma, Paget
disease, and sebaceous carcinoma. In contrast to
melanoma, tricholemmal carcinoma cells strongly and
diffusely express cytokeratin but not gp100 (recognized
with HMB45) or MART1. In contrast to Paget disease,
tricholemmal carcinoma cells express high-molecularweight
keratin and lack CEA, GCDFP15, or mucin core
proteins (MUC) 1 and 5. In contrast to sebaceous
carcinoma, tricholemmal carcinoma cells do not show
scalloped nuclei and their positivity with PAS is removed
after diastase treatment.
Pilomatricoma (calcifying epithelioma of
Malherbe)/pilomatrix carcinoma
Pilomatricoma and pilomatrix carcinoma are follicular
lesions that contain cells displaying a pattern of keratinization
similar to that seen in the hair bulb, so-called
matrical type (see below). Lately, some authors have
proposed the existence of a third type of matrical lesions,
i.e., matricoma. Until more research is performed
on this topic, we prefer to designate such lesions
within the group of pilomatricomas.
Pilomatricomas present usually as solitary, small (but
rarely up to 5 cm in size), tan, firm nodules, on the face
and upper extremities, although they may occur in
almost any hair-bearing area. A majority of lesions arise
during the first two decades of life. Familial occurrence
is rarely reported, particularly in association with
myasthenia gravis. Some of these lesions have been
shown to contain mutations of the beta-catenin gene.
Such anomaly has been also reported in other ghostcell-containing
tumors, such as craniopharyngioma and
calcifying odontogenic cyst.
Pilomatrix carcinomas, the malignant counterpart, are
very uncommon. The few cases reported have occurred
mainly on sun-exposed areas of elderly individuals.
The hallmark of this type of tumors is the presence of
“ghost” cells (polygonal, deeply eosinophilic, with a
centrally located clear area corresponding to the absent
nucleus, typical of metrical differentiation), arranged in
nests within a generally fibrous stroma. In addition,
these lesions have different percentages of basaloid cells
(round, with small cytoplasm and hyperchromatic
nucleus) and calcification with or without ossification.
In some areas there is a transition between the basaloid
and ghost cells. Some of these lesions contain melanophages
in the stroma and dendritic melanocytes
within the clusters of basaloid cells. Mitotic figures are
not in themselves evidence of malignancy.
Most cutaneous lesions with “ghost” cells will behave
in a benign fashion, regardless of the number of mitotic
figures. Therefore, the main feature that will help in
differentiating between them will be the low-power architecture.
Nodular, circumscribed lesions should be
considered as benign, whereas infiltrative lesions may
recur or, rarely, metastasize.
Basal cell carcinoma
Basal cell carcinoma (BCC) is the most common malignant
neoplasm, not only in the skin but also in the
body. BCC is a malignant tumor that may cause severe
tissue destruction and even death when vital structures

48
ATTI CONGRESSUALI
(brain, heart) are involved. In addition, rare BCC have
resulted in distant metastasis. BCC mainly occurs on
sun-exposed skin in elderly individuals, in general in
any hair-bearing area. The main etiologic factor is prolonged
exposure to radiation.
The most common appearance is that of a nodule
usually ulcerated (“ulcus rodens”). Some lesions may
contain melanin pigment, infiltrate deep in the dermis
or subcutaneous tissue (infiltrating pattern), extend
over relatively large areas in the skin (superficial pattern),
or protrude the skin surface (fibroepitheliomalike).
There are six main histologic criteria to diagnose BCC:
basaloid cells, peripheral palisade, mitotic figures,
apoptotic bodies, myxoid stroma, and peritumoral clefting.
BCCs with superficial pattern grow as nests attached
to the epidermis. The nodular pattern has nests of
different sizes, at least focally detached from the epidermis
and involving the reticular dermis. The fibroepitheliomatous
pattern is defined as a relatively polypoid
growth of basaloid cells forming interconnecting
cords and trabeculae within a relatively edematous
stroma. The two most important patterns indicating a
greater potential for locally aggressive behavior are infiltrative
and micronodular. The former is also called
sclerodermoid, morpheaform, or “aggressive”, in which
the basaloid cells form either nests with an irregular,
spiky configuration or else narrow cords of around two
cells in thickness within a markedly fibrous stroma.
The micronodular pattern has small nests of basaloid
cells (smaller than a medium vessel ~ 0.2 mm).
Another variant apparently associated with a more aggressive
behavior is the BCC with eccrine differentiation.
Such lesions show focal duct formation in the
context of a classic BCC.
Other less common patterns include pigmented BCC
(with melanophages in the stroma or dendritic melanocytes
within the epithelium) and BCC with focal
squamous differentiation. We prefer to leave the term
metatypical or basosquamous carcinoma for other areas
of pathology.
The differential diagnosis with trichoepithelioma/trichoblastoma
is discussed above. Various basaloid neoplasms
occur in nevus sebaceus of Jadassohn, but only
some of which fully meet criteria for BCC. Lesions resembling
a superficial pattern of BCC commonly occur
as an inductive phenomenon in the epidermis overlying
a dermatofibroma.
Malignant eccrine poroma (eccrine
porocarcinoma)
This malignant tumor may arise de novo or within a
long-standing eccrine poroma. Mostly as a single nodule,
with ulceration, on the distal lower extremities.
Eccrine duct adenocarcinoma is the generic term for
cutaneous adenocarcinomas, not otherwise identified,
which involve the dermis and subcutaneous tissue.
The diagnosis is relatively easy for those cases arising
within an eccrine poroma; such lesions have two distinct
areas: benign proliferation of basaloid cells and clear
cells (eccrine poroma) associated with an area composed
of pleomorphic keratinocytes with numerous mitotic figures
and necrosis, infiltrating the dermis and involving
the overlying epidermis in a pagetoid manner. Ducts can
usually be identified within the tumor. Some lesions have
squamous cell differentiation. The stroma may be fibrous,
hyalinized, or myxoid. Immunohistochemical studies
may help confirming the presence of eccrine ducts
within the tumor nests (CEA positive).
Around 10% of these lesions may metastasize to the
skin, lymph nodes, or internal organs. A number of these
cases have been studied by sentinel lymphadenectomy.
For these cutaneous metastases, the tumor cells
may involve the dermis and epidermis, thus resembling
a primary lesion.
Sebaceous carcinoma can also have pagetoid extension
in the epidermis. Most of such cases will have at least
focal sebaceous differentiation with nuclear scalloping.
Tricholemmal carcinoma also has clear cells, but lacks
eccrine ducts and may show trichohyaline granules.
Eccrine papillary adenoma/aggressive
digital papillary
adenoma – adenocarcinoma
These are solitary lesions, on middle-aged individuals,
on the distal extremities. Up to 50% of the lesions occurring
on the hands and feet may develop distant metastasis.
Usually well circumscribed, symmetrical, composed of
lobules of epithelial cells arranged in tubular structures
with a double layer of myoepithelial cells (cuboidal,
clear cytoplasm) and secretory cells (eosinophilic cytoplasm
with cuticle); some of these structures contain
papillae with central fibrovascular cores.
A group of neoplasms with similar histology but occurring
on the hands and feet have been denominated aggressive
digital papillary lesions. These lesions may recur
and metastasize. Most authors consider that all papillary
tumors arising in the hands and feet should be
designated as aggressive digital papillary adenocarcinoma
and be completely excised.
Microcystic adnexal carcinoma
(sclerosing sweat duct adenocarcinoma)
This is a solitary lesion, on middle-aged individuals, on
the upper lip or around the mouth, presenting as a deeply
infiltrative plaque. The lesion has a high recurrence
rate so it requires complete surgical excision.
Histologically it is a poorly circumscribed dermal tumor
that frequently extends into the subcutis (and skeletal
muscle). There usually are two components. The
superficial one has basaloid keratinocytes arranged in

ATTI CONGRESSUALI
49
nests with a central lumen filled with keratin. The second,
deeper component, has ducts and gland-like
structures with a one- or two-celled lining. The cells
are mainly cuboidal, with slightly hyperchromatic nuclei.
Marked pleomorphism, prominent nucleoli, or
evident mitotic figures are uncommon. Perineural invasion
is frequent. Immunohistochemical studies confirm
the presence of glandular differentiation in the cells lining
the deep lumina, as shown by CEA expression.
Regarding the differential diagnosis, the presence of
both keratin-filled cysts and eccrine glands rules out
desmoplastic trichoepithelioma and syringoma. Since
this finding is only obvious when the entire lesion is
examined, any syringomatous or trichoepitheliomalike
lesion involving the deep margin and located
around the mouth should probably be completely excised.
Eccrine adenocarcinoma, not otherwise specified,
lacks the superficial component with keratin-filled
cysts and shows significant cytologic atypia and
mitotic figures.
Mucinous adenocarcinoma
This is a rare, solitary lesion, on middle-aged and elderly
individuals, on any location but with a predilection
to involve the eyelids. Slowly growing, deeply infiltrative
plaque.
Mucinous adenocarcinoma is a poorly circumscribed
dermal tumor that frequently extends into the subcutis
(and skeletal muscle). It is composed by ducts lined by
a single layer of hyperchromatic and pleomorphic
epithelial cells with abundant cytoplasm and extensive
extracellular mucin. This mucin is positive with alcian
blue, colloidal iron, and PAS. Mitotic figures are common.
Perineural invasion is frequent. Tumor cells express
low-molecular-weight cytokeratin, epithelial
membrane antigen, and carcinoembryonic antigen.
Estrogen and progesterone receptors and GCDFP15 expression
are also commonly expressed. According to
analysis of enzymes, tumors with this morphology may
have either eccrine or apocrine differentiation.
The main differential diagnosis is with mucinous adenocarcinoma
metastatic to the skin. The two most common
origins are the breast and the gastrointestinal tract.
Due to the similarities in morphology and immunohistochemical
features, clinico-pathologic correlation is
essential in establishing the correct diagnosis.
Sebaceous adenoma/sebaceous
carcinoma
These are lesions typically associated with Muir-Torre
syndrome (see below). They are usually a raised papule
or nodule, slightly firm, yellow.
Sebaceous adenomas are usually solid or cystic lesions,
characterized by a well-circumscribed growth
of partially differentiated sebaceous lobules, of irregular
size and shape. Two types of cells are present:
basaloid (cuboidal, basophilic cells, similar to those
seen at the periphery of normal sebaceous lobules)
and sebocytes. The latter display a vacuolated cytoplasm
due to the large amount of cytoplasmic lipids.
These vacuoles surround and impinge a central nucleus
(“scalloping”). Depending on the relative proportion
of basaloid cells and sebocytes, these lesions
are called sebaceous epithelioma (predominance of
basaloid cells) or sebaceous adenoma (predominance
of sebocytes).
In the last years there has been controversy over the
classification of sebaceous adenomas. It has been proposed
that all sebaceous neoplasms should be classified
as carcinomas. In our opinion it is possible to distinguish
between most benign (adenomas) and malignant
sebaceous neoplasms (carcinomas) when applying
standard histologic features: circumscription, absence
of necrosis, and paucity of mitotic figures support a
diagnosis of sebaceous adenoma while infiltrative lesions
with tumor necrosis and abundant mitotic figures
may behave aggressively, with development of recurrences
and metastases.
Some pathology features seem to be associated with
poor prognosis: large tumor size, minimal lymphocytic
infiltrate, vascular invasion, orbital extension, high cytologic
grade, infiltrative growth so they should be included
in the pathology report.
Well-differentiated sebaceous carcinomas may be cytologically
identical to sebaceous adenomas. The key to
distinguishing such lesions is the ability to examine the
deep edge of the tumor; sebaceous carcinomas usually
display an infiltrative rather than pushing pattern of
growth. We have examined lesions of extremely welldifferentiated
sebaceous glands diffusely infiltrating
the subcutaneous tissue.
Sebaceous carcinomas in periocular location have a
propensity for epidermotropic spread and therefore
extramammary Paget disease and malignant melanoma
may enter into the differential diagnosis. Apart
from the typical differences in anatomic location, unlike
most lesions of Paget disease sebaceous carcinoma
lacks expression of carcinoembryonic antigen
(CEA) and gross cystic disease fluid protein
(GCDFP15). Unlike melanoma, S100, MART-1, tyrosinase
and gp100 (with HMB45) are not expressed by
sebaceous carcinoma.
Regarding sebaceomas, we share the opinion of many
authors that they may correspond to BCC with sebaceous
differentiation. The important point to remember
is that these lesions may be associated with the Muir-
Torre syndrome.
In addition to basal cell carcinoma, sebaceous differentiation
can be seen in seborrheic keratosis, verruca vulgaris,
and mixed tumors (chondroid syringoma). Dermatofibromas
can have prominent sebaceous glands attached
to the overlying epidermis.

50
ATTI CONGRESSUALI
Apocrine mixed tumor
(apocrine chondroid syringoma)
This is a relatively rare lesion, most common on the
head and neck, in middle-aged and elderly individuals,
slightly more frequent on men. Apocrine mixed tumor
presents as a dermal or subcutaneous nodule, up to 3
cm in diameter.
Apocrine mixed tumors are well-circumscribed lesions
occupying the dermis and, less commonly, the subcutis.
The hallmark of all mixed tumors is the combination of
both epithelial and mesenchymal components. Mixed tumors
have lobules of epithelial cells arranged in nests and
branching cords, and ducts with at least focal apocrine secretion.
The intervening stroma has areas with fibrous,
myxoid, and chondroid tissue. Some lesions may have
squamous or sebaceous differentiation. Immunohistochemical
studies confirm that these lesions contain both
epithelial and myoepithelial cells. The chondroid areas
express collagen type II and the protein BM1, which are
present in mature cartilage. The myoepithelial cells are
specialized cells located close to the basement membrane
of eccrine and apocrine glands and have features of both
epithelial (desmosomes, keratin filaments) and muscle
cells (subplasmalemmal bodies, actin filaments).
Some mixed tumors with an infiltrative pattern of
growth and conspicuous mitotic figures have been designated
“atypical mixed tumors”.
Myoepitheliomas are cutaneous neoplasms composed
of a stroma very similar to that seen in mixed tumor but
lack the epithelial component. It is our opinion that
chondroid syringoma and myoepithelioma are just ends
of a spectrum of lesions with different degrees of
epithelial and myoepithelial differentiation. In those lesions
from the cheek, it is very important to rule out the
possibility of a parotid mixed tumor (pleomorphic adenoma)
with secondary involvement of the overlying
skin. Due to their deep involvement, such parotid-based
lesions require specialized surgical treatment and
complete extirpation.
Extramammary Paget disease
Paget disease in general is defined as an intraepidermal
involvement of adenocarcinoma. Here we will study
only the extramammary form. The cell of origin of extramammary
Paget disease (EPD) is still unknown. Immunohistochemical
studies suggest the Toker cells (large
intraepidermal, epithelial cells with clear cytoplasm)
and Bartholin glands (perivulvar glands) (see below).
The most common location is the anogenital region,
followed by the axilla. It occurs mainly in elderly individuals
as red, pruritic, eczematous-appearing patches
and plaques, with peripheral growth.
The main histologic feature in all types of Paget disease
is the diffuse infiltration of the epidermis by large, round
cells with hyperchromatic, pleomorphic nuclei and
usually prominent nucleoli. Mitotic figures may be seen.
The cells are arranged as single units or small, irregular
nests, without a tendency to be located at the base, but
rather at all levels of the epidermis. As with other cells
populating the epidermis, Paget cells may contain melanin
pigment that has been transferred from surrounding
melanocytes. Primary, and most secondary, EPD cases
display features of adenocarcinoma: intracytoplasmic
mucin can be detected with the PAS/diastase or with the
mucicarmine/Alcian blue techniques. A minority of cases
not classifiable as adenocarcinomas, such as those
secondary to urinary bladder or urethra carcinomas, will
fail to reveal cytoplasmic mucin.
There are several intraepidermal lesions characterized
by diffuse involvement with large, epithelioid cells at
all layers of the epidermis (pagetoid extension). The
main differential diagnosis is with melanoma and squamous
cell carcinoma (Bowen disease). As mentioned
above, Paget cells may contain melanin pigment, so
immunohistochemical studies may be very important in
establishing the correct diagnosis. Melanoma cells in
the epidermis almost invariably express, in addition to
S100 protein, gp100 (with HMB45), MART1, and tyrosinase.
Squamous cell carcinoma cells express lowand
high-molecular-weight keratins. A very important
finding is the presence of keratohyaline granules in the
atypical cells; that feature is present only in keratinocytes,
not melanoma or Paget cells. Another differential
diagnosis, primarily on the breast, is with Toker
cells. These are large cells with clear cytoplasm, located
at all levels of the epidermis. Similar to EPD, Toker
cells express CK7, low molecular weight cytokeratin,
MUC1, and MUC5AC. In contrast with EPD, Toker
cells show small, uniform nuclei with inconspicuous
nucleoli. Most primary EPD express CK7 but not
CK20, in contrast with EPD secondary to colorectal or
urinary neoplasms, which usually express CK20.
Adenoid cystic carcinoma
This very rare tumor is most commonly observed on
the scalp and trunk. This lesion is identical to that seen
in the salivary glands: cords and nests of basaloid cells
with cribriform pattern leaving mucinous areas. Wellformed
glands are not prominent. A hallmark is the exquisite
degree of perineural invasion, which probably
explains the high rate of recurrence (20%).
Systemic syndromes associated
with adnexal neoplasms
GARDNER SYNDROME
Gardner syndrome is a variant of familial adenomatous
polyposis, an autosomal dominant disease due to mutations
in the Adenomatous Polyposis Coli gene (APC)
characterized by gastrointestinal polyps (in colon, stomach,
and upper small intestine), multiple osteomas,

ATTI CONGRESSUALI
51
congenital hypertrophy of retinal pigmented epithelium
(CHRPE), and skin and soft tissue tumors. Cutaneous
findings include follicular cysts (infundibular type,
with focal ghost cells or focal parakeratosis) and desmoid
tumors. Since the gastrointestinal polyps have a
very high risk of becoming malignant, early identification
of the disease is critical.
XERODERMA PIGMENTOSUM
These patients have impaired ability to repair the damage
induced by ultraviolet radiation to the DNA, due
to deficient function of the nucleotide excision repair.
There are at least 7 genes associated with a DNA-polymerase
(XP-A to XP-G) and a different gene named XP
variant (XP-V). These patients show from early age severe
actinic damage with mottled cutaneous pigmentation
and malignancies, including BCC, squamous cell
carcinoma, and melanoma.
NEVOID BASAL CELL CARCINOMA SYNDROME AND
ASSOCIATED DISEASES
The nevoid BCC syndrome (also known as the basal
cell nevus and Gorlin syndrome) is an autosomal dominant
disease. These patients show between hundreds
and thousands of papules and nodules, even before puberty.
While the patients grow older, the lesions increase
in size and number and may behave as aggressively
as standard BCC. In contrast with classic BCC, many
of these patients show basaloid tumors (“pits”) in the
palms and soles. In addition to the BCC, patients with
basal cell nevus syndrome have a characteristic facies
including frontal bossing and may show numerous follicular
cysts, skeletal lesions (odontogenic keratocysts
of the jaws, anomalies of the ribs, and scoliosis) mental
retardation, medulloblastoma, and calcification of
the falx cerebri. Very rarely, lesions similar to those of
the basal cell nevus syndrome may be limited to an area
of the skin (linear unilateral basal cell nevus); however,
these lesions usually do not become full blown BCCs.
The autosomal dominant Bazex syndrome has dermal
atrophy with widened follicular openings like “ice-pick
marks” and multiple basal cell carcinomas on the face.
There may be also localized or generalized hypohidrosis,
and congenital hypotrichosis on the scalp.
COWDEN SYNDROME
This syndrome is inherited as an autosomal dominant
trait involving the PTEN/MMAC1 gene (chromosome
10q), with multiple organ involvement, including tricholemmomas,
oral papillomatosis, gastrointestinal
polyp and carcinoma, thyroid goiter and carcinoma, fibrocystic
disease/gynecomastia, leukemia and lymphoma.
Also, some patients with sclerotic fibromas can
present with Lhermitte-Duclos disease (dysplastic cerebellar
gangliocytoma).
MUIR-TORRE SYNDROME
Muir-Torre syndrome is characterized by cutaneous
and visceral neoplasms, usually gastrointestinal carcinomas
and polyps, but also laryngeal, genitourinary,
and hematolymphoid neoplasms. Most patients present
with cutaneous neoplasms, including various sebaceous
lesions, keratoacanthomas (with sebaceous differentiation),
and follicular cysts. Some reports indicate
that the sebaceous carcinomas occurring in patients
with Muir-Torre syndrome behave in a less aggressive
fashion than the sporadic ones. Genetic studies have revealed
mutations involving DNA mismatch-repair genes,
similar to those seen in hereditary non-polyposis
colorectal cancer families (hMSH2/hMLH1). In summary,
since a significant number of patients with sebaceous
skin neoplasms are at risk of internal malignancies,
they should be evaluated clinically for Muir-Torre
syndrome and this possibility should be stated in the
pathology report.
References
Bettencourt MS, Prieto VG, Shea CR. Trichoepithelioma: a 19-year
clinicopathologic re-evaluation. J Cutan Pathol 1999;26:398-404.
Burgdorf WHC, Pitha J, Fahmy A. Muir-Torre syndrome. Histologic
spectrum of sebaceous proliferations. Am J Dermatopathol
1986;8:202-8.
Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus:
A study of 596 cases. J Am Acad Dermatol 2000;42:263-
8.
Diaz de Leon E, Carcangiu ML, Prieto VG. Extramammary Paget
disease is characterized by the consistent lack of estrogen and progesterone
receptors but frequently expresses androgen receptor. Am
J Clin Pathol 2000;113:572-5.
Duke WH, Sherrod TT, Lupton GP. Aggressive digital papillary adenocarcinoma
(aggressive digital papillary adenoma and adenocarcinoma
revisited). Am J Surg Pathol 2000;24:775-84.
Folpe AL, Reisenauer AK, Mentzel T, Rutten A. Solomon AR. Proliferating
trichilemmal tumors: clinicopathologic evaluation is a guide
to biologic behavior. J Cutan Pathol 2003;30:492-8.
Hartschuh W, Schulz T. Merkel cells are integral constituents of desmoplastic
trichoepithelioma: an immunohistochemical and electron
microscopic study. J Cutan Pathol 1995;22:413-21.
Kirchmann TT, Prieto VG, Smoller BR. Use of CD34 in assessing
the relationship between stroma and tumor in desmoplastic keratinocytic
neoplasms. J Cutan Pathol 1995;22:422-6.
Kruse R, Rutten A, Lamberti C. Muir-Torre phenotype has a frequency
of DNA mismatch-repair-gene mutations similar to that in
hereditary nonpolyposis colorectal cancer families defined by the
Amsterdam criteria. Am J Hum Genet 1998;63:63-70.
Kuan SF, Montag AG, Hart J, Krausz T, Recant W. Differential expression
of mucin genes in mammary and extramammary Paget’s disease.
Am J Surg Pathol 2001;25:1469-77.
Machin P, Catasus L, Pons C. Microsatellite instability and immunostaining
for MSH-2 and MLH-1 in cutaneous and internal tumors
from patients with the Muir-Torre syndrome. J Cutan Pathol
2002;29:415-20.
Mentzel T, Requena L, Kaddu S, Soares de Aleida LM, Sangueza
OP, Kutzner H. Cutaneous myoepithelial neoplasms: clinicopathologic
and immunohistochemical study of 20 cases suggesting a continuous
spectrum ranging from benign mixed tumor of the skin to cutaneous
myoepithelioma and myoepithelial carcinoma. J Cutan
Pathol. 2003;30:294-302.
Narisawa Y, Kohda H. Cutaneous cysts of Gardner’s syndrome are
similar to follicular stem cells. J Cutan Pathol 1995;22:115-21.
Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect.
J Am Acad Dermatol 1995;33:90-104.

52
ATTI CONGRESSUALI
Neuroendocrine Tumors of the Lung
CESAR A. MORAN, M.D.
Primary neuroendocrine tumors of the lung encompass
a variety of lesions, which for many years have been
the subject of intense study in an attempt to provide clinical
parameters, which may help clinically in predicting
outcome in these tumors. Although for many years,
there appeared to be a reasonable agreement regarding
the classification of these tumors, more recently there
have been some changes in the histopathologic criteria
in order to classify these tumors. Nevertheless, controversy
still exists and very likely it will remain for the
foreseeing future. In addition, in some cases the diagnostic
criteria are not quite define and the diagnosis
can be made only with the use of immunohistochemical
studies or electron microscopy. Although the idea
has been to provide a clear understanding and definition
for these tumors, great confusion has been generated
regarding classification and criteria for diagnosis.
Herein we will review the current status of the classification
of neuroendocrine tumors of the lung making in
addition a historical review of previous terms used in
the literature.
Classification and criteria for diagnosis
In 1907 Obendorfer introduced the term “Carcinoid”
by separating a group of tumors in the small intestine,
which behave better than conventional carcinomas 1 .
Years later, Gosset and Masson suggested that “carcinoid
tumors” derived from Kulchitsky cells by demonstrating
the presence of argentaffin granules in tumor
cells 2 . However, it became evident that similar tumors
were also present in other locations outside of the gastrointestinal
tract. One of the first classifications of
this type of tumors was the one proposed by Williams
and Sanders who classified “Carcinoids” by anatomic
site into: foregut, midgut, and hindgut with their respective
hormonal associations 3 .
Those previously mentioned reports and classification
although very important did not include cytomorphologic
features of the tumor. It was not until a few decades
later that cytomorphological features were assessed
and presented as a component to predict behavior in
those tumors. Interestingly, even in earlier reports in
which morphological parameters were taken into account,
those parameters were drawn from tumors arising
in the respiratory tract, namely in the bronchus.
One of the earliest descriptions in which morphological
features were stressed was presented by Engelbreth-
Holm 4 , who essentially laid the basis for what later on
was described as “Atypical Carcinoid”. In Engelbreth-
Holm’s report, the tumors were described as showing:
variability in size and shape, presence of mitosis, polymorphous
nucleolar configuration, and absence of metastasis.
Von Albertini 5 also presented similar findings
and separated those tumors into: Carcinoid type and
Oat cell type. Needless to say, even in those earlier publications
there were already some controversial issues
regarding the proper histopathologic classifications of
these tumors. Further studies addressing whether histopathological
parameters correlate with behavior have
generated controversy 6-8 .
In 1972 Arrigoni et al. 9 presented a series of cases with
similar histopathological features as those previously
described under “carcinoid tumor,” but noted some histopathological
differences namely in terms of mitotic
activity, nuclear pleomorphism, and necrosis. Based on
those differences the term “Atypical Carcinoid” was
embraced for similar tumors. Despite the criteria set
forward by Arrigoni et al. 9 , similar studies of “atypical
carcinoids” have differed mainly in the number of mitotic
figures that are allowed in these neoplasms 10 .
However, one important aspect in separating such tumors
has been the designation in the biologic behavior
of those tumors, which places “Atypical Carcinoid” in
an intermediate category between conventional carcinoid
and small cell carcinoma. The recognition of
“Atypical Carcinoid” allowed separating neuroendocrine
tumors in mainly three entities: conventional carcinoid,
atypical carcinoid, and small cell carcinoma and
for many years that has become the conventional classification
of these tumors. In 1983, Gould et al. 11 presented
a new classification with the objective of ridding
the nomenclature of the term “carcinoid”. Such
classification proposed a four-stage system for the classification
of neuroendocrine tumors and although interesting,
it did not fulfill their specified goal. However,
one important aspect of this new approach was the separation
of these tumors in a four-stage category. On
the other hand, the authors also stated that not all small
cell carcinomas are neuroendocrine and that one should
make an effort in separating those that are neuroendocrine
and those that are not neuroendocrine. A couple
of years later, Warren et al. 12 proposed that the terms
oat cell carcinoma, small cell anaplastic carcinoma,
and small cell undifferentiated carcinoma be discarded
and replaced by the term small cell neuroendocrine carcinoma
when the appropriate features are present. A
different proposal was presented by Paladugu 13 who
stated that carcinoid and small cell carcinoma belong to
the same family of Apudomas arising from the bronchopulmonary
Kulchitsky cells. Thus, the author suggested
using the term Kulchitsky cell carcinoma (KCC)
grade 1-3 for carcinoid, atypical carcinoid and small
cell carcinoma. One interesting aspect of this proposal
is the concept of considering all these neoplasms as
carcinomas. However, it recognizes only a three-stage
system. Due to the controversy generated by the diffe-

ATTI CONGRESSUALI
53
rent classification schemes, the Pathology Committee
of the International Association for the Study of Lung
Cancer reiterated the criteria for the histopathologic
diagnosis of small cell carcinoma and concluded that
the term small cell carcinoma includes tumors previously
designated as intermediate and oat cell subtype 14 .
Up to this point, most pathologists felt confident that
this family of tumors had three major components and
reports addressing the importance of separating these
tumors into three major categories with their respective
clinical behavior were presented 15 .
In 1991, Travis et al. 16 presented a study of 35 cases of
neuroendocrine tumors in which a new term was introduced,
that of “Large cell neuroendocrine carcinoma”
which in turn also lead to a four-stage classification system.
However, at that time the authors concluded that
large cell neuroendocrine carcinoma belonged to an intermediate
stage between atypical carcinoid and small
cell carcinoma. This new term introduced by Travis et
al. 16 might be similar to that described by Gould 11 under
the designation of Bronchopulmonary neuroendocrine
carcinoma of intermediate size cell type. On the other
hand, other studies on atypical carcinoid have used much
different criteria namely in the number of mitotic figures
allowed in order to make that diagnosis 17 . What is
more interesting is that a study of 40 cases evaluating
the reproducibility of neuroendocrine tumors based on
the classification proposed by Travis et al. 16 involving
five pulmonary pathologist only yielded a 55% of unanimous
agreement 18 . In that study the most common
disagreement was with large cell neuroendocrine carcinoma.
Although it is expected to find disagreements
with any classification system, the fact that large cell
neuroendocrine carcinoma was confused with atypical
carcinoid and small cell carcinoma, denotes a lack of
clarity in the concept of this particular entity. Interestingly,
in 1995 a European Group 19 presented a new
classification of neuroendocrine tumors in which the
tumors were divided into three separate categories ranging
from benign or low to high-grade tumors. A draw
back to this view is the fact that conventional carcinoids
were included into the benign or low-grade category
and atypical carcinoids into the low-grade category,
thus leading to some confusion. In addition, Dressler
et al. 20 presented a study of 40 patients with large
cell neuroendocrine carcinoma in which the authors
concluded that the identification of neuroendocrine differentiation
in lung carcinoma by itself portends a poor
prognosis.
One of the latest attempts to clarify the issue of neuroendocrine
carcinomas is the one presented by Travis
et al. 21 in a study of 200 cases. In this study, the authors
concluded that mitotic counts were the only independent
predictor of prognosis. Interestingly, the previous
mitotic criterion used to diagnosed atypical carcinoid
was changed from 10 mitosis x 10 HPF to more than 2
x 10 HPF. In the same study, the authors also reaffirmed
the concept of a four-way classification system and stated
that the survival for large cell neuroendocrine carcinoma
was not different than the one of small cell carcinoma.
One important issue to keep in mind with this
entity (Large Cell Neuroendocrine Carcinoma) is the
fact that it is not a light microscopic diagnosis. The use
of neuroendocrine markers (chromogranin, synaptophysin,
etc.) and/or positive evidence of neuroendocrine
differentiation by electron microscopy are required.
Thus, the use of only light microscopy in the evaluation
of large cell neuroendocrine carcinoma is not
enough.
The last attempt in classifying these tumors is the one
presented by Huang et al. 22 . The authors reviewed 234
cases of neuroendocrine tumors and presented a subclassification
that separates these tumors into five categories.
Although the authors used the well, moderately
and poorly differentiated classification system, the
terms vary considerably. The well-differentiated neuroendocrine
carcinoma corresponds to the carcinoid tumor;
the moderately differentiated neuroendocrine carcinoma
corresponds to the atypical carcinoid; however,
the poorly differentiated carcinoma corresponds to the
same atypical carcinoid but one with increased mitotic
activity (> 10 mitosis per 10 hpf). The authors include
the terms undifferentiated large cell neuroendocrine
carcinoma for the tumor known as large cell neuroendocrine
carcinoma; and, undifferentiated small cell
neuroendocrine carcinoma for the one known as small
cell carcinoma.
Prognosis
Based on the published literature on the subject, it is
evident that there is definitely a spectrum of neuroendocrine
tumors in the lung. This spectrum can be summarized
in three main categories: low grade, intermediate
grade, and high-grade tumors. Conventional carcinoid
represents the best differentiated of these neoplasms
and its prognosis after complete resection appears
to be good 23 24 . Nevertheless, about 15% of these
tumors give rise to metastasis, thus, it is not entirely
correct to label them as benign tumors. On the other
hand, atypical carcinoids have been consistently shown
to have a survival rate of 56% and 35% after 5 and 10
years respectively 21 . Small cell carcinoma and large
cell neuroendocrine carcinoma have invariably bad
prognosis.
Critical comment
The controversy surrounding the classification of neuroendocrine
tumors is most likely to be debated for some
time to come. Some of the most difficult issues included
the continue use of the term “carcinoid” and the
new descriptions of tumors with neuroendocrine differentiation.
A more practical approach would be to use
the three-way system of low, intermediate, and high
grade tumors and that the corresponding histologies be

54
ATTI CONGRESSUALI
placed into that framework. In addition, other clinical
aspects such as the clinical staging of the tumor at the
time of diagnosis cannot be overemphasized. As it is
currently diagnosed, the possibility of over diagnosing
“atypical carcinoid” is very likely, namely because of
the strict mitotic count. On the other hand, it is interesting
that most of the classifications presented, namely
the most recent ones, seem to be based on complete
surgical resections. This latter issue becomes critical
when evaluating bronchial biopsies. Thus, the used of a
more generic terminology such a neuroendocrine carcinoma
will lend itself for better communication and understanding
of the problem.
References
1
Obendorfer S. Frankfurt Z. Karzinoide tumoren des duenndarms.
Pathol 1907;1:426-30.
2
Gosset A, Masson P. Tumeurs endocrines de l’appendice. Pr Med
1914;22:37-40.
3
Williams ED, Sander M. The classification of carcinoid tumours.
Lancet 1963;2:238-9.
4
Engebreth-Holm J. Benign bronchial adenomas. Acta Chir Scand
1945;90:383-5.
5
Von Albertini A. Pathologisch-anatomisches Kurzreferat zum
Thema Lungenkrebs. Schweiz Med Wochenschr 1951;81:659-63.
6
Goodner JT, Berg JW, Watson WL. The non-benign nature of
bronchial carcinoids and cylindromas. Cancer 1961;14:539-45.
7
Markel SF, Abell MR, Haight C, French AJ. Neoplasms of bronchus
commonly designated as adenomas. Cancer 1964;17:590-
605.
8
Smith RA. Bronchial carcinoid tumors. Thorax 1969;24:43-7.
9
Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors
of the lung. J Thorac Cardiovasc Surg 1972;64:413-21.
10
Mill SE, Walker AN, Cooper PH, Kron IL. Atypical carcinoid tumor
of the lung. A clinicopathologic study of 17 cases. Am J Surg
Pathol 1982;6:643-54.
11
Gould VE, Linnoila RI, Memoli VA, Warren WH. Neuroendocrine
cells and neuroendocrine neoplasms of the lung. Pathol Annu
1983;18:287-330.
12
Warren WH, Gould VE, Faber PL, Kittle FC, Memoli VA. Neuroendocrine
neoplasms of the bronchopulmonary tract. J Thorac
Cardiovasc Surg 1985;89:819-25.
13
Paladugu RR, Benfield JR, Pak HY, Ross RK, Teplitz RL. Bronchopulmonary
kultchizky cell carcinoma. A new classification
scheme for typical and atypical carcinoids. Cancer
1985;55:1303-11.
14
Hirch FR, Matthews MJ, Aisner S. Histopathologic classification
of small cell lung cancer. Changing concepts and terminology.
Cancer 1988;62:973-7.
15
Grote TH, Macon WR, Davis B, Greco FA, Johnson DH. Atypical
carcinoid of the lung. A distinct clinicopathologic entity. Chest
1988;93:370-5.
16
Travis WD, Linnoila RI, Tsokos MG. Neuroendocrine tumors of
the lung with proposed criteria for large cell neuroendocrine carcinoma.
An ultrastructural, immunohistochemical, and flow cytometric
study of 35 cases. Am J Surg Pathol 1991;15:529-53.
17
Valli M, Fabris GA, Dewar A, Hornl D, Sheppard MN. Atypical
carcinoid tumour of the lung: a study of 33 cases with prognostic
features. Histopathology 1994;24:363-9.
18
Travis WD, Gall AA, Colby TV. Reproducibility of neuroendocrine
lung tumor classification. Hum Pathol 1998;29:272-9.
19
Capella C, Heitz PU, Hofler H, Solcia E, Kloppel G. Revised
classification of neuroendocrine tumours of the lung, pancreas
and gut. Virch Arch 1995;425:547-60.
20
Dresler CM, Ritter JH, Patterson GA, Ross E, Bailey MS, Wick
MR. Clinical-pathologic analysis of 40 patients with large cell
neuroendocrine carcinoma of the lung. Ann Thorac Surg
1997;63:180-5.
21
Travis WD, Rush W, Flieder DB. Survival analysis of 200 pulmonary
neuroendocrine tumors with clarification of criteria for
atypical carcinoid and its separation from typical carcinoid. Am
J Surg Pathol 1998;22:934-44.
22
Huang Q, Muzitansky A, Mark EJ. Pulmonary neuroendocrine
carcinomas: A review of 234 cases and a statistical analysis of 50
cases treated at one institution using a simple clinicopathologic
classification. Arch Pathol Lab Med 2002;126:545-53.
23
Schreurs JM, Westermann JJ, van den Bosch JMM. A twenty-five
year follow-up of ninety-three resected typical carcinoid tumors
of the lung. J Thorac Cardiovasc Surg 1992;104:1470-5.
24
Wilkins EW, Grillo HC, Moncure AC, Scannell JG. Changing times
in surgical management of bronchopulmonary carcinoid tumor.
Ann Thorac Surg 1984;38:339-44.

ATTI CONGRESSUALI
55
Pleural Mesothelioma and its Mimickers
CESAR A. MORAN, M.D.
Malignant mesothelioma
Primary malignant tumors of the pleura are in general
dominated by malignant mesothelioma. Not only it is
the most common malignant tumor in the pleura but also
the one that poses more difficulty in the diagnosis.
Due to its legal implications and its varied histopathological
appearance, mesotheliomas have been the
subject of extensive studies. Interestingly, malignant
mesotheliomas are unusual tumors and it has been estimated
that their incidence in the United States is of approximately
3 to 7 cases per million persons in the population
per year. Although mesotheliomas have been
associated to the exposure of asbestos fibers, approximately
50% of individuals affected by mesotheliomas
do not disclose an asbestos exposure, leading to believe
that their etiopathology may be a multifactorial one
and not one limited to the exposure of asbestos fibers.
However, those cases in which there is an association
with the exposure to asbestos are the ones that generally
gain more attention because are the ones that are
usually followed by legal counsel.
In general mesotheliomas are more common in adult
individuals over 50 years of age. In those cases in which
the tumor is associated with asbestos, the patient had
been exposed for over 15 years to the asbestos fibers.
The stated latency period for asbestos in mesothelioma
is of 15 to 60 years, thus, it would be very unusual to
find a case in which the tumor is linked to asbestos in a
patient with only a few years of exposure. One other
debated issue is the type of asbestos fibers that produce
mesotheliomas, arguments against some fibers as
non-carcinogenic have been made. This latter, issue is
one usually brought up in court by the legal system attempting
to defend a particular exposure to asbestos fibers.
In this review, we will not get into that issue and
will reserve it to the legal establishment. Nevertheless,
a documented history of asbestos exposure of more
than 15 years is a powerful argument in favor of linking
asbestos and mesothelioma in a particular case. What is
more interesting is the fact that mesotheliomas, as stated
before, can occur in the setting of a negative history
of asbestos exposure, and examples of it, are the cases
that have been described in children and women (house-wives).
Other possible etiopathologic causes in the
development of mesothelioma includes radiation, chronic
inflammation, viral infections, and diethylstilbestrol.
However, some of those associations are to some
extend easier to establish by clinical means.
Clinical features
Clinical and radiological information play a highly important
role in the diagnosis of mesothelioma. Ignoring
clinical and radiological information may conduce to
an erroneous diagnosis even by the most experienced
pathologist. History of longstanding exposure to asbestos
whether factual or not, should lead to a careful
analysis of a particular biopsy material from a particular
individual. However, one of the most important
aspects in the diagnosis of mesothelioma is the radiological
evaluation. Either a plain chest radiograph or more
sophisticated studies such as computerized tomography
is an important tool in the evaluation of a possible
case of mesothelioma. In cases in which a question
of mesothelioma arises, one should inquire in the
following aspects:
• Diffuse involvement of the pleura (studding by nodules);
• Intraparenchymal tumor nodules or masses (peripheral);
• Diffuse thickening of the pleura;
• Encasement of the lung;
• Unilateral or bilateral pleural involvement;
• Pleural base tumor mass.
A careful analysis of the radiological studies with the
appropriate material for histopathological evaluation
should lead both clinicians and pathologists to seek the
necessary tools in order to arrive at a more specific diagnosis.
In this regard, many times the clinical and radiological
aspects of the cases are clear but the available
material for histopathological examination is not
adequate. In such circumstances, one should not make
a definitive diagnosis but rather raise the level of suspicion
and request additional material if clinically indicated.
Part of this rationale is the fact that the surgical
treatment for cases of mesothelioma can be extreme,
thus, it is imperative for a pathologist to be absolutely
sure about the diagnosis. Furthermore, it is well
known that there are other pleural conditions of an inflammatory
nature that may clinically and radiologically
mimic malignant mesothelioma. Therefore, one
should use the clinical and radiological information not
to make a diagnosis per se but rather to orient one self
in the plan to follow with the use of immunohistochemistry
and/or electron microscopy. Ultimately the diagnosis
of mesothelioma is a pathological one and not a
clinical or radiological diagnosis alone.

56
ATTI CONGRESSUALI
Pathological features
GROSS CHARACTERISTICS
Mesotheliomas are tumors with a characteristic gross
appearance that rarely pose a problem with the diagnosis.
The tumor will show diffuse pleural involvement.
In some cases, the tumor follows the intrapulmonary
septum and in rare instances the tumor may involve the
lung parenchyma with small nodules in the surface of
the lung parenchyma. However, the presence of a well
defined tumor mass in the periphery, even if the tumor
also shows diffuse pleural involvement should alert the
pathologist about the possibility of an adenocarcinoma
with diffuse involvement of the pleura, such tumors have
been coded under the designation of Pseudomesotheliomas
adenocarcinoma due to its similarity to
malignant mesothelioma.
HISTOPATHOLOGIC CHARACTERISTICS
Mesotheliomas may show a variety of histopathological
growth patterns. However, traditionally mesotheliomas
have been divided into three categories:
• Epithelial;
• Sarcomatoid;
• Biphasic (combination of epithelial and sarcomatoid).
EPITHELIAL MESOTHELIOMA
Probably the most common of the three variants, it has
been estimated that represents about 70% of all mesotheliomas.
Several distinct histopathological growth
patterns of epithelial malignant mesothelioma have
been described and in some occasions may represent a
diagnostic challenge. Among the variants that have
been recognized are:
• Tubulopapillary;
• Epithelioid;
• Deciduoid;
• Clear cell;
• Glandular;
• Myxoid;
• Adenomatoid.
As it can be seen, it will depend on the histopathologic
growth pattern observed, the degree of discomfort with
the case in question. It is comforting however that
among those previously stated histopathological
growth patterns, the epithelioid and tubulopapillary is
the most common. Nevertheless, it is very important to
be at least theoretically familiar with the other different
growth patterns in order to properly orient our differential
diagnosis. Regardless of the histopathological
growth pattern, whether the tumor shows clear cell
change, myxoid areas, glandular differentiation, or an
adenomatoid pattern, one can not overlooked the fact
that radiologically the tumor is involving diffusely the
pleura. This latter fact should alert and lead the pathologist
to alt least rule out the possibility of mesothelioma.
Thus, the use of histochemical and immunohistochemical
studies becomes a crucial factor in the evaluation
of such lesions.
Ancillary studies
HISTOCHEMICAL STUDIES
Traditionally and before the advent of immunohistochemistry,
histochemical studies play an important role
in the diagnosis of mesothelioma. Currently in some
circumstances they can solve the problem easily in the
more banal cases. The use of periodic acid-Schiff with
and without diastase digestion and mucicarmine or on
the other hand hyaluronic acid with and without diastase
digestion has been used in the past with some success.
Although either histochemical technique is very
good, one should evaluate the one that one is more familiar
with, and only one of those procedures is enough
in order to evaluate a particular lesion. Needles to
say, if one encounters a difficulty with one of those techniques,
the use of an alternative one is indicated. It is
important to state that although the positive finding of
intracellular mucin is a strong feature of adenocarcinoma,
this finding has also been reported in some mesothelioma
in up to 5% of the cases. On the other hand,
it is also important to note that some mesotheliomas
will show abundant presence of extracellular mucin;
however, not intracellular mucin. Thus, in the current
practice the use of those histochemical techniques
many times is by-pass for the use of immunohistochemistry.
IMMUNOHISTOCHEMICAL STUDIES
A great deal of information regarding immunohistochemical
studies in the evaluation of mesotheliomas is
available. Numerous studies attempting to positively
identified mesotheliomas have been published, some of
them with relative usefulness while other have merely
have attempted to identified adenocarcinoma in order
to properly rule out the presence of mesothelioma.
Thus, the diagnosis of mesothelioma has in the past
been considered one of exclusion. However, that is not
necessary the case, since if one properly evaluate clinical,
radiological, histopathological and immunohistochemical
features, the degree of certainty can be fairly
high. Although there are essentially dozen of immunohistochemical
markers that have been stated to be
helpful in the diagnosis of mesothelioma, the fact is
that only a few are use in practice. Currently, markers
that have been use in the diagnosis of mesothelioma or
adenocarcinoma in the pleura include: keratin broad
spectrum, keratin 5/6, calretinin, Leu-M1, CEA, B72.3,
and Ber-ep4. Some of those markers have been stated
to positively stain mesothelial cells (keratin 5/6 and
calretinin) while other have been stated to identify cases
of adenocarcinoma (CEA, Leu-M1). Broad-spectrum
keratin obviously stains both tumors while Berep4
has been found in up to 27% positive in cases of

ATTI CONGRESSUALI
57
mesothelioma. It is exactly in the setting of an epithelial
mesothelioma where all these markers become important
in the evaluation of the tumor. However, it is
important to mention that even though these immunohistochemical
markers are very important in the evaluation
of mesotheliomas, their positive staining does
not constitute a full proof diagnosis of the tumor. For
instance, depending on the antibody use, it may alter
the interpretation of it. One of those cases is CEA, which
has been demonstrated to show some positivity in
about 5% of cases of mesothelioma. However, it is possible
that this phenomenon may be explained by the use
of unabsorbed heteroantisera to CEA. The use of monoclonal
CEA appears to be more reliable in this evaluation.
In short, we can summarize the immunohistochemical
studies in the following manner: if the tumor
in question shows positive for either of these antibodies
- broad-spectrum keratin, keratin 5/6, and calretinin,
then the most likely interpretation is that of mesothelioma.
However, if there is positive staining for either
CEA, Le-M1, B72.3 or other carcinomatous epitope,
then the diagnosis should lean more towards adenocarcinoma.
ELECTRON MICROSCOPIC STUDIES
The use of ultrastructural studies in cases of mesothelioma
is very important due to the specific features that
mesotheliomas have. However, the use of ultrastructural
studies in many cases is hampered by the lack of
material when it is needed the most. In most of the times,
the material does not become available until there
is a more extensive procedure while in the majority
of the cases the initial biopsy which is the one in which
one needs to establish the diagnosis is the only material
available for diagnosis. Thus it limited use. On
the other hand, the use of electron microscopic features
is helpful in the better-differentiated tumors while
those cases in which the tumor is poorly differentiated;
the ultrastructural findings are rarely helpful. Usually
in most cases in which immunohistochemistry has failed
to provide a clear interpretation of a lesion, electron
microscopy will also be questionable. Nevertheless,
it can be very helpful and if one should make
every effort to obtain a sample for such studies. The
finding of long, slender microvilli is a classical feature
for mesothelioma.
Differential diagnosis
In the setting of an atypical epithelial cellular proliferation
the most important conditions to rule out are
either an adenocarcinoma that has extended into the
pleura, a metastatic epithelial tumor of other origin, or
more importantly a mesothelial hyperplasia. If one
has concluded that the cellular proliferation in question
is malignant, then the use of immunohistochemical
studies, namely the use of carcinomatous epitopes,
as previously mentioned in the section of immunohistochemistry,
will be the next step. Similar steps
are adequate in the event of a metastatic epithelial
neoplasm from other source to the pleura. However,
Tab. I. Histopathological features of Mesothelioma vs. Mesothelial Hyperplasia.
Feature Mesothelioma Hyperplasia
Penetration into adipose tissue or muscle +++ —-
Stromal invasion +++ —-
Inflammation — +++
Cellular atypia + +
Mitoses + +
Cellular proliferation in surface - +++
Granulation tissue - +++
Fibrin - +++
Tab. II. Immunohistochemical Features of Mesothelioma and Adenocarcinoma.
Antibody Adenocarcinoma Mesothelioma
CEA +++ —-
Leu-M1 +++ —-
B72.3 +++ —-
Ber-ep4 +++ -/+
Calretinin —- +++
Keratin 5/6 —- +++
Broad-spectrum keratin +++ +++
EMA ++ ++

58
ATTI CONGRESSUALI
the interpretation can be more difficult in cases of mesothelial
hyperplasia. In this setting, there is no immunohistochemical
stain, which can separate a neoplastic
cellular proliferation from a hyperplastic one.
Thus, even though one has followed the necessary steps,
it is imperative not only to correlate the histology
with the clinical and radiological features but also to
properly interpret the results of the immunohistochemical
studies. As a matter of fact even electron microscopic
studies would fail to separate such cellular
proliferations. In essence the diagnosis is a morphologic
one and one that requires careful attention to specific
features (Tabs. I, II).
SARCOMATOID MESOTHELIOMA
This variant of mesothelioma is less common than the
epithelial one and probably represents less than 15% of
all these tumors in its pure form. As its name implies,
the tumor characteristically has a growth pattern of
spindle cells with an elongated nuclei and inconspicuous
nucleoli in a manner mimicking a sarcoma of
soft tissues. Due to the presence of extensive collagenization
there have been recognized some histopathological
growth patterns that are very important and includes:
• Spindle cell type (fibrosarcoma-like or MFH-like);
• Desmoplastic variant;
• Lymphohistiocytoid.
Of these variants, the desmoplastic variant offers a special
difficulty since it can be incorrectly diagnosed as a
benign fibrous pleurisy. However, when the tumor
exhibits all the features of malignancy, i.e., necrosis,
cellular atypia, mitotic activity with atypical mitoses,
stromal and adjacent soft tissue invasion, the most important
issue would be to rule out either a sarcomatoid
carcinoma with extension into the pleura or a sarcoma
of soft tissue. The presence of an atypical spindle cell
proliferation with stromal invasion and necrosis is
usually a good sign of a sarcomatoid mesothelioma. By
far the most difficult diagnosis is the Desmoplastic mesothelioma.
In these cases, the pleural biopsy may
show more collagenization and only a paucicellular
proliferation which may not show marked cytologic
atypia; however, in these circumstances, similar
morphologic characteristics such as stromal invasion,
adjacent tissue invasion, i.e., adipose tissue and muscle
are important features. Nevertheless in limited (small)
pleural biopsies, the diagnosis may not be apparent and
one can only make such suggestion if the clinical and
radiological findings are in keeping with such diagnosis.
Ancillary studies
HISTOCHEMICAL STUDIES
The use of histochemical studies such as D-PAS and
mucicarmine or hyaluronic acid with and without diastase
digestion has no role in the diagnosis of these tumors.
IMMUNOHISTOCHEMICAL STUDIES
In the setting of a spindle cell mesothelioma whether
the tumor is desmoplastic or not, the role of immunohistochemistry
is relatively limited since most of the
antibodies use in regular epithelial mesotheliomas have
no practical use in sarcomatoid mesotheliomas. The use
of broad- spectrum keratin is by far the most important
of them. All other carcinomatous epitopes are known
not to react with sarcomatoid tumors. In addition, the
use of calretinin and keratin 5/6 is rather limited since
its positivity may vary and negative results do not mean
that the tumor in question is not a mesothelioma.
Furthermore, because of the lack of more specificity
from immunohistochemical markers, the issue of fibrous
pleurisy and desmoplastic mesothelioma cannot
be solved by immunohistochemistry since both lesions
may cross-react with keratin antibodies. In essence, the
use of immunohistochemistry is relevant to rule-out
other spindle cell tumor of different lineage including
leiomyosarcomas, MFH or other mesenchymal tumors.
Differential diagnosis
In cases in which there is no doubt about the neoplastic
nature of the tumor, the most important differential diagnosis
is with another spindle cell neoplasm of mesenchymal
origin. In this case, the use of proper immunohistochemical
studies and/or electron microscopy
will lead to amore appropriate interpretation. In cases
of sarcomatoid carcinoma involving the pleura in a diffuse
manner, the finding by radiographic studies of an
intrapulmonary tumor mass will lead to a more appropriate
interpretation. By far the most difficult diagnosis
is with fibrous pleurisy of a reactive or inflammatory
nature. In these cases, the diagnosis is based on
morphologic grounds since immunohistochemistry
cannot solve the problem (Tab. III).
BIPHASIC MESOTHELIOMAS
As its name implies these tumors are composed of a mixture
of epithelial and sarcomatoid areas. As a rule one
should have unequivocal sarcomatoid areas and/or
epithelial areas in order to code these cases as biphasic.
One important differential diagnosis with biphasic mesotheliomas
is the fact that primary synovial sarcomas of
the pleura have been described. However, in that setting
the tumor is a pleural-based mass without diffuse involvement
of the pleura. Once again, close clinical and radiological
correlation is highly advised in that setting.
OTHER VARIANTS
In very unusual cases, mesotheliomas have been encountered
to show extensive areas of cartilage and bone
metaplasia. In these cases, a small biopsy may not
sample representative areas, which may represent a

ATTI CONGRESSUALI
59
Tab. III. Histopathological features of Sarcomatoid Mesothelioma and Fibrous Pleurisy.
Feature Mesothelioma Fibrous Pleurisy
Transitions between cellular and acellular +++ —-
Cellular atypia ++ ++
Granulation tissue — ++
Fibrin — ++
Inflammatory reaction — ++
Mitotic activity + +
Immunohistochemistry
Broad-spectrum keratin ++ ++
Keratin 5/6 -/+ -/=
Calretinin - -
Smooth muscle actin + +
diagnostic challenge for the pathologist. In addition,
due to its rarity, one should be familiar with these unusual
features in order to properly labeled those cases as
mesotheliomas with osseous and cartilaginous component
instead of naming those tumors by other name,
which may include pleuropulmonary blastomas or carcinosarcomas
of the pleura.
Treatment and prognosis
One of the most common modalities of treatment is Extrapulmonary
Pneumonectomy. In some centers that
procedure is performed only in epithelial neoplasms
while in other center it is done with all mesotheliomas.
It appears that the procedure increases the survival curve
in these patients whom in the past used to be poor.
However, in the majority of cases the prognosis is still
poor with survival rates of no more than 12 and 18
months after diagnosis. In view of the widespread acceptance
of this procedure is that now more than ever
the diagnosis of mesothelioma is one that requires a careful
attention not only to the histology of the tumor but
also to the clinical and radiological aspects.
Practical approach
Since the diagnosis of mesothelioma is a multifactorial,
we have devised a conceptual approach to these lesions,
which in the majority of cases can be applied, namely
when there are some doubts about the diagnosis.
These include:
• Detail clinical history;
• Detail radiological information;
• Adequate biopsy material;
• Immunohistochemical studies;
• Electron microscopy.
CLINICAL SETTING
• If the tumor is epithelial, then the use of a battery of
immunohistochemical studies is in order and these
will include: keratin 5/6, calretinin, CEA, Leu-M1,
B72.3, and Ber-ep4.
• If the tumor is sarcomatoid, then the immunohistochemical
studies can be limited to broad- spectrum
keratin. Keratin 5/6 and calretinin can be added,
however, it is well known that those antibodies may
be negative in sarcomatoid mesotheliomas. Other
immunohistochemical studies to rule out other mesenchymal
neoplasms may be included depending
on the degree of suspicion.
References
1
Hinds MW. Mesothelioma in the United States: Incidence in the
1970s. J Occupational Med 1978;20:469-71.
2
Craighead JE. The epidemiology and pathogenesis of malignant
mesothelioma. Chest 1989;96:92-3.
3
Wright WE, Sherwin RP. Histological types of malignant mesothelioma
and asbestos exposure. Br J Industrial Med
1984;41:514-7.
4
Borow M, Conston A, Livornese L. Mesothelioma following exposure
to asbestos: a review of 72 cases. Chest 1973;64:641-6.
5
Peterson JT, Greenberg DS, Buffler PA. Non-asbestos related malignant
mesothelioma. A review. Cancer 1984;54:951-60.
6
Grundy GW, Miller RW. Malignant mesothelioma in childhood:
report of 13 cases. Cancer 1972;30:1216-8.
7
Huncharek M, Kelsey K, Mark EJ. Treatment and survival in diffuse
malignant pleural mesothelioma: a study of 83 cases from
Massachusetts General Hospital. Anticancer Res 1996;16:1265-
8.
8
Ordoñez NG. Epithelial mesothelioma with deciduoid features:
report of four cases. Am J Surg Pathol 2000;24:816-23.
9
Ordoñez NG, Mackay B. Clear cell mesothelioma. Ultrastruct
Pathol 1996;20:331-6.
10
Henderson DW, Attwood HD, Constance TJ, Shilkin KB, Steele
RH. Lymphohistiocytoid mesothelioma: a rare lymphomatoid variant
of predominantly sarcomatoid mesothelioma. Ultrastruct
Pathol 1988;12:367-84.
11
Yousem SA, Hochholzer L. Malignant mesothelioma with osseous
and cartilaginous differentiation. Arch Pathol Lab Med
1987;111:62-6.
12
Koss MN, Travis WD, Moran C, Hochholzer L. Pseudomesotheliomatous
adenocarcinoma: a reappraisal. Sem Diagn Pathol
1992;9:117-23.

60
ATTI CONGRESSUALI
13
Bedrossian CMW, Bonsib S, Moran CA. Differential diagnosis
between mesothelioma and adenocarcinoma: a multimodal approach
based on ultrastructure and immunohistochemistry. Sem
Diagn Pathol 1992;9:124.
14
Moran CA, Wick MM, Suster S. The role of immunohistochemistry
in the diagnosis of malignant mesothelioma. Sem Diagn
Pathol 2000;17:178-83.
15
Wick MR, Moran CA, Mills SE, Suster S. Immunohistochemical
differential diagnosis of pleural effusions with emphasis on malignant
mesothelioma. Curr Opin Pulmonary Med 2001;7:187-92.

ATTI CONGRESSUALI
61
Controversial Salivary Gland Lesions
MARIO A. LUNA, M.D.
Sclerosing polycystic adenosis.
A pre-neoplastic lesion
In the group of tumor-like lesions that are listed in the
1991 World Health Organization (WHO) classification
of salivary gland tumors, seven entities are distinguished
1
. Clinically or morphologically, these lesions can mimic
malignant neoplasms. For example, necrotizing sialometaplasia
can resemble mucoepidermoid carcinoma. In
1996, a new entity that was not included in the tumorlike
lesions of the WHO classification was described by
the pathologists of the Armed Forces Institute of Pathology
(AFIP). The authors suggested the term “sclerosing
polycystic adenosis” (SPA) for these lesions and described
nine cases 2 . The same year, Batsakis 3 confirmed these
results, discussed the etiology, and reported five cases
from the pathology files of The University of Texas M.
D. Anderson Cancer Center 3 . A year later, four similar
cases were analyzed in the Salivary Gland Register of the
University of Hamburg 4 . Since then, approximately 40
cases have been reported in world literature 5-9 .
The new entity SPA is a pseudoneoplastic process similar
to fibrocystic disease of the breast. The key histologic
features of SPA are the following:
• Resemblance of fibrocystic disease of breast in its
diversity;
• Preservation of lobular architecture;
• Duct ectasia, with or without epithelial hyperplasia;
• Occasional collagenous spherulosis;
• Tubuloacinar structures filled with bright eosinophilic
granules;
• Apocrine-like metaplasia;
• Fibrotic, widened septa, with nodular fibrosis;
• Uncapsulated but often demarcated;
• Variable acute and chronic inflammatory cellular
aggregates;
• Limitation of nodules from the adjacent salivary
gland tissue;
• No infiltrating growth or metastases.
This constellation of features could not be identified in
previously reported salivary gland lesions. Ninety-fiver
percent of the cases of SPA reported to date have been
localized in the parotid gland. The incidence of SPA
peaks in third and fourth decades of life, with a female
predominance.
Local recurrence near the scar tissue has been documented
in approximately 20% of the cases 2-9 . SPA resembles
the proliferative and reactive changes in the
mammary gland that are well documented. Similar lesions
are fibrocystic changes, sclerosing adenosis, duct
ectasia, or intraductal hyperplasia. The differential diagnosis
includes the following:
1. dysgenetic polycystic parotid gland which involves
the entire parotid gland and shows cystic ducts with
apocrine metaplasia, but not duct proliferation or interstitial
fibrosis 10 11 ;
2. obstructive sialadenitis, which contains both inflammation
and fibrosis, but it lacks the proliferative
epithelial component 1 ;
3. pleomorphic adenoma which is characterized by the
presence of a distinct myxoid, chondroid or mucoid
stromal component in addition to neoplastic glandular
formations and solid areas of myoepithelial proliferation;
4. mucopidermoid carcinoma (MEC) 2-4 , which as a rule
is characterized by loss of the lobular pattern and
presence of satellite cysts. The cellular components
of MEC are clear cells, mucinous cells, intermediate,
and/or epidermoid cells. A stromal sclerosis of
MEC is largely absent. In addition, acinic cell nests
and apocrine secretion or intraductal epithelial hyperplasia
with epithelial bridges are not typical signs
of MEC.
Despite the histologic similarity between SPA and benign
proliferative fibrocystic disease of the breast, the
etiology of SPA is unclear. The females predominance
for both diseases may be indication of the role of secretory
disturbance of the salivary duct epithelium and
the additional influence of hormones. In normal salivary
gland ducts, the immunohistochemical expression
of estrogens, progesterone, and progesterone receptors
is observed. Similar findings are seen in the parotid
glands of rats after combined treatment with estradiol
and progesterone 12 Skalova et al. 5 demonstrated for the
first time immunoreactivity for estrogens and progesterone
receptors in three cases of SPA, suggesting that
hormone stimulation may play a role in its pathogenesis.
In addition, the same authors demonstrated foci of
dysplasia of the ductal epithelium, which in one case
was severe enough to amount to carcinoma in situ 5 .
These authors are convinced that SPA is a neoplastic lesion
with a low-grade malignancy potential, but this
view is controversial and not shared by all investigators
in the field. In our series 2 cases of SPA were associated
to benign tumors, Warthin’s and sebaceous adenoma
and one case exhibited atypical intraductal hyperplasia,
the last patients is free of disease 10 years after
treatment. To date, as there were no SPA- related mortality
or morbility we have to conclude that PSA is a
benign entity that carries the potential for misdiagnosis
as the proliferation of bland ducts may mimic a low
grade carcinoma. In regard to the be a preneoplastic
condition; more cases of SPA with longer follow-up are
needed to evaluate the true biological behavior of the
lesion 9 .

62
ATTI CONGRESSUALI
Low-grade cribriform
cystadenocarcinoma (Low grade salivary
duct carcinoma)
Salivary duct carcinoma (SDC), one of the most malignant
salivary gland tumors, predominates in the parotid
gland of men in the fifth decade of life. SDC histologically
resembles ductal carcinoma of the breast and
is highly invasive. It can arise de novo or in a mixed tumor;
66% of the patients develop distant metastases,
and 66% of patients die within 3 years after treatment 1-
5
. These tumors overexpress Her2/neu, androgen receptors,
and CFBP. In addition, they do not contain myoepithelial
cells.
In 1996, Delgado et al. 6 and Tatemoto et al. 7 reported
a group of salivary carcinomas that have a ductal appearance
but are of low-grade malignancy, these carcinomas
were termed “low-grade salivary duct carcinoma”
(LG-SDC).The WHO committee of Classification
of Salivary Gland Tumor does not accept this lesion as
a variant of the Salivary Duct Carcinoma and coined
the term “Low-Grade cribriform cystadenocarcinoma
(LGCCC)” and in addition declared that all SDC
should be considered as a high-grade carcinomas 8 . In
contrast to the classic SDC, these LGCCC are composed
of small cells with fine chromatin and small nucleoli;
they are not anaplastic and are very regular. The
cells have fine granular cytoplasm, and some contain
brown pigment, microvacuoles, or both. The cells are
arranged in cystic spaces with papillary projection or in
solid nests with no comedonecrosis. The cysts and nests
are well-circumscribed and noninvasive. The papillary
projections are short and contain a central fibrovascular
core. These tumors show numerous myoepithelial
cells in the periphery of the nests and cysts. In addition,
LG-SDC is strongly and diffusely S-100 protein
positive, in contrast to high-grade SDC, which is usually
negative for S-100 protein.
The differential diagnosis of LG-CCC includes mainly
acinic cell carcinoma of the cystic and papillary variant
(ACC-PC), polymorphous low-grade adenocarcinoma
(PLGA), and high-grade SDC. Both LG-CCC and
ACC-PC contain vacuolated cells and may have cystic
spaces lined by bland atypical tumor cells. However,
the vacuoles of the latter are smaller and refractile and
are associated with yellow-brown pigment; PAS-diastase-resistant
fine cytoplasmic granules are found in
ACC-PC. Furthermore, the EM appearance differs
between these tumors. PLGA can be distinguished
from LG-CCC by its distinctive neurotropism and infiltrative
lobular, trabecular, and tubular patterns. SDC,
in contrast to LG-CCC, exhibits a highly invasive
growth pattern. The cells are anaplastic, numerous atypical
mitoses are present, and extensive comedonecrosis
is observed.
Some reports have suggested that purely intraductal or
minimally invasive high-grade SDC might be associated
with an improved prognosis 10-12 . This is controversial
and should not be relied upon. As with intraductal
breast carcinoma, there remains a definite possibility of
recurrence or disease progression in these cases. However,
it is important to indicate the noninvasive or minimally
invasive characteristics of the lesion in the surgical
pathology report.
In cases of LG-CCC, wide resection with free surgical
margins is the treatment of choice. Adjuvant therapy
can be withheld, with close follow-up. Of the six patients
reported by Delgado et al. 6 , all were tumor free
at 2 to 12 years follow-up (mean, 7 years). Recently,
Gnepp et al. 9 15 patients with LG-CCC all patienst are
alive and free of disease from 6 to 132 months (median
30 months) However, data from additional cases are
necessary to confirm this trend and most important to
elucidate the true nature of the low-grade carcinoma.
Cribriform adenocarcinoma
of the tongue
Michal et al. proposed the term “cribriform adenocarcinoma
of the tongue” (CAT) to describe a distinctive
type of adenocarcinoma that originates almost exclusively
at the base of the tongue 1 . Most of these CATs are
locally aggressive, and by the time patients seek medical
treatment, most of the tumor have metastasized to
the cervical lymph nodes. However, all the seven patients
reported by Michal et al. 1 in-spite of the metastases
to the cervical lymph nodes were alive from 2 to
6 years after treatment.
The most striking cytologic feature was that the tumor
nuclei were pale-staining, they have a ground-glass
quality, and they appeared to overlap and resembled
both solid and follicular variants of papillary thyroid
carcinoma. All tumors were encapsulated unencapsulated
and were divided by fibrous septi in lobules. Major
parts of the neoplasms were arranged in solid and microcystic
growth patterns. Immunohistochemistry the
tumors expressed cytokeratin and S 100 protein and, focally
actin; thyroglobulin was negative. Ultrastructurally
many tumor cells had combined features of both
myoepithelial and secretory differentiation, well formed
microvilli on their apical borders and bundles of
microfilaments.
The differencial diagnosis includes polymorphous low
grade adenocarcinoma (PLGA), adenoid cystic carcinoma
and primary or metastatic thyroid carcinoma. PL-
GA is excluded by the lack of a wider range of architectural
patterns and the presence of ground-glass nuclei.
Adenoid cystic carcinoma is discounted because
the characteristic collagen deposition is absent. Also in
adenoid cystic carcinoma, the cells are basaloid and
contain dark, hyperchromatic, and angulated nuclei.
CAT is most difficult to distinguish from solid and follicular
variants of papillary thyroid carcinoma (FVPC)
either metastatic or as primary from the lingual thyroid
2
. Most important CAT is always thyroglobulin negative,
but there are a few morphological clues visible on
H & E; the deeply eosinophilic colloid material seen in

ATTI CONGRESSUALI
63
FVPC is absent, the mucin present in the lumen of the
tubules in CAT and the immunohistochemical and EM
evidence of myoepithelial differentiation in CAT 1-3 .
The authors hypothesized that CAT might arise from
thyroglossal duct anlage. We
have seen only 3 case of CAT and in addition to the original
INH findings described by Michal et al. 1 the tumors
have been positive for CK 19, negative for CK 7
and negative for TTF-1 supporting the hypothesis that
CAT are not of salivary gland origin. In two of our cases
we observed squamoid nests resembling the ultimobranchial
boy (UBB) solid cell nests seen in thyroid gland.
Squamous cell carcinoma
of salivary glands
Primary squamous cell carcinoma (PSCC) is among the
rarest of major salivary gland neoplasms 1 . In surveying
the literature, the incidence of PSCC is difficult to asses
because of reporting biases, but it constitutes less
than 1% of all parotid tumors 1 2 . PSCC of the salivary
glands is a diagnostic of exclusion, SCC in major salivary
gland has several possible sources: 1) high grade
mucoepidermoid carcinoma (MEC); 2) metastasis or
direct extension from a primary skin tumor; 3) metastasis
from a distant primary SCC; 4) rarely as malignant
component of carcinoma ex pleomorphic adenoma;
5) a primary salivary gland carcinoma 1-3 . The most
common location of PSCC is the parotid galnd followed
by the submandibular gland 3 . Histologically
they are characterized by the presence of keratinizing
cells squamous cells that gives few hints with regard to
putative origin. Perineural and lymphovascular invasion
are common findings. Clinically the patients are
predominantly males and the patients typically present
with a large (more than 3 cm) aymptomatic poorly encapsulated
mass. The cervical lymph nodes are clinically
involved from 20% to 45%. Of the cases 1-3 .
High grade MEC is excluded by the demostration of
two direction differentiation, mucin positive cells and
presence of intermediate cells. In addition it has been
claimed that MEC is CK 7 positive, whereas SCC is
weakly positive or negative for CK 7 4 .
If the tumor is microscopically well circumscribed,almost
round, without invasion of the salivary gland stroma,
the possibility of being metastatic should be entertained,
also the presence of multiple tumors favors metastases.
The histologic presence of residual lymph node
structure (peripheral sinuses and germinal center)
would favor metastases.
SCC arising in a pleomorphic adenoma, although rare,
can be excluded by examining multiple histologic sections.
It has to be emphasized that the clinical history
and the careful physical examination of the patients is
of paramount importance to decide whether the SCC is
primary or metastatic.
Surgery is the treatment of choice. Adjuvant treatments,
radiation and/or chemotherapy is based on the
extend and distribution of the carcinoma. The natural
evolution of the neoplasm is aggressive, irrespectively
of clinical context. The reported survival data for
PSCC.is strongly influenced by the clinical stage of the
tumor (TNM). The 5-year survival is 14% for stage II-
III tumors and range from 50% to 80% for 5-years for
anatomically confined carcinomas 1-3 .
Is there a high grade acinic cell
and polymorphous low grade carcinoma
The concept of dedifferentiation was first proposed in
osteoskeletal pathology 1 . Although the term has been interpreted
somewhat differently by subsequent authors 2 ,
dedifferentiation is now commonly applied when a
low-grade tumor is juxtaposed to or complicated by a
malignancy, which is usually high-grade and in which
the original line of differentiation is lost, or in which
there may even be acquisition of a new line of differentiation.
The high-grade component can arise ab initio,
in the setting of a long-standing neoplasm, or following
recurrence. In salivary glands, malignant transformation
or dedifferentiation has been well documented in pleomorphic
adenoma and acinic cell carcinoma. In recent
years, the concept of dedifferentiation of salivary gland
tumors has gained popularity and has been described in
adenoid cystic carcinoma (ADC), polymorphus lowgrade
carcinoma (PLGA), and epithelial-myoepithelial
carcinoma 3-9 .
Although dedifferentiation is always associated with tumor
progression, little is known about the molecular
events that regulate it, and immunohistochemistry and
molecular studies on the expression of p53 oncoprotein
have not provided conclusive results 3-9 . It is of clinical interest
that in some cases of salivary gland carcinomas that
have shown dedifferentiation, the patients have received
irradiation. This factor should be further investigated.
The prognostic value of dedifferentiation is still to be
defined, and statistically significant conclusions on the
biologic behavior of these tumors is not possible because
of the small number of cases described. It is generally
accepted that differentiated carcinomas are associated
with a poor clinical outcome 3-9 .
References
SCLEROSING POLYCYSTIC ADENOSIS
1
Seifert G. WHO international histological classification of tumours.
Histological typing of salivary glands tumours. 2nd Ed.
Berlin Heidelberg, New York: Springer p. 34.
2
Smith BC, Ellis GI, Salter LJ. Sclerosing polycystic adenosis of
major salivary glands. A clinicopathologic study of 9 cases. Am
J Surg Pathol 1996;20:161-70.
3
Batsakis JG. Sclerosing polycystic adenosis. Newly recognized
salivary gland lesion- a form of chronic sialoadenitis Advances
Anat Pathol 1996;5:298-304 (Commentary).
4
Donath K, Seifert G. Skelerosierende plyzystische sialadenopathie.
Eine seltene rich-tumorose. Erkrankung Pathloge
1997;18:368-73.

64
ATTI CONGRESSUALI
5
Skalova A, Michal M, Simpson RHW. Sclerosing polycystic adenosis
of the parotid gland with dysplasia and ductal carcinoma in
situ. Report of three cases with immunohistochemical and ultrastructural
examination. Virchows Arch 2002;440:29-35.
6
Aviles-Salas A, Pichardo-Bahena R. Adenosis poliquistica esclerosante
de la glandula parotida. Presentacion de un caso y revision
de la literature. Patologia 2000;39:107-11.
7
Gnepp D, Brandwine M, Slotweg P. Parotid polycystic adenosis.
Our experience from four institutions. Mod Pathol 2002;14;150A.
8
Kabani S, Galalgher G. Sclerosing polycystic adenosis of minor
salivary glands. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontics.
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