—  NORTH AMERICAN SOCIETY OF HEAD & NECK PATHOLOGY   —

Sinonasal Undifferentiated Carcinoma


Bruce M. Wenig
Beth Israel Medical Center
New York, NY


Introduction
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
Rhabdomyosarcoma
Hematolymphoid malignancies (nasal-type T/NK cell lymphoma)
PNET/Ewings sarcoma
Other

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 clinicopathologic entity.

Sinonasal Undifferentiated Carcinoma (SNUC)

Definitions:

  1. 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.
  2. 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.
Clinical
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.

Etiology
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.

Pathology
Gross
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.

Microscopic
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.

Special Studies
Histochemical studies are noncontributory to the diagnosis of SNUC; stains for epithelial mucin are negative.

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.

Differential Diagnosis
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

Cytokeratin staining differences have been reported between keratinizing squamous cell carcinoma, non- keratinizing squamous cell carcinoma, sinonasal undifferentiated carcinoma and nasopharyngeal undifferentiated carcinoma (Table 3).

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.

Histogenesis
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.

Classification
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.

References

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NK/T Cell Lymphomas

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Sinonasal Tract Neuroendocrine Carcinoma

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PNET/Ewings Sarcoma

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Rhabdomyosarcoma

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