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Undifferentiated malignant neoplasms of the sinonasal tract.


Sinonasal undifferentiated carcinoma (SNUC) was originally defined as 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. (1) Subsequently, SNUC was redefined according to the World Health Organization classification as 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 it should be differentiated from other carcinomas or olfactory neuroblastoma.2

Clinical Features

Sinonasal undifferentiated carcinoma is a rare tumor, with fewer than 100 reported cases.2 However, since its identification as a distinct sinonasal neoplasm, SNUC is being diagnosed with increasing frequency (B.M.W., unpublished data, 2009). Neoplasms heretofore unclassified and/or previously "lumped" under the rubric of another defined sinonasal tract neoplasm are now being classified as SNUCs, contributing to greater frequency of diagnosis/ identification. There is a male predominance (2:1 to 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. Sinonasal undifferentiated carcinomas 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, because of invasive growth, proptosis, cranial nerve palsies, visual disturbances, and pain. (1-4) Symptoms are usually of short duration (weeks to months), representing a characteristic although not pathognomonic feature associated with SNUCs, contrasting with the more gradual onset of symptoms usually seen in association with other sinonasal tract undifferentiated malignant neoplasms. Radiographic studies often demonstrate a large (sinonasal) mass lesion, typically with invasive growth and often involving multiple separate although contiguous anatomic sites with extension into or destruction of bone and invasion of vital structures (eg, cranial nerves, orbit, optic chiasm, and/or cranial bones), and not infrequently with intracranial extension.


There are no known etiologic agents. Sinonasal undifferentiated carcinomas are typically negative for Epstein-Barr virus (EBV) by immunohistochemistry and in situ hybridization for EBV-encoded RNA, (5-7) although there are reports of SNUC-positive cases in Asian patients (8) and in Western (Italian) patients.9 Some cases have been reported to develop following radiation therapy for nasopharyngeal carcinoma. (7)


Gross Pathology.--Sinonasal undifferentiated carcinomas are usually large tumors typically measuring more than 4 cm in greatest dimension, and they tend to be fun-gating with poorly defined margins, and with invasion into adjacent structures and anatomic compartments, including bone destruction.

Microscopic Pathology.--The histologic appearance is characterized by a hypercellular proliferation with varied growth, including trabecular, sheetlike, ribbon, lobular, and organoid patterns (Figure 1). 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 (Figure 2). The nuclear to cytoplasmic ratio is high. The mitotic rate is very high, including atypical mitoses, and there is often prominent tumor necrosis, with individual cell and confluent foci. Invasive growth, including neurotropism, lymphatic-vascular invasion, or invasion of soft tissues (eg, skeletal muscle, bone, and others), is often identified. Given its undifferentiated features and definition requiring an absence of differentiated foci, squamous and glandular differentiation are not present, and neurofibrillary material and neural-type rosettes are not identified.

Special Stains

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 (AE1/AE3; Figure 3), low-molecular weight cytokeratin (CAM 5.2), and simple keratins (CKs 7, 8, and 19), but usually not CK4, CK5/CK6, and CK14. (6) Reactivity for keratins is often strong and diffuse. P63 staining (nuclear reactivity) is variably identified from case to case and even within the same case, but it is usually present, even if only focally. Fewer than half of the cases have been reported to be positive for epithelial membrane antigen, neuron-specific enolase, or p53. (6) A high proliferation rate as determined by Ki-67 (MIB1) staining is present. 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. (1,2)

Differential Diagnosis

The differential diagnosis of SNUC primarily includes poorly differentiated squamous cell carcinoma, high-grade/poorly differentiated adenocarcinoma, olfactory neuroblastoma (high-grade), small cell undifferentiated neuroendocrine carcinoma (NEC), mucosal malignant melanoma, nasal-type natural killer (NK)/T-cell lymphoma, and rhabdomyosarcoma. Although differences can be seen by light microscopic evaluation, often the distinction rests on the immunohistochemical staining profile for a given tumor (Table 1). Cytokeratin staining differences have been reported between keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, SNUC, and nasopharyngeal undifferentiated carcinoma (Table 2). (10)

Treatment and Prognosis

The ideal therapy for SNUCs remains controversial, but multimodality therapy, including neoadjuvant chemotherapy followed by surgery in resectable cases, may result in improved prognosis. Despite aggressive management, the prognosis remains poor, with a median survival rate of less than 18 months (6,7) and a 5-year survival of less than 20%. (1) Despite the overall poor survival, dramatic response to chemoradiation has been described. (11) 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 suggestion has been made that even in the presence of differentiated foci (eg, squamous cell differentiation), albeit focally, the diagnosis of SNUC can be rendered in the appropriate clinical setting unique to this neoplasm. (12) Recently, the entity of midline carcinoma with NUT rearrangement (NUT-rearranged carcinomas) has been identified. (13) In these cancers there is a balanced chromosomal translocation t(15;19), resulting in BRD4-NUT oncogene. These carcinomas arise from midline epithelial structures, occur in children and young adults, are undifferentiated carcinoma with striking squamous differentiation, are CD34 positive, and are highly lethal, with short survival (28 weeks). More recently, this entity termed undifferentiated carcinomas of upper aerodigestive tract with NUT rearrangements was identified in adults and characterized by the presence of undifferentiated carcinomas, some with abrupt squamous differentiation. (14) These cancers were EBV negative, showed rearrangements of NUT and BRD4 by fluorescent in situ hybridization, had more than 90% nuclear expression of NUT by immunohistochemistry, and were variably p63 immunoreactive. (14) Given their identification in adults, it is possible that one or more of the lesions described by Ejaz and Wenig (12) represent a NUT-rearranged carcinoma.


Olfactory neuroblastoma (ONB) is a malignant neoplasm thought to arise from the olfactory membrane of the sinonasal tract. Light microscopic and ultrastructural studies support the bipolar neurons of the olfactory membrane as the cell of origin. (15,16)


Clinical Features

Olfactory neuroblastoma is an uncommon malignant neoplasm. There is slight female predominance; ages at onset range from 3 years to the ninth decade, with a bimodal peak in the second and sixth decades of life. (15,16) The main presenting symptoms include unilateral nasal obstruction and epistaxis; less common manifestations include anosmia, headache, pain, excessive lacrimation, and ocular disturbances. It appears that ONB takes origin from the olfactory membrane located in the upper nasal cavity, which is the most common site of presentation. Included in the areas of proposed origin are Jacobson organ (vomeronasal organ), sphenopalatine (pterygoid palatine) ganglion, olfactory placode, and the ganglion of Loci (nervus terminalis). (16) "Ectopic" origin within one of the paranasal sinuses may occur.16 Radiologically, a sinonasal mass causing sinus opacification with or without bone erosion may be seen. Olfactory neuroblastoma may be associated with calcifications producing a speckled pattern by radiographic analysis. Angiographic studies may disclose a hypervascular neoplasm. (16)


There are no known etiologic agents. Cytogenetic abnormalities (translocation) have been seen in association with olfactory neuroblastomas. These include the 11:22 chromosomal translocation, a similar finding identified in both primitive (peripheral) neuroectodermal tumor and Ewing sarcoma. (17,18) Based on finding this chromosomal translocation in ONB, there is speculation relative to a shared histogenesis of ONB with the group of primitive neuroectodermal tumors. (19,20) However, unequivocal confirmation supporting the concept that ONB, SNUC, or NEC belong to the primitive neuroectodermal tumor family has not been identified, and many studies have contradicted the notion that ONB represents a PNET. (21-23) The chromosomal translocation is probably a key factor in oncogenesis rather than a "marker" of histogenesis.


Gross Pathology.--The gross appearance of ONB includes a glistening, mucosal-covered, soft, polypoid mass varying from a small nodule less than 1 cm to a mass filling the nasal cavity with possible extension into adjacent pranasal sinuses and nasopharynx.

Microscopic Pathology.--The histologic appearance is divided into 4 grades as defined by Hyams (Table 3). For the purposes of this manuscript relative to "undifferentiated malignant neoplasms of the sinonasal tract," this discussion will be limited to the histologically higher-grade ONBs (ie, grades 3 and 4). Regardless of the histologic grade, ONBs are submucosal-based neoplasms that retain lobular growth. However, in the histologically higher-grade neoplasms, the lobular architecture may be limited in extent, with much of the neoplasm showing solid growth. Grade 3 and grade 4 ONBs are characterized by a hypercellular neoplastic proliferation in which the cells are more anaplastic and hyperchromatic and have increased mitotic activity, including atypical mitoses, compared with grade 1 or 2 tumors (Figure 4). The neoplastic component in grade 4 neoplasms is the most undifferentiated and anaplastic of all the histologic grades characterized by pleomorphic nuclei, often with prominent eosinophilic nucleoli and indistinct cytoplasm. Further, necrosis (individual cell and/or confluent foci) is present. A neurofibrillary component may be focally present, but it is much less conspicuous compared with grade 1 or 2 tumors. True neural rosettes (Flexner-Wintersteiner rosettes) may be seen (Figure 5); however, in general, these structures are uncommonly identified. The Homer Wright pseudorosettes that can be seen in lower-grade ONBs are not a feature of the higher-grade neoplasms. Calcification is typically absent.

Special Stains

In general, the lower-grade ONBs are readily recognizable and diagnostic by light microscopy. Adjunct studies, particularly in the higher-histologic grade tumors, may assist in the diagnosis. Histochemical stains have been replaced by immunohistochemistry in the diagnosis of ONB. Nevertheless, silver stains, such as Bodian, Grimelius, and Churukian-Schenk, may be helpful. The most consistent immunohistochemistry stain in the diagnosis of ONB is the nonspecific stain neuron-specific enolase. In addition, characteristic S100 protein staining limited to the periphery of the neoplastic lobules (sustentacular cell-like staining pattern) is present, although such S100 protein staining diminishes with increased histologic grade, and in higher-grade ONBs it may be extremely limited in extent or absent (Figure 6). Variable reactivity is seen with glial fibrillary acidic protein, neurofibrillary protein, beta-tubulin, microtubule-associated protein, chromogranin, synaptophysin, and Leu-7. (15,16,24,25) Cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, leukocyte common antigen, HMB-45, and myogenic markers (eg, desmin, Myf-4, and others) are absent. Electron microscopy evaluation is a useful adjunct in the diagnosis and includes the presence of dense-core neurosecretory granules measuring from 80 to 250 nm in diameter. (16) In addition, neurofilaments, neurotubules and, occasionally, Schwann-like cells can be seen.

Differential Diagnosis

The differential diagnosis of ONBs, particularly the higher-grade neoplasms, primarily includes the other "undifferentiated" sinonasal tract neoplasms discussed in this article. Although differences can be seen by light microscopic evaluation, especially in the lower-histologic grade ONBs but also in higher-histologic grade ONBs, often the differentiation rests on the immunohistochemical staining profile for a given tumor (Table 1).

Treatment and Prognosis

For ONB, complete surgical eradication is the treatment of choice, followed by full-course radiotherapy. Limited success using chemotherapeutic modalities has been achieved for advanced unresectable tumors or for disseminated disease. Clinical staging as proposed by Kadish et al (26) correlates with 5-year survival: stage A, tumor confined to the nasal cavity (75%); stage B (most common), tumor involves the nasal cavity plus one or more para nasal sinuses (68%); stage C, extension of tumor beyond the sinonasal cavities (41%). Eden et al (27) reviewed the University of Virginia (Charlottesville) experience with ONB and reported that the overall 5-, 10-, and 15-year survival rates were 78%, 71%, and 68%, respectively. Mills and Frierson15 reported that complete tumor resection was of greater prognostic significance than the Kadish stage. More recently, disease-free actuarial survival and overall survival were reported to be 77% and 61% at 5 years and 53% and 42% at 10 years, respectively. (28) Most tumors behave as locally aggressive lesions mainly involving adjacent structures (orbit and cranial cavity). Local recurrence and distant metastasis may occur years after the initial diagnosis. From 30% to 70% of patients will experience local recurrence, 20% to 40% will have cervical lymph node metastasis, and approximately 10% of patients will experience distant metastasis.16 The more common sites of metastatic disease include lymph nodes, lungs, and bone. All histologic grades have the capacity to metastasize. Intracranial extension and orbital involvement have been identified as independent factors affecting outcome. (28)



Malignant melanomas are neural crest-derived neoplasms originating from melanocytes and demonstrating melanocytic differentiation.

Clinical Features

Approximately 15% to 20% of all malignant melanomas arise in head and neck sites, and of these, more than 80% are of cutaneous origin. Of the remaining approximately 20%, most are of ocular origin. Mucosal malignant melanomas (MMMs) of the upper aerodigestive tract represent from 0.5% to 3% of melanomas of all sites. (16) In the upper aerodigestive tract, the most common sites of occurrence are the oral cavity, (29) followed by the sinonasal tract. (16) Less common upper aerodigestive tract mucosal sites of occurrence include the nasopharynx, pharynx (oropharynx and hypopharynx), larynx, and the middle ear.

Mucosal malignant melanoma of the nasal cavity and paranasal sinuses affects men more than women; it occurs spanning a wide age range but most frequently in the sixth to eighth decades of life. (16) Symptoms vary according to the site of occurrence and include nasal obstruction, epistaxis, painful mass, hoarseness, and dysphagia. Nasal cavity malignant melanomas occur more frequently than those arising in the paranasal sinuses; however, concurrent nasal cavity and paranasal sinus melanomas frequently occur either as a result of direct extension or as multicentric tumors. Primary sites of involvement in the nasal cavity are septum, then lateral wall, and then middle and inferior turbinates. (30) Primary sites of involvement in the paranasal sinuses are maxillary (antrum), and then ethmoid. (30) Other sinuses rarely are involved as primary sites.



Gross Pathology.--A variety of gross appearances can be seen, including polypoid or sessile with or without ulceration, brown, black, pink or white, friable to rubbery, measuring from 1.0 cm to large tumors occluding the nasal cavity and/or paranasal sinus.

Microscopic Pathology.--In general, surface ulceration is a common finding. In tumors with intact surface epithelium, continuity of the tumor with the surface epithelium (junctional or pagetoid changes) can usually be identified. Cytomorphologic features include epithelioid or spindled cells; tumors with mixed epithelioid and spindle cells can be seen. Epithelioid cell features are varied, including solid, organoid, nested, trabecular, alveolar, and any combination of these growth patterns. The cells are round to oval, markedly pleomorphic with increased nuclear to cytoplasmic ratio, vesicular to hyperchromatic nuclei, prominent eosinophilic nucleoli, nuclear grooves, nuclear pseudoinclusions, and eosinophilic to clear cytoplasm (Figure 7). Plasmacytoid features may be prominent, but a paranuclear clear zone is not seen. Spindle cell features include storiform or fascicular patterns, which may be associated with a myxoid stroma. The cells are oblong to cigar shaped, and markedly pleomorphic, with large vesicular to hyperchromatic nuclei, absent to prominent nucleoli, and scant eosinophilic cytoplasm. For both cytomorphologic types, necrosis and increased mitoses with atypical mitotic figures are common findings. Neoplastic giant cells can be found rarely; glandular differentiation may be seen. Melanin may be heavily deposited with easy identification, or it may be limited or absent (Figure 7).

Special Stains

Histochemical stains show the tumor cells to be argentaffin and argyrophilic positive. Immunohistochemistry remains the diagnostic parameter of choice, with the presence of S100 protein (Figure 8, A) and HMB-45 (Figure 8, B); in addition, reactivity with Melan-A and tyrosinase are present. Vimentin positivity also is consistently identified. These immunohistochemical staining patterns are identified in all melanoma cell types, including epithelioid cells, spindle cells, and plasmacytoid cells. Cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, leukocyte common antigen, and myogenic markers (eg, desmin, Myf-4, and others) are absent. Ultrastructurally, melanosomes and premelanosomes can be seen.

Differential Diagnosis

The differential diagnosis of MMM primarily includes the other "undifferentiated" sinonasal tract neoplasms discussed in this article. Although differences can be seen by light microscopic evaluation, often the distinction rests on the immunohistochemical staining profile for a given tumor (Table 1).

Treatment and Prognosis

Radical surgical excision is the treatment of choice. Adjuvant radiotherapy and chemotherapy are of questionable value in the management of MMM. The recurrence rate for MMM varies from 67% to 92%. (16) Overall, the prognosis for MMM of all upper aerodigestive tract sites is poor, with 5-year survival rates generally less than 30%; 5-year disease-specific survival rates for sinonasal MMM range from 17% to 47%, and median survival is around 2 years. (16) Metastatic disease occurs most frequently to the lungs, lymph nodes, and brain. Pathologic criteria that are used to predict the biologic behavior in association with cutaneous melanomas, including the depth of invasion, age and sex of the patient, and cytomorphology, do not apply for MMM. In fact, for MMM of the head and neck, there is a lack of correlation between the depth of invasion and prognosis. However, significant adverse prognostic factors for MMM of the head and neck have been linked to advanced clinical stage at presentation, tumor thickness of greater than 5 mm, histologically proven lymph-vascular space invasion, and metastatic disease (regional and distant). (16) Nasal cavity melanomas have a better prognosis than paranasal sinus melanomas, perhaps because of earlier clinical presentation.



Neuroendocrine carcinoma (NEC) is a malignant neoplasm with divergent differentiation along both epithelial and neuroendocrine cell lines.


The classification of NEC is the subject on ongoing debate. The time-honored classification scheme divides these tumors into 3 types, including carcinoid tumor, atypical carcinoid tumor, and small cell carcinoma. Other schemes have proposed classifying these tumors according to differentiation to include: (1) well-differentiated NEC (equated with carcinoid tumor), (2) moderately differentiated NEC (equated with atypical carcinoid), and (3) poorly differentiated NEC (equated with small ["oat"] cell undifferentiated NEC [SCUNC]). (31) In the head and neck, some atypical carcinoids may fulfill diagnostic criteria of the large cell NEC of the lung. (32) Because of the time-honored terminology and to minimize confusion, the terms carcinoid, atypical carcinoid, and small cell carcinoma, as proposed by the World Health Organization, will be used in this section. (32,33) However, it should be kept in mind that the "atypical" carcinoid tumor is a fully lethal tumor, and the term atypical should not lull the clinician into a false sense of security that this tumor is only slightly different in its behavior from the relatively indolent "classic" carcinoid tumor. Among the group of NECs, the one that represents an "undifferentiated" malignant neoplasm and the only one to be discussed herein is the SCUNC.

Clinical Features

As a group, NECs are uncommon neoplasms of the head and neck. Neuroendocrine carcinomas may be identified in virtually all sites of the head and neck and are most common in the larynx. Involvement of other sites, including the sinonasal tract, is uncommon. (33) Among sinonasal tract NECs, the most common morphologic subtype is SCUNC. (33,34) Sinonasal tract SCUNC affects men and women equally and may occur spanning a wide age range, from 26 to 77 years and with a mean of 49 years. (32) The most common site of occurrence is the superior or posterior nasal cavity, often extending into the maxillary or ethmoid sinuses. (32) Primary tumors of the paranasal sinuses without nasal cavity involvement may occur in approximately 45% of cases. (32) There are no known etiologic agents in the development of sinonasal tract SCUNC.


Regardless of the site of occurrence, the histologic appearance of SCUNC is the same. These tumors are hypercellular and have varied growth, including sheets, cords, or ribbons. The cells are small and hyperchromatic, with oval to spindle-shaped nuclei, absent nucleoli, and minimal cytoplasm (Figure 9). Cellular pleomorphism, increased nuclear to cytoplasmic ratio, increased mitotic activity, confluent necrotic areas, and individual cell necrosis are readily apparent. Characteristically, crush artifact of the neoplastic cells is seen. Squamous cell foci may occasionally be present; glandular or ductal differentiation is rarely seen. Although uncommon, neural like rosettes can be seen in association with SCUNC. Small cell undifferentiated NECs are infiltrative tumors frequently associated with lymphatic-vascular space invasion and/or perineural invasion.

Special Stains

Small cell undifferentiated NECs may demonstrate the presence of epithelial mucin. Argyrophilia can be seen, but argentaffin staining is absent. Because of its poor differentiation, the immunohistochemical antigenic profile of SCUNC may be quite variable from case to case. Reactivity with the following antibodies may be present to a varying degree: cytokeratins, chromogranin (Figure 10), synaptophysin, CD56, neuron-specific enolase, and S100 protein. Cytokeratin reactivity may include a punctate paranuclear or globoid pattern. The paranuclear punctate staining for cytokeratin is a characteristic feature of Merkel cell carcinoma. Calcitonin is rarely present. Leukocyte common antigen, CK20, HMB-45, and HBA-71 (CD99, Ewing marker) are absent. Ultrastructural studies may show the presence of neurosecretory granules (when identified, measuring from 50 to 200 nm). Cellular junctional complexes, including desmosomes and tonofilaments, are scanty, and lumina (intercellular and intracellular) are usually absent.

Differential Diagnosis

The differential diagnosis of SCUNC primarily includes the other "undifferentiated" sinonasal tract neoplasms discussed in this article. Although differences can be seen by light microscopic evaluation, often the differentiation rests on the immunohistochemical staining profile for a given tumor (Table 1). Because of differences in the approach to therapy, the identification of SCUNC and differentiation from other "undifferentiated" malignant neoplasms carry significant importance.

Treatment and Prognosis

Sinonasal SCUNCs are highly malignant tumors commonly associated with local recurrence and distant metastatic disease.33 Because of the high rate of metastatic disease, surgery is not considered appropriate therapy. The preferred treatment for SCUNC is systemic chemotherapy and therapeutic irradiation. Prognosis is poor, with median survival rates of 14.5 months. (35) Metastatic disease is common, involving lung, liver, bone, lymph nodes, and brain.



Non-Hodgkin lymphoma of the sinonasal tract is a heterogeneous group of hematolymphoid malignancies in which the bulk of disease is within the sinonasal tract. (36) Non-Hodgkin lymphoma of the sinonasal tract includes lymphomas of B-cell lineage, T-cell lineage, and NK/ T-cell lineage: nasal cavity lymphomas are predominantly of NK/T-cell type, (36,37) and most B-cell lymphomas occur in the paranasal sinuses. (36,38) Among the B-cell lymphomas, the diffuse large B-cell lymphoma is the most common type; less often, other B-cell lymphomas of these sites occur, including Burkitt lymphoma, extranodal marginal B-cell lymphoma of the MALT type, and follicular lymphoma. (36,38) This discussion will be limited to extranodal (nasal type) NK/T-cell lymphoma, because it represents the most common lymphoma of these anatomic sites. (36)


Synonyms for Non-Hodgkin lymphoma of the sinonasal tract have included such terms as polymorphic reticulosis, lethal midline granuloma, midline malignant reticulosis, and idiopathic midline destructive disease. Although these terms have been used over the years synonymously with Non-Hodgkin lymphoma of the sinonasal tract, these designations are inaccurate. Nonneoplastic lesions, inflammatory and infectious diseases, as well as numerous benign and malignant neoplasms of the sinonasal tract may all result in a destructive process occurring in the midline aspect of this region. Therefore, idiopathic midline destructive disease is not a specific term and should never be used to indicate a diagnosis of a malignant lymphoproliferative neoplasm. The current designations for these lymphomas include angiocentric immunoproliferative lesions, peripheral T-cell lymphomas and, more recently, extranodal (nasal-type) angiocentric T/NK-cell (malignant) lymphomas. (36)

Clinical Features

Natural killer/T-cell lymphoma of nasal type primarily affects men and is a disease of adults, with a median age in the sixth decade of life. (36) It is most common in Asians and has been reported with significant frequency in South and Central America and Mexico. (36,39) In these populations, the disease is seen primarily in individuals of Native American origin. These findings suggest a racial predisposition for the disease. Although uncommon, NK/T-cell lymphomas of nasal type also occur in Western populations and can affect whites.

Natural killer/T-cell lymphoma of nasal type commonly presents as a destructive process of the midfacial region, with nasal septal destruction, palatal destruction/perforation, or orbital swelling, or with obstructive symptoms related to a mass. (36) A small percentage of cases present with hematophagocytic syndrome with pancytopenia. (36,40,41) Antineutrophil cytoplasmic antibody levels are not elevated in association with NK/T-cell lymphoma (or with B-cell lymphomas).


Regardless of ethnic background, NK/T-cell lymphoma of the nasal type is strongly associated with EBV. (36) An increased risk of sinonasal lymphomas, primarily diffuse large cell B-cell lymphoma, but also NK/T-cell lymphoma of nasal type, is also associated with immunosuppression, including posttransplantation and human immunodeficiency virus infection. (36)


Histologically, NK/T-cell lymphomas may show a broad cytologic spectrum, but cytologically atypical cells are usually present. (42,43) The atypical cells may vary from small- and medium-sized cells to large, hyperchromatic cells. The atypical cells may have irregular and elongated nuclei, prominent nucleoli, or clear cytoplasm (Figure 11). Increased mitotic activity often is seen. An associated prominent admixed inflammatory cell infiltrate may be present. The polymorphous cell population may obscure the atypical cells, causing diagnostic difficulties. The benign inflammatory cell infiltrate may include plasma cells, histiocytes, and eosinophils; multinucleated giant cells and true granulomas are absent. In adequately sampled material, the low-power appearance includes the presence of geographic necrosis characterized by bluish or so-called gritty necrosis. Necrosis is a virtually constant (but not pathognomonic) feature; the zonal pattern of distribution suggests a vascular pathogenesis. The atypical cells invade and destroy blood vessels (Figure 12, A). The vascular invasion and destruction are responsible for the designation angiocentric lymphomas. Angiocentricity is defined as the presence of tumor cells around and within vascular spaces, with infiltration and destruction of the vessel wall; perivascular localization is not sufficient for the designation of angiocentricity. (42) Epitheliotropism and pseudoepitheliomatous hyperplasia may be present.

Special Stains

Histochemical stains for microorganisms are negative. Elastic stains may assist in the identification of angioinvasion (Figure 12, B). An NK-cell immunophenotype is most commonly present, including CD2 positive, surface (membranous) CD3 negative, cytoplasmic CD3e positive, and CD56 (neural cell adhesion molecule) positive. (36,42,43) T-cell markers, including CD43 and UCHL1 (CD45RO), are positive. Expression of perforin, TIA 1, and granzyme B, indicative of a cytotoxic phenotype, is present. (36,44) T-cell receptor genes are often in germ line configuration. Tumors that are CD56 negative may still be classified as NK/T-cell lymphomas if they express T-cell markers and cytotoxic markers and are EBV positive.


Cytogenetics and Molecular Genetics

Natural killer/T-cell lymphomas are positive for EBV in more than 95% of cases by in situ hybridization for EBV-encoded early RNAs. (36) Because EBV-positive cells are typically absent in the nasal cavity mucosa or in inflammatory diseases of the nasal cavity, the presence of EBV by in situ hybridization can be used in conjunction with light microscopy in the diagnosis of nasal cavity NK/T-cell lymphomas. Epstein-Barr virus may induce the expression of cytokines (eg, TNFa), which could lead to the presence of necrosis; this might then represent the pathogenesis for the observed necrosis in those cases without vascular invasion. A similar phenomenon can be seen in benign and malignant EBV-positive lymphoproliferative disorders, including infectious mononucleosis, posttransplantation lymphoproliferative disorders, and lymphomatoid granulomatosis. Expression of Fas and Fas ligand, a frequent finding in NK/T-cell lymphomas, also may account for the presence of necrosis. (36,44) Overexpression of p53 protein occurs in up to 86% of cases; p53 mutation is less common. (45)

Differential Diagnosis

The differential diagnosis includes infectious diseases (eg, mucormycosis, aspergillosis), and histochemical stains for microorganisms are indicated in order to exclude the presence of an infectious agent. In addition, the differential diagnosis also includes Wegener granulomatosis (Table 4). The constellation of histologic features associated with Wegener granulomatosis, coupled with the absence of cytologic atypia and the presence of elevated antineutrophil cytoplasmic antibodies, assists in confirming a diagnosis of Wegener granulomatosis and differentiating it from NK/T-cell lymphoma. The differential diagnosis also includes the other "undifferentiated" sinonasal tract neoplasms discussed in this article. Although differences can be seen by light microscopic evaluation, often the differentiation rests on the immunohistochemical staining profile for a given tumor (Table 1).

Treatment and Prognosis

Most NK/T-cell lymphomas of nasal type are localized at presentation (stage IE/IIE). Radiotherapy and/or chemotherapy is the treatment of choice for localized disease. (36) Natural killer/T-cell lymphomas are radiosensitive tumors, but the prognosis is generally poor once dissemination occurs. The treatment in disseminated disease is aggressive chemotherapy. In some patients, surgical resection may be needed for symptomatic relief (eg, airway obstruction). The overall survival is 30% to 50%. (36) Local recurrence/relapse and systemic failure are common. In patients achieving complete remission, local relapse occurs in 33% to 50% of cases. (46,47) Systemic failure includes increased risk of dissemination to skin, testes, and gastrointestinal tract. A complication seen in some cases of NK/ T-cell lymphoma of nasal type is hemophagocytic syndrome, which adversely affects survival. Other factors that have a negative impact on prognosis include advanced-stage disease, poor performance status, B symptoms (eg, fever, night sweats), and bulky disease. (48)



Rhabdomyosarcomas (RMS) are malignant mesenchymal tumors of skeletal muscle cells (rhabdomyoblasts).

Clinical Features

Rhabdomyosarcoma comprises approximately 8% of all pediatric sarcomas and 2% to 5% of all adult sarcomas. (49) Rhabdomyosarcoma is the most common sarcoma to occur in the head and neck, with up to 45% of rhabdomyosarcomas occurring in this location. (49) In the head and neck region, the most common site of occurrence is parameningeal RMSs (16%), followed by the orbit (9%).49 Among the other (less common) sites of occurrence in the head and neck (in descending order) are the nasopharynx, ear (middle ear and mastoid), and sinonasal cavity; less commonly, RMS may occur in other sites of the head and neck.

For head and neck RMSs, there is no sex predilection, and they most commonly occur in the first and second decades of life; occurrence is uncommon beyond the fifth decade of life. However, RMS can occur in the adult population and should be considered in the differential diagnosis of any small round cell malignant tumor, regard less of age. Relative to sinonasal tract RMSs, symptoms include nasal obstruction, epistaxis, pain, refractory otitis media, otorrhea, temporofacial swelling or deformity, and neurologic deficits. There are no known associated etiologic factors.


Gross Pathology.--The gross appearance may vary according to the site involved. Sinonasal RMSs tend to be small and appear as a nasal polyp. Nasopharyngeal RMSs tend to be fairly well circumscribed, polypoid or multinodular, tan-white, glistening or gelatinous, and capable of attaining large sizes. Aural RMSs most commonly present as an otic (external or middle ear) polyp. Approximately 25% of nasopharyngeal and sinonasal cavity RMSs assume a sarcoma botryoides appearance with a "grapelike" multinodular or polypoid configuration. Sarcoma botryoides is a macroscopic identification and is not considered a separate histologic variant.


Microscopic Pathology.--Most RMSs of the head and neck are of the embryonal type (71%), followed by alveolar type (13%). (49,50) The botryoid type of embryonal RMS represents approximately 2% of head and neck RMSs. (49,50) The other histologic types may occur in the head and neck but are uncommon. Of reported cases of spindle cell RMS, an uncommon subtype of embryonal RMS, 27% are located in the head and neck region. (49)

Embryonal RMS represents the most common histologic variant seen in the head and neck region and is the most common type seen in pediatric age groups. Typically, there is a variation in the cellularity of these tumors, with alternating hypercellular and hypocellular areas; the latter often are associated with a myxoid stroma (Figure 13). The cellular components consist of both round and spindle cells. The round cells resemble lymphocytes and are round to oval, with hyperchromatic nuclei and an acidophilic to amphophilic, distinct to indistinct cytoplasm. The spindle cells are elongated, with central hyperchromatic nuclei and eosinophilic cytoplasm. The nuclei tend to have pointed ends. Mitoses and necrosis are commonly seen. The stroma may be myxoid, fibrillary, or edematous. Sarcoma botryoides (botryoid RMS) is a variant of embryonal RMS characterized by its gross appearance that includes a polypoid and a myxoid mass. Histologically, the tumor may demonstrate the presence of a cambium layer, in which a subepithelial condensation of the neoplastic cells is seen.

Alveolar RMS predominates in adults and is characterized by the presence of ill-defined collections of noncohesive tumor cells, the central portions of which appear empty or markedly hypocellular, giving the appearance of forming spaces or alveoli (Figure 14). Portions of the tumor do not take on the alveolar appearance, but rather are composed of solid aggregates of tumor cells arranged in a trabecular pattern. The cellular portions of the tumor are separated by dense, fibrous, connective tissue forming septa and associated with prominent vascular spaces. The tumor cells are round to oval to spindle shaped, with hyperchromatic nuclei, inconspicuous nucleoli, and an acidophilic to amphophilic cytoplasm. Increased mitotic activity, including atypical mitoses, may be present, and necrosis can be seen. Multinucleated giant cells with peripherally placed nuclei are a prominent feature.

Regardless of the histologic variant, rhabdomyoblasts, the cells of origin for this sarcoma, represent the key di agnostic feature. Rhabdomyoblasts take on numerous appearances, including small round cells to ribbon or strap shaped to large and pleomorphic. Rhabdomyoblasts with cross-striations are not always identified, and their absence does not exclude the diagnosis of RMS.

Special Stains

Histochemical stains may be of assistance in the diagnosis. The neoplastic cells demonstrate the presence of intracytoplasmic glycogen (diastase sensitive, periodic acid-Schiff positive). Stains for epithelial mucin are negative. Intracellular myofibrils can be seen by Masson trichrome and phosphotungstinic acid hematoxylin stains.

Immunohistochemistry is an important adjunct in the diagnosis of RMS and includes immunoreactivity with desmin, myoglobin, MyoD1 (Myf-4), muscle-specific actin positive, and vimentin (Figure 15). In general, there is no immunoreactivity seen with epithelial markers (cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, and others), leukocyte common antigen, neuroendocrine markers (chromogranin, synaptophysin, neuron-specific enolase, Leu-7, glial fibrillary acidic protein, neurofibrillary protein), S100 protein, or HMB-45 (CD99 or Ewing marker).

Cytogenetic Abnormalities

Cytogenetic abnormalities (Table 5) have been identified with certain histologic types of RMS, and their identification may assist in the diagnosis.

Differential Diagnosis

The differential diagnosis also includes the other "undifferentiated" sinonasal tract neoplasms discussed in this article. Although differences can be seen by light microscopic evaluation, often the distinction rests on the immunohistochemical staining profile for a given tumor (Table 1).

Treatment and Prognosis

A major factor dictating the mode of therapy used in the treatment of RMS is the anatomic site of occurrence. (49) For head and neck RMS, including the sinonasal tract, multimodality therapy, including surgery, radiation, and chemotherapy, is typically indicated. The role of surgery may be limited to tissue diagnosis in patients with small, metastatic, or unresectable lesions. (51) Following biopsy diagnosis, recommendations for treatment depend on several factors, including site of the disease, clinical group of the disease, and stage of the disease. Tumor staging is an important element in the overall approach to treating the disease; because there is a tendency to bone marrow metastasis, a bone marrow aspiration/biopsy is part of the staging process. Clinical staging is detailed in Table 6. (52) Tumor-node-metastasis classification is listed53 in Table 7; this classification relies on pretreatment assessment of the extent of tumor. Favorable and unfavorable factors are listed in Table 8. (49) Overall 5-year survival rates based on clinical staging into low-risk, intermediate-risk, and high-risk groups are 95%, 75%, and 27%, respectively. (49,54) Prognosis is best for orbital RMS, followed by head and neck and genitourinary (nonbladder/prostate) RMS; 5-year survival rates include: orbit, 92%; head and neck, nonprostate/ bladder RMS, 80%; and parameningeal, bladder, prostate, extremities, 70%. (49) Adverse outcomes accounting for prognostic differences related to anatomic sites have been linked to late detection of tumor, large tumor size, difficulties during surgical excision, meningeal involvement with or without spinal fluid spread, and metastatic disease. (49) Metastatic sites may include regional lymph nodes and/or distant hematogenous metastasis to the lungs, bone marrow, and other viscera (eg, brain, meninges, liver, kidney, pancreas, and heart).

Accepted for publication January 15, 2009.


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Bruce M. Wenig, MD

From the Department of Pathology and Laboratory Medicine, Beth Israel Medical Center, St. Luke's-Roosevelt Hospitals, New York, New York.

The author has no relevant financial interest in the products or companies described in this article.

Presented in part at the Surgical Pathology of Neoplastic Diseases course, Memorial Sloan-Kettering Cancer Center, New York, New York, May 12-16, 2008.

Reprints: Bruce M. Wenig, MD, Department of Pathology and Laboratory Medicine, Beth Israel Medical Center, St. Luke's-Roosevelt Hospitals, First Avenue at 16th Street, New York, NY 10003 (e-mail:
Table 1. Immunohistochemical (Selective) Reactivity of Sinonasal Tract

           CK   NSE   CG   SYN   S100    HMB   LCA   CD56   CD99

SCC        +    -     -    -     -       -     -     -      -
SNUC       +    v     -    -     -       -     -     -      -
ONB        -    +     v    v     + (a)   -     -     -      -
SCUNC      +    +     +    +     +       -     -     -      -
MMM        -    -     -    -     +       +     -     -      -
T/NK ML    -    -     -    -     -       -     v     +      -
RMS        -    -     -    -     -       -     -     -      -
PNET/EWS   R+   v     -    v     v       -     -     -      +

           VIM   DES   Myf-4

SCC        -     -     -
SNUC       -     -     -
ONB        -     -     -
SCUNC      -     -     -
MMM        +     -     -
T/NK ML    v     -     -
RMS        +     +     +
PNET/EWS   +     -     -

Abbreviations: CD99, Ewing marker; CG, chromogranin; CK, cytokeratin;
DES, desmin; HMB, HMB-45 (as well as other melanocytic markers
[Melan-A]); LCA, leukocyte common antigen; MMM, mucosal malignant
melanoma; NSE, neuron-specific enolase; ONB, olfactory neuroblastoma;
PNET/EWS, primitive (peripheral) neuroectodermal tumor/extraosseous
Ewing sarcoma; RMS, rhabdomyosarcoma; SCC, squamous cell carcinoma;
SCUNC, small cell undifferentiated neuroendocrine carcinoma; SNUC,
sinonasal undifferentiated carcinoma; SYN, synaptophysin; S100, S100
protein; T/NK ML, nasal-type natural killer/T-cell lymphoma; v,
variably positive; VIM, vimentin; +, positive; -, negative; R+, rarely

(a) Positive in the peripherally situated sustentacular cells.

Table 2. Cytokeratin (CK) Expression in Various Carcinoma Types of the
Sinonasal Tract and Nasopharynx (a)

        AE1/AE3   CK5/6      CK7        CK8        CK13

SCC     +         + (9/10)   + (6/10)   + (9/10)   + (9/10)
NKSCC   +         + (9/10)   -          + (9/10)   + (9/10)
SNUC    +         -          + (3/6)    + (6/6)    -
NPC     +         + (4/5)    -          + (4/5)    + (4/5)

        CK14       CK19

SCC     + (8/10)   + (9/10)
NKSCC   + (8/10)   + (9/10)
SNUC    -          + (3/6)
NPC     -          + (5/5)

Abbreviations: NKSCC, nonkeratinizing squamous cell carcinoma; NPC,
nasopharyngeal carcinoma, undifferentiated type; SCC, squamous cell
carcinoma; SNUC, sinonasal undifferentiated carcinoma.

(a) Values show positive (+) or negative (-), with number expressing
positivity over total number in parentheses.

Table 3. Hyams Histologic Grading System for Olfactory Neuroblastoma

Features          Grade 1       Grade 2       Grade 3       Grade 4

Architecture      Lobular       Lobular       With or       With or
                                              without       without
                                              lobular       lobular

Pleomorphism      Absent to     Present       Prominent     Marked

Neurofibrillary   Prominent     Present       May be        Absent
matrix                                        present

Rosettes          Present (a)   Present (a)   May be        May be
                                              present (b)   present (b)

Mitoses           Absent        Present       Prominent     Marked

Necrosis          Absent        Absent        Present       Prominent

Glands            May be        May be        May be        May be
                  present       present       present       present

Calcification     Variable      Variable      Absent        Absent

(a) Homer-Wright rosettes (pseudorosettes).

(b) Flexner-Wintersteiner rosettes (true neural rosettes).

Table 4. Wegener Granulomatosis (WG) Versus Natural Killer/T-Cell
(NK/T-Cell) Lymphoma

                                                Angiocentric NK/T-Cell
                       WG                       Lymphoma

Sex/age                Male > female; fourth    Male > female; sixth
                       to fifth decades;        decade; most common in
                       laryngeal WG affects     Asians; occurs in
                       female > male            Western population but
                                                with less frequency

Location               Localized UADT WG most   Generally limited to
                       common in nasal          the sinonasal region;
                       cavity > paranasal       extrasinonasal occurs
                       sinuses; other sites     and represents a
                       may include              higher-stage tumor
                       nasopharynx, larynx
                       (subglottis), oral
                       cavity, trachea, ear,
                       salivary glands

Symptoms               Sinonasal tract:         Destructive process of
                       sinusitis, with or       midfacial region: nasal
                       without purulent         septal perforation,
                       rhinorrhea,              obstruction, palate
                       obstruction, pain,       destruction, orbital
                       epistaxis, anosmia,      swelling
                       headaches; larynx:
                       dyspnea, hoarseness,
                       voice changes; oral:
                       ulcerative lesion;
                       ear: hearing loss,

Systemic involvement   ELK Classification:      Most are localized
                       E, ear, nose, throat;    (stage IE/IIE); may
                       L, lung; K, kidney;      progress to
                       E, EL (limited-form      disseminated/
                       WG); ELK (systemic       systemic involvement

Serology               ANCA positive:           ANCA negative; no
                       increased in both        specific serologic
                       primary disease          marker(s)
                       and recurrent
                       disease; C-ANCA
                       more specific
                       than P-ANCA

Histology              Polymorphous (benign)    Overtly malignant
                       cellular infiltrate;     cellular infiltrate,
                       vasculitis;              but in early phases
                       ischemic-type            malignant cells may
                       necrosis; isolated       not be overtly
                       multinucleated           identifiable;
                       giant cells (not         angiocentricity and
                       well-formed              angioinvasion;
                       granulomas);             ischemic-type necrosis
                       negative cultures and    no giant cells or
                       stains for organisms     granulomas; negative
                                                cultures and stains
                                                for organisms

Immunohistochemistry   Polymorphous and         CD56, CD2, cytoplasmic;
                       polyclonal               CD3e positive; T-cell
                                                markers (CD3, UCHL-1)

EBV                    Negative                 Strong association
Treatment                                       Cyclophosphamide and
                                                prednisone Radiotherapy
                                                for localized disease;
                                                chemotherapy for

Prognosis              Limited disease          Overall survival
                       associated with a        30%-50%; local
                       good to excellent        recurrence/relapse
                       prognosis and            and systemic failure
                       occasional               common
                       mortality related
                       to complications
                       of renal and

Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; EBV,
Epstein-Barr virus; UADT, upper aerodigestive tract.

Table 5. Cytogenetics of Rhabdomyosarcoma (RMS)

Embryonal RMS
  Loss of heterozygosity at chromosome 11p15.5
  Short arm of chromosome 11 abnormalities
  PAX3/FKHR and PAX7/FKHR fusion transcripts uncommonly

Botryoid variant of embryonal RMS
  Deletion of short arm of chromosome 1
  Trisomies of chromosomes 13 and 18e

Spindle cell RMS

  No data regarding cytogenetic abnormalities

Alveolar RMS
  t(2;13)(q36;q14) translocation: most cases
  t(1;13)(p36;q14) translocation: minority of cases
  PAX3/FKHR fusion transcript (80%-90% of cases)
  PAX7/FKHR fusion transcript (10%-20% of cases)

Table 6. Clinical Staging of Rhabdomyosarcoma

Group I

  Localized disease, completely resected (regional nodes not

  Confined to muscle or site/organ of origin

  Contiguous involvement with infiltration outside the muscle
    or organ of origin, as through fascial planes

Group II

  Grossly resected tumor with microscopic residual disease

  No evidence of gross residual tumor; no evidence of regional
    nodal involvement

  Regional disease completely resected

  Regional disease with involved nodes, grossly resected but
    with evidence of microscopic residual disease

Group III

  Incomplete resection or biopsy with gross residual disease

Group IV

  Distant metastatic disease at presentation

Table 7. Tumor-Node-Metastasis (TNM) Staging for Rhabdomyosarcoma

Stage   Sites                  Tumor      Size

1       Orbit, head            T1 or T2   [less than or
        and neck, GU                      equal to] 5 cm;
                                          >5 cm

2       Bladder, prostate,     T1 or T2   [less than or
        extremity, cranial                equal to] 5 cm
        parameningeal sites,
        other (trunk,

3       Bladder, prostate,     T1 or T2   [less than or
        extremity, cranial                equal to] 5 cm;
        parameningeal sites,              >5 cm
        other (trunk,

4       All                    T1 or T2   [less than or
                                          equal to] 5 cm;
                                          >5 cm

Stage   Sites                  Node       Metastasis

1       Orbit, head            N0 or N1   M0
        and neck, GU           or Nx

2       Bladder, prostate,     N0 or Nx   M0
        extremity, cranial
        parameningeal sites,
        other (trunk,

3       Bladder, prostate,     N1 N0 or   M0 M0
        extremity, cranial     N1 or Nx
        parameningeal sites,
        other (trunk,

4       All                    N0 or N1   M1

Abbreviations: GU, genitourinary excluding bladder and prostate; M0,
no distant metastasis; M1, distant metastasis; N0, regional lymph
nodes not clinically involved; N1, regional lymph nodes clinically
involved; NX, status of regional lymph nodes unknown; T1, confined to
anatomic site; T2, extension and/or fixation to surrounding tissues.

Table 8. Favorable and Unfavorable Factors
for Rhabdomyosarcoma

Prognostically favorable

  Infants and children
  Orbital or genitourinary location (nonbladder or prostate)
  Small size (less than 5 cm)
  Botryoid or spindle cell type
  Localized noninvasive tumor without regional lymph node
    involvement or distant metastasis
  Complete initial resection

Prognostically unfavorable

  Location in head and neck (nonorbital), paraspinal region,
    abdomen, biliary tract, retroperitoneum, perineum, or extremities
  Large size (greater than 5 cm)

  Alveolar (especially PAX3/FKHR fusion transcript positive) or
    pleomorphic type
  Local tumor invasion, especially parameningeal or paraspinal
    region, paranasal sinuses, or skeleton
  Local recurrence whether or not during therapy
  Regional lymph node or distant metastasis
  Incomplete initial resection or unresectability
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Date:May 1, 2009
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