Undifferentiated malignant neoplasms of the sinonasal tract.
SINONASAL UNDIFFERENTIATED CARCINOMA Definitions
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
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since its identification as a distinct sinonasal neoplasm, SNUC is being diagnosed with increasing frequency (B.M.W., unpublished data, 2009).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.
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)
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 Definition
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)
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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.
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.
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)
MUCOSAL MALIGNANT MELANOMA
Malignant melanomas are neural crest-derived neoplasms originating from melanocytes and demonstrating melanocytic differentiation.
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.
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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).
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.
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.
SMALL CELL (UNDIFFERENTIATED) NEUROENDOCRINE CARCINOMA
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.
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.
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.
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 LYMPHOMAS OF THE SINONASAL TRACT
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)
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.
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.
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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)
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).
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.
[FIGURES 13-15 OMITTED]
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.
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 (Table 5) have been identified with certain histologic types of RMS, and their identification may assist in the 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: email@example.com).
Table 1. Immunohistochemical (Selective) Reactivity of Sinonasal Tract Malignancies 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 positive. (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 Microscopic 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 Slight 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, pain 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 WG) 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) positive EBV Negative Strong association Treatment Cyclophosphamide and prednisone Radiotherapy for localized disease; chemotherapy for disseminated disease Prognosis Limited disease Overall survival associated with a 30%-50%; local good to excellent recurrence/relapse prognosis and and systemic failure occasional common spontaneous remissions; mortality related to complications of renal and pulmonary involvement 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 present 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 involved) 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, retroperitoneum) 3 Bladder, prostate, T1 or T2 [less than or extremity, cranial equal to] 5 cm; parameningeal sites, >5 cm other (trunk, retroperitoneum) 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, retroperitoneum) 3 Bladder, prostate, N1 N0 or M0 M0 extremity, cranial N1 or Nx parameningeal sites, other (trunk, retroperitoneum) 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 Adults 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