Sinonasal Undifferentiated Carcinoma
Bruce M. Wenig
Beth Israel Medical Center
New York, NY
The most commonly encountered malignant neoplasms of the sinonasal tract are the keratinizing and
nonkeratinizing types of squamous cell carcinoma. However, this complex anatomic region may represent
the site of aggressive non-epithelial malignant neoplasms of varying histogenesis, which may be grouped
under the term "small round blue cell tumor." Frequently, these undifferentiated tumors share clinical
and light microscopic features making differentiation one from the other difficult without the use of
adjunct analyses (immunohistochemistry, electron microscopy or molecular biologic studies). In general,
these tumors tend to be clinically aggressive and often fatal despite attempts at controlling disease.
Nevertheless, differentiating these tumor types has clinical import as advances in therapeutic
intervention may increase survival, enhance quality of life and occasionally result in a cure.
The group of sinonasal "small round blue cell tumors" may include squamous cell carcinoma, sinonasal
undifferentiated carcinoma, small cell undifferentiated (neuroendocrine) carcinoma, mucosal malignant
melanoma, rhabdomyosarcoma, hematolymphoid malignancies, and other malignant neoplasms (Table 1).
Table 1. Sinonasal Tract "Small Round Cell" Malignancies
|Squamous cell carcinoma|
Sinonasal undifferentiated carcinoma
Small cell undifferentiated (neuroendocrine) carcinoma
Mucosal malignant melanoma
Hematolymphoid malignancies (nasal-type T/NK cell lymphoma)
The following discussion will focus on the sinonasal undifferentiated carcinoma. The controversy
surrounding sinonasal undifferentiated carcinoma revolves around several issues, including (but not
limited to) its possible histogenesis, classification, and merit in considering it as a specific
Sinonasal Undifferentiated Carcinoma (SNUC)
- A high-grade malignant epithelial neoplasm of the
nasal cavity and paranasal sinuses of uncertain histogenesis with or without neuroendocrine
differentiation but without evidence of squamous or glandular differentiation.
- A highly aggressive and clinicopathologically
distinctive carcinoma of uncertain histogenesis that typically presents with locally extensive disease.
It is composed of pleomorphic tumor cells with frequent necrosis, and should be differentiated from other
carcinomas or olfactory neuroblastoma.
SNUC is a rare tumor, with fewer than 100 reported cases. There is a male predominance (2-3:1).
The age range is broad, usually ranging from the third to ninth decades; the median age at
presentation is in the sixth decade. SNUCs generally present as large tumors involving multiple
(sinonasal tract) sites and may also extend into the nasopharynx. Typically, patients present with
multiple symptoms, including nasal obstruction, epistaxis, and due to invasive growth proptosis, cranial
nerve palsies, visual disturbances, and pain. Symptoms are usually of short duration (weeks to months).
Radiographic studies often demonstrate a large (sinonasal) mass typically with local invasive growth
extending beyond its bony confines with involvement of orbital and/or cranial bones. Intracranial
extension may occur.
There are no known etiologic agents; SNUCs are typically negative for Epstein-Barr virus (EBV). Some
cases have been reported to develop following radiation therapy for nasopharyngeal carcinoma.
SNUCs are usually large tumors typically measuring more than 4 cm in greatest dimension, and tend to
be fungating with poorly-defined margins, and with invasion into adjacent structures and/or anatomic
compartments, including bone destruction.
The histologic appearance is characterized by a hypercellular proliferation with varied growth,
including trabecular, sheet-like, ribbons, lobular and organoid patterns. Surface involvement may be
seen in the form of severe dysplasia/carcinoma in-situ, but often there is ulceration which precludes
evidence of epithelial derivation. The cellular infiltrate consists of polygonal cells composed of
medium to large-sized, round to oval, hyperchromatic nuclei, inconspicuous to prominent nucleoli and a
varying amount of eosinophilic cytoplasm lacking syncytial quality; distinct cell borders can be seen.
The nuclear to cytoplasmic ratio is high. The mitotic rate is very high, including atypical mitoses and
there is often prominent tumor necrosis and apoptosis. Lymphovascular invasion is often identified, and
neurotropism is often present. Squamous or glandular differentiation is not present; neurofibrillary
material and true neural rosettes are not identified.
Histochemical studies are noncontributory to the diagnosis of SNUC; stains for epithelial mucin are
The immunohistochemical antigenic profile may vary from case to case, but SNUCs are consistently
immunoreactive with epithelial markers, including pan-cytokeratins, simple keratins, (CK 7, CK8 and
CK19), but not CK4, CK5/CK6 and CK14 (Tables 2 and 3). Reactivity for keratins is often intense and
diffuse. Less than half of the cases have been reported to be positive for epithelial membrane antigen,
neuron specific enolase (NSE), or p53. Positivity for synaptophysin, chromogranin, S100 protein or Leu-7
is only rarely observed. Vimentin, muscle markers (desmin, myoglobin, myf-4, actins) hematolymphoid
markers (leukocyte common antigen, B- and T-cell), melanocytic cell markers (HMB-45, melan A) and CD99
(Ewing marker) are absent.
By electron microscopy, rare membrane-bound, dense core neurosecretory granules have been noted, and
poorly formed desmosomes may occasionally be found.
Treatment and Prognosis
The treatment for SNUC includes intensive multimodality therapy, including surgical resection and
adjuvant therapy (radiotherapy, chemotherapy). However, SNUC is a highly-aggressive neoplasm that often
cannot be completely eradicated by surgery nor is it responsive to radiation treatment. Despite
aggressive management, the prognosis remains poor. The median survival is less than 18 months with a
5-year survival of less than 20%. Recent results suggest that more promising outcome may be achieved by
multimodality therapy including chemotherapy (cyclophosphamide, doxorubicin, and vincristine) followed by
radiotherapy and then radical surgery. High dose chemotherapy and autologous bone marrow transplantation
have been used. Local recurrence is common and is the major cause of morbidity and mortality. The tumor
can metastasize to cervical lymph nodes and to more distant sites, including liver, lung, bone and brain.
The differential diagnosis of SNUC includes poorly-differentiated squamous cell carcinoma, poorly
differentiated adenocarcinoma, olfactory neuroblastoma (high-grade), small cell undifferentiated
neuroendocrine carcinoma, mucosal malignant melanoma, nasal-type NK/T cell lymphoma, rhabdomyosarcoma,
others. While differences can be seen by light microscopic evaluation, often the differentiation rests
on the immunohistochemical staining profile for a given tumor (Table 2).
Table 2. Immunohistochemical (Selective) Reactivity of SNT Malignancies
| ||CK ||NSE ||CG ||SYN ||S100 ||HMB ||LCA ||CD56 ||CD99 ||VIM ||DES ||Myf4|
|SCC ||+ ||- ||- ||- ||- ||- ||- ||- ||- ||- ||- ||-|
|SNUC ||+ ||+ ||- ||- ||- ||- ||- ||- ||- ||- ||- ||-|
|ONB ||- ||+ ||+/- ||+/- ||+* ||- ||- ||- ||- ||- ||- ||-|
|SCNUC ||+ ||+ ||+ ||+ ||+ ||- ||- ||- ||- ||- ||- ||-|
|MMM ||- ||- ||- ||- ||+ ||+ ||- ||- ||- ||+ ||- ||-|
|T/NK ML ||- ||- ||- ||- ||- ||- ||v ||+ ||- ||v ||- ||-|
|RMS ||- ||- ||- ||- ||- ||- ||- ||- ||- ||+ ||+ ||+|
|PNET/EWS ||R+ ||v ||- ||v ||v ||- ||- ||- ||+ ||+ ||- ||-|
SCC - squamous cell carcinoma
SNUC - sinonasal undifferentiated carcinoma
SCUNC - small cell undifferentiated neuroendocrine carcinoma
MMM - mucosal malignant melanoma
T/NL ML - nasal type T/NK cell lymphoma
RMS - rhabdomyosarcoma
PNET/EWS - primitive (peripheral) neuroectodermal tumor/Extraosseous Ewings sarcoma
CK - cytokeratin
NSE - neuron specific enolase
CG - chromogranin
SYN - synaptophysin
S100 - S100 protein
HMB - HMB 45 (as well as other melanocytic markers [melanA])
CD99 - Ewing marker
VIM - vimentin
DES - desmin
+ = positive
- = negative
+/- = variably positive
R+ = rarely positive.
* = positive in the peripherally situated sustentacular cells
differences have been reported between keratinizing squamous cell carcinoma, non- keratinizing squamous
cell carcinoma, sinonasal undifferentiated carcinoma and nasopharyngeal undifferentiated carcinoma (Table
Table 3. Cytokeratin Expression in Various Carcinoma Types of the Sinonasal Tract and Nasopharynx*
| ||AE1/AE3 ||CK5/6 ||CK7 ||CK8 ||CK13 ||CK14 ||CK19|
|Squamous cell carcinoma ||+ ||+ (9/10) ||+ (6/10) ||+ (9/10) ||+ (9/10) ||+ (8/10) ||+ (9/10)|
|Nonkeratinizing squamous cell carcinoma ||+ ||+ (9/10) ||- ||+ (9/10) ||+ (9/10) ||+ (8/10) ||+ (9/10)|
|Sinonasal undifferentiated carcinoma ||+ ||- ||+ (3/6) ||+ (6/6) ||- ||- ||+ (3/6)|
|Nasopharyngeal carcinoma, undifferentiated type ||+ ||+ (4/5) ||- ||+ (4/5) ||+ (4/5) ||- ||+ (5/5)|
* from Franchi et al.
SNUC is a tumor of uncertain histogenesis. It seems likely that SNUC arises from the Schneiderian
epithelium and, therefore, is of ectodermal derivation. However, while speculative, given overlapping
clinical, light microscopic, immunohistochemical and ultrastructural features with olfactory
neuroblastoma and neuroendocrine carcinoma, the cell of origin may be related to both the Schneiderian
membrane and olfactory epithelia. Some authorities based on finding neuroendocrine features by
immunohistochemistry and electron microscopy have suggested that SNUC may be a neuroendocrine carcinoma
with classification essentially equivalent to the pulmonary large cell (neuroendocrine) carcinoma.
Irrespective of its cell of origin and perhaps even in the face of differentiated foci in limited
parts of the tumor (e.g., squamous cell differentiation), given its rather unique clinicopathologic
characteristics this tumor should be identified and classified as SNUC, thereby differentiating it from
the other specific types of sinonasal carcinomas and non-epithelial malignant tumors.
Sinonasal Undifferentiated Carcinoma
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NK/T Cell Lymphomas
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Sinonasal Tract Neuroendocrine Carcinoma
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