Issue 4 - August 2010 - Pacini Editore

140
concerning the diagnosis of sinonasal undifferentiated and
poorly differentiated carcinomas, neuroendocrine carcinoma
and olfactory neuroblastoma.
Sinonasal poorly differentiated and undifferentiated
carcinomas
The group of high grade poorly differentiated and undifferentiated
sinonasal carcinomas include nasopharyngeal-type
undifferentiated carcinoma (lymphoepithelioma), sinonasal
undifferentiated carcinoma (SNUC), NUT midline carcinoma,
and poorly differentiated keratinizing and non-keratinizing
variants of squamous cell carcinoma.
Nasopharyngeal-type undifferentiated carcinoma is typically
associated with EBV infection, and this is a useful feature
to separate this entity from other sinonasal undifferentiated
carcinomas, which are typically EBV negative 1 .
SNUC is a rare highly aggressive tumour of uncertain histogenesis.
The term “undifferentiated” has been applied inconsistently
in the past, but should now be applied more selectively
with better methods of cell study. By definition SNUC
does not show any overt squamous or glandular differentiation,
whereas neuroendocrine features have been frequently
noted, both histologically and immunohistochemically 2 .
SNUC can be distinguished from poorly differentiated
squamous cell carcinoma variants for the different pattern
of cytokeratins subtypes expression, since SNUC is positive
for simple epithelia cytokeratins and lacks the expression
of cytokeratins 5/6 and 13, which instead are expressed by
squamous cell carcinoma variants 3 . In addition, SNUC has a
limited expression of p63, which is present in squamous cell
carcinoma variants 4 .
NUT midline carcinoma (NMC) is a rare, clinically aggressive
carcinoma, which is defined by a translocation involving
the NUT (nuclear protein in testis) gene on chromosome
15q14 and, in most cases, the BRD4 gene on chromosome
19p13.1. Initial cases were reported in young patients affected
by intrathoracic carcinomas, but it is now well established
that these tumours may occur in adults and involve
other anatomic sites, including the sinonasal tract 5 . So far
less than ten cases have been described in the nasal cavity
and paranasal sinuses. These tumours affected young adults
of both sexes and showed an aggressive clinical behaviour.
However, there is certainly an underestimation of their occurrence
due to the lack of specific diagnostic features.
Histologically, these carcinomas are composed of undifferentiated
basaloid cells with focal, often abrupt, squamous
differentiation. Therefore, the diagnosis of NMC requires
the demonstration of the NUT translocation, which can be
achieved by karyotyping, reverse transcription polymerase
chain reaction (RT-PCR), and FISH. Recently, a monoclonal
antibody to NUT has been developed, which showed a sensitivity
of 87%, a specificity of 100%, a negative predictive
value of 99%, and a positive predictive value of 100% when
tested in a large panel of carcinoma tissues 6 . Moreover, the
expression of normal NUT protein is limited to the germ cells
of the testis and ovary, thus increasing the reliability of the
use of immunohistochemistry in the diagnosis of NMC. The
use of this antibody may help to separate NMC from other
poorly differentiated sinonasal carcinomas, thus contributing
to their clinico-pathologic characterisation. In addition,
it appears that the distinction of NMC from other sinonasal
carcinomas is of clinical relevance, in view of the favourable
response to certain treatment regimes, including chemotherapy
according to Ewing’s sarcoma protocols 7 or docetaxel
and radiotherapy 8 .
5 th triennial congress of the italian society of anatomic Pathology and diagnostic cytoPathology
Small cell carcinoma, neuroendocrine type (SCC-
NET)
Currently, WHO classification of head & neck tumours,
places SCCNET in the category of neuroendocrine tumours
together with carcinoid tumour, which can be further sub-classified
into typical and atypical 9 . SCCNET of the nasal cavities
and paranasal sinuses is a very uncommon neoplasm of which
only small series and isolate case reports have been reported
in the English literature 10 . A critical review of these reports
reveals that in some cases the clinico-pathological features
of the lesions described were more consistent with other diagnoses,
including olfactory neuroblastoma and SNUC. This
underlines the current lack of criteria, including a definition
of a panel of immunohistochemical markers, to make the diagnosis
of SCCNET. Small cell neuroendocrine carcinoma of
the sinonasal tract is histologically indistinguishable from its
pulmonary counterpart. Immunohistochemically, it is positive
for cytokeratins and neuroendocrine markers such as NSE
(neuron specific enolase), synaptophysin, and chromogranin,
although with variable intensity 10 . As small cell neuroendocrine
carcinomas of other sites, sinonasal tumours express
CD57 11 . These features allow the distinction from SNUC,
malignant melanoma, olfactory neuroblastoma, lymphoma,
Ewing’s sarcoma/PNET and rhabdomyosarcoma.
Olfactory Neuroblastoma (ON)
ON is a rare neoplasm occurring in a broad age range, which
most commonly originates in the region of the cribriform plate
from the olfactory mucosa 12 . More frequently, the tumour
grows in nests separated by fibrovascular septa, or sometimes
it may show a diffuse growth pattern. The neoplastic cells
typically have small and round nuclei with stippled chromatin,
absent or small nucleoli, and scanty cytoplasm. They are
embedded in a fibrillary background formed by cell processes.
Homer-Wright type of rosettes, or more rarely Flexner rosettes
can be found. Immunohistochemically, ON shows diffuse
positivity for NSE and synaptophysin, while chromogranin,
GFAP and leu-7 are less often positive. S-100 protein stains
sustentacular cells around neoplastic nests, but in less differentiated
tumours there may be few scattered S-100 protein
positive cells. Neurofilament protein and other markers of neural
differentiation are more often expressed in tumours with
diffuse, sheet-like pattern. Cytokeratins are generally negative,
although in ON with nesting pattern a few tumours cells may
exhibit staining for low molecular weight cytokeratins. A subgroup
of ON with gland-like formations and more widespread
cytokeratin positivity has been designated “olfactory neuroepithelioma”
13 . EMA is consistently negative, as they are CD99,
CD45, HMB-45 and muscle markers. Ultrastructural analysis
shows evidence of neuroblastic differentiation, including the
presence of dendritic processes containing dense core granules
and neurotubules, and occasional synaptic junctions. ON lacks
the t(11; 22) translocation of Ewing’s sarcoma/PNET.
references
1 Cerilli LA, Holst VA, Brandwein MS, et al. Sinonasal undifferentiated
carcinoma: immunohistochemical profile and lack of EBV association.
Am J Surg Pathol 2001;25:156-63.
2 Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis
on neuroendocrine carcinomas. Mod Pathol 2002;15:264-78.
3 Franchi A, Moroni M, Massi D, et al. Sinonasal undifferentiated carcinoma,
nasopharyngeal-type undifferentiated carcinoma, and keratinizing
and nonkeratinizing squamous cell carcinoma express different
cytokeratin patterns. Am J Surg Pathol 2002;26:1597-604.
4 Bourne TD, Bellizzi AM, Stelow EB, et al. p63 expression in olfactory
neuroblastoma and other small cell tumors of the sinonasal tract. Am
J Clin Pathol 2008;130:213-8.