Sabato 27 ottobre 2012 - Pacini Editore

RElaziONi
references
1 Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the
epidermal growth factor receptor underlying responsiveness of nonsmall-cell
lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.
2 Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:
correlation with clinical response to gefitinib therapy. Science
2004;304:1497-500.
3 Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations
are common in lung cancers from “never smokers” and are associated
with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci
U S A 2004;101:13306-11.
4 Soda M, Choi YL, Enomoto M, et al. Identification of the transforming
EML4-ALK fusion gene in non-small-cell lung cancer. Nature
2007;448:561-6.
5 Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine
signaling identifies oncogenic kinases in lung cancer. Cell
2007;131:1190-203.
6 Chen Y, Takita J, Choi YL, et al. Oncogenic mutations of ALK kinase
in neuroblastoma. Nature 2008;455:971-4.
7 George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide
a therapeutic target in neuroblastoma. Nature 2008;455:975-8.
8 Janoueix-Lerosey I, Lequin D, Brugieres L, et al. Somatic and germline
activating mutations of the ALK kinase receptor in neuroblastoma.
Nature 2008;455:967-70.
9 Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoforms
of the EML4-ALK transforming gene in non-small cell lung cancer.
Cancer Res 2008;68:4971-6.
10 Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-
PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res
2008;14:6618-24.
11 Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene
and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer
Res 2008;14:4275-83.
12 Mano H. Non-solid oncogenes in solid tumors: EML4-ALK fusion
genes in lung cancer. Cancer Sci 2008;99:2349-55.
13 Perner S, Wagner PL, Demichelis F, et al. EML4-ALK fusion lung
cancer: a rare acquired event. Neoplasia 2008;10:298-302.
14 Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is
involved in various histologic types of lung cancers from nonsmokers
with wild-type EGFR and KRAS. Cancer 2009;115:1723-1733.
15 Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and
outcome of patients with non-small-cell lung cancer who harbor
EML4-ALK. J Clin Oncol 2009;27:4247-53.
16 Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are
characterized by rare other mutations, a TTF-1 cell lineage, an acinar
histology, and young onset. Mod Pathol 2009;22:508-15.
17 Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features
of non-small-cell lung cancer with EML4-ALK fusion gene. Ann
Surg Oncol 2010;17:889-97.
18 Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated
with development of lung adenocarcinomas lacking EGFR and
KRAS mutations and is correlated with ALK expression. Mol Cancer
2010;9:188.
19 McDermott U, Iafrate AJ, Gray NS, et al. Genomic alterations of anaplastic
lymphoma kinase may sensitize tumors to anaplastic lymphoma
kinase inhibitors. Cancer Res 2008;68:3389-95.
20 Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor
activity of PF-2341066, a novel inhibitor of anaplastic lymphoma
kinase and c-Met, in experimental models of anaplastic large-cell
lymphoma. Mol Cancer Ther 2007;6:3314-22.
21 Zou HY, Lee JH, Arango ME, et al. An orally available small-molecule
inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor
effi cacy through antiproliferative and antiangiogenic mechanisms.
Cancer Res 2007;67:4408-17.
22 Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma
kinase inhibition in non-small-cell lung cancer. N Engl J Med
2010;363:1693-1703.
23 US Food and Drug Administration. FDA labeling information -
Xalkori. [FDA Web site]. 2011. Available at: http://www.accessdata.
fda.gov/drugsatfda_docs/label/2011/202570s000lbl.pdf.
24 Marchetti A, Normanno N. Recommendations for mutational analysis
of EGFR in lung carcinoma. Pathologica 2010;102:119-126.
25 Pirker R, Herth FJ, Kerr KM, et al. Consensus for EGFR mutation testing
innon-small cell lung cancer: results from a European workshop. J
Thorac Oncol 2010;5:1706-13.
Prospettive future e gestione del materiale:
ruolo del patologo
P. Graziano
Paper not received
221
Lung cancer diagnosis: from morphology
to molecular biology through
immunohistochemistry
G. Rossi, G. Pelosi, M. Barbareschi, P. Graziano, A. Cavazza,
M. Papotti
Azienda Ospedaliera St Maria Nuova, IRCCS, Reggio Emilia (GR,
AC); Department of Pathology and Laboratory Medicine, Fondazione
IRCCS National Cancer Institute and University of Milan School
of Medicine, Milan (GP); Division of Pathologic Anatomy, Forlanini
Hospital, Rome (PG); Division of Pathologic Anatomy, Santa Chiara
Hospital, Trento (MB); San Luigi Hospital and University of Turin,
Orbassano (MP), Italy
The new aspect of the recent classification of adenocarcinoma
provides guidance for small biopsies and cytology specimens,
non-small cell lung carcinomas (NSCLC), in patients
with advanced stage disease, requiring to be classified into
more specific types, such as adenocarcinoma or squamous
cell carcinoma, whenever possible, for several reasons: (a)
adenocarcinoma or NSCLC not otherwise specified should
be tested for EGFR mutations, because the presence of these
mutations is predictive of responsiveness to EGFR tyrosine
kinase inhibitors; (b) adenocarcinoma histology is a strong
predictor for improved outcome with pemetrexed therapy; and
(c) squamous histology is a risk factor for life-threatening hemorrhage
with bevacizumab therapy. NSCLC- not otherwise
specified by light microscopy alone should be studied with
immunohistochemistry. The advent of histology-based therapies
have consistently changed the pathologists’ perspectives
when diagnosing NSCLC. In fact, at the minimum the distinction
between squamous cell carcinoma and adenocarcinoma is
mandatory when using some new drugs, as pemetrexed, bevacizumab,
or even molecular therapies as EGFR inhibitors.
A good agreement between pathologists (K = 0.48-0.88) has
been observed in differentiating squamous and non-squamous
cell carcinoma based just on morphology and in some recent
papers highlighting the accuracy of cytology in subtyping
NSCLC. A definitive diagnosis of NSCLC subtype was obtained
in 88% preoperative cytology samples. In addition, a
diagnosis of favored histologic type was made in another 8%,
then leaving unclassified 4% of NSCLC. The concordance between
cytology and histology was > 90% (Rekhtman N, et al.
J Thorac Oncol 2011; Nizzoli R, et al. J Thorac Oncol 2011).
Finally, Pelosi et al (J Thorac Oncol 2012) recently showed
that the correct morphologic diagnoses on small biopsies of
NSCLC arose from 67% to 84% when slides were reviewed
by expert pulmonary pathologists. Several papers have investigated
the role of immunohistochemistry on NSCLC
subtyping. Immunohistochemistry is the less expensive and
most quick ancillary technique in subtyping NSCLC. As
matter of fact there are various commercially available antibodies
with different sensitivity and specificity that can find
out squamous, glandular as well as neuroendocrine differentions.
Among many immunomarkers, high-molecular-weight
cytockeratins (HMWCK), CK5/6 and p63 are considered
more specific for squamous differentiation, while positivity
for TTF-1, CK7 and Napsin A is generally used to confirm
adenocarcinoma. Finally, chromogranin A, synaptophysin