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Updates on Immunohistochemical and Molecular Markers in Selected Head and Neck Diagnostic Problems.

The head and neck branch of surgical pathology embraces diseases arising from the ear, nose, sinuses, mouth, pharynx, larynx, trachea, thyroid, parathyroid, and salivary glands. The most common malignant neoplasm in these regions is squamous cell carcinoma. However, owing to the complex anatomic structures of the head and neck, a large variety of tumors of epithelial, mesenchymal, lymphoid, melanocytic, and sometimes uncertain origins are encountered. These tumors could mimic reactive, inflammatory, and infectious conditions, and also share morphologic similarities in the form of epithelioid cell, spindle cell, and small round cell differentiation.

Some of the tumors are very rare, highly aggressive, and diagnostically challenging. They often present as an advanced disease with regional or distant metastases. In most cases, surgical excision with wide and clear margins is the best treatment option to achieve optimal prognosis. However, sometimes the neoplasms may involve a relatively small region containing nearby cranial bones, the palate and mandible, cranial nerves, and major vessels, and this may render complete excision of the tumor difficult. Awareness of these highly malignant entities and prompt diagnosis is important to early intervention. Thus, immunohistochemical and emerging molecular markers play an important role in aiding in the diagnosis of these tumors. Some markers can also be used as indicators for disease progression and prognosis. In this article we reviewed the most recent updates of immunohistochemistry and molecular studies of selected head and neck neoplasms.

Head and neck tumors can be classified according to the location of anatomy structures as follows: (1) nasal cavity and paranasal sinus; (2) oral cavity, larynx, and hypopharynx; (3) trachea; (4) ear and temporal bone; (5) major and minor salivary glands; and (6) thyroid and parathyroid. By definition, some entities are site specific, such as sinonasal undifferentiated carcinoma and parathyroid carcinoma, while other entities may arise from multiple sites, such as mucosal melanoma. The epidemiology, demographics, signs and symptoms, gross morphology, and the updated utility of immunohistochemical and molecular markers are discussed for each selected disease.


Example 1: Mammary Analog Secretory Carcinoma

A 59-year-old woman presented with a left parotid mass (Figure 1, A and B), which was well circumscribed with secretory cells, adjacent to parotid gland (Figure 1, C).1 Some areas of the carcinoma exhibited features similar to ductal carcinoma in situ of the breast (Figure 1, D). There was a ductal cystic area with intraductal papillae (Figure 1, E). The morphology of the carcinoma appeared to be low grade, but with vascular invasion (Figure 1, F). The carcinoma was positive for cytokeratin (CK) 7 (Figure 1, G), CK18, mammaglobin (Figure 1, H), S100 protein (S100) (Figure 1, I), and signal transducer and activator of transcription 5a (STAT5a); focally positive for p63 protein (p63); and negative for gross cystic disease fluid protein 15 (GCDFP-15), discovered on GIST-1 (DOG1), smooth muscle actin (SMA), calponin, and estrogen receptor/ progesterone receptor (ER/PR). Finally, the ETS variant 6-neurotrophic tyrosine receptor kinase 3 gene fusion (ETV6NTRK3) by fluorescence in situ hybridization was diagnostic (Figure 1, J). (2)

Mammary analog secretory carcinoma (MASC) was first described in 2010 as a rare salivary gland malignancy characterized by its similarities to breast secretory carcinoma by histology, immunohistochemistry, and genetics. (3) In the original report, (3) the incidence was 0.53% of all salivary tumors (16 of 3000), with a mean age of 46 years (range: 21-75 years). Most cases occurred in the parotid gland, and the mean size of the tumor was 2.1 cm (range: 0.7-5.5 cm). There was no sex predilection.

MASC is a low-grade, well-circumscribed, painless, and slow-growing malignant tumor. (4) It is composed of variable papillary, micropapillary, cystic, microcystic, tubular, and solid growth patterns with extracellular secretion (Figure 1). The tumor cells have low proliferation rate with low-grade nuclei and moderate eosinophilic and granular cytoplasm. (4,5)

MASC and breast secretory carcinoma share positivity for mammaglobin, S100, vimentin, and epithelial membrane antigen (EMA). They also have a common balanced translocation, t(12; 15)(p13; q25). The resultant ETV6-NTRK3 fusion product is a constitutively active chimeric tyrosine kinase and has transformation capacity in the mammary epithelial and myoepithelial cells. (3) One report (6) showed that MASC did not have the mutations associated with 50 common cancer-related genes or methylation of Ras association domain family 1 isoform A (RASSF1A) and retinoic acid receptor [beta]2 (RARB2), which had been observed in other malignant salivary gland tumors.

GCDFP-15, p63, and calponin also show positivity in some MASC tumors, and the latter are negative for ER, PR, and human epidermal growth factor receptor 2 (HER2). (7,8) In addition, they are positive for pancytokeratin AE1/AE3 (AE1/AE3), CK7, CK8, CK18, and STAT5a. (7,9) The major differential diagnoses of MASC are acinic cell carcinomas (ACCs); mucoepidermoid carcinomas (MECs); adenocarcinomas, not otherwise specified; and cystadenocarcinomas. (3,8) It should be mentioned that in salivary gland tumors, the ETV6-NTRK3 fusion is unique to MASC. (10) The fusion protein can be used to distinguish MASC from ACC. Although MASC is considered a type of secretory carcinoma of salivary gland, not uncommonly it has been misdiagnosed as ACC. MASC can also be distinguished from ACC by the lack of zymogen granules and by its unique immunoprofile such as strong S100, vimentin, and mammaglobin positivity. Meanwhile, ACC is positive for DOG1, a salivary acini and intercalated duct marker. (3,8,10) MASC also may be differentiated from MEC by the strong expression of S100.

The prognosis for low-grade MASC is very good, although local recurrence may occur, and rarely there is distant metastasis. Only 5 cases of high-grade MASC have been reported, with perineural invasion and lymphovascular invasion, metastasis to cervical lymph nodes, and poor prognosis. (9)


Example 2: Salivary Duct Carcinoma of the Parotid

An 85-year-old man presented with a right partoid mass (Figure 2, A). Microscopically it showed areas of tumor necrosis (Figure 2, B), solid areas with high-grade invasive tumor (Figure 2, C), and intraneural invasion (Figure 2, D). Immunostains showed CK18 positivity (Figure 2, E) and androgen receptor positivity (Figure 2, F).

Salivary duct carcinoma (SDC) is a rare malignant neoplasm that represents approximately 1% to 6% of all salivary gland malignancies. The parotid gland is most commonly involved. (11) It was first described by Kleinsasser et al (12) in 1968. Morphologically, it is similar to a high-grade breast ductal carcinoma. It is an aggressive disease with early facial nerve involvement, rapid progression, local recurrence, early metastasis, and high mortality rate. (13) The median overall survival and disease-free survival are approximately 3 years. It affects more males than females, and the male to female ratio is about 4:1 to 5:1. It usually occurs in the sixth to seventh decade of life. (13)

Patients with SDC present with a nodular, grey-white, ill-defined, firm, and painless parotid mass with cervical lymphadenopathy. (14-16) At the time of diagnosis, 66.0% (93 patients) of patients with SDC have a stage T3/T4 disease, and 50.4% (71 patients) have positive lymph nodes. (13,14) Microscopically, SDC shows a high-grade adenocarcinoma that bears resemblance to mammary ductal carcinoma and ductal carcinoma in situ with solid, papillary, micropapillary, cribriform growth patterns, and intraductal comedo-type necrosis (Figure 2). Rare morphologic variations, such as the presence of mucin-rich, sarcomatoid, and micropapillary carcinoma, have also been reported. (14-16)

The most commonly used immunomarkers for various components of the normal salivary gland are summarized in Table 1. Salivary duct carcinoma is positive for AE1/ AE3 and EMA; strongly and diffusely positive for CK7, GATA binding protein 3 (GATA3), and GCDFP-15; but negative for CK20, mucin 4, S100, SMA, and calponin. Except for the micropapillary variant, CK5/6 usually shows negativity. Unlike breast carcinoma, ER and PR show negativity, and androgen receptor shows positivity in about 70% (16 of 23 patients) of cases. Similar to breast carcinoma, HER2 only shows positivity in 30% (7 of 23 patients) of cases. (14) HER2 expression, overexpression of p53, and negative expression of androgen receptor have been found to be associated with more aggressive behaviors in SDC. (16-18) Other genetic changes also have been detected in SDC, such as phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit [alpha] (PIK3CA), Harvey murine sarcoma virus oncogene (HRAS), AKT serine/threonine kinase 1 (AKT1), phosphatase and tensin homolog (PTEN), and epidermal growth factor receptor (EGFR) (18) B-Raf proto-oncogene (BRAF) mutations are usually absent in SDC. (14)


Example 3: Epithelial-Myoepithelial Carcinoma

A 60-year-old woman presented with a 3.0-cm right parotid mass (Figure 3, A). Microscopically, it showed a biphasic pattern with an outer layer of clear myoepithelial cells and an inner layer of epithelial ductal cells arranged in mixed tubular to solid patterns (Figure 3, B). The epithelial cells showed strong positivity for Oscar keratin (OSCAR) (Figure 3, C), AE1/AE3 (Figure 3, D), EMA, and protooncogene c-Kit protein product (c-Kit, also known as CD117), while the myoepithelial cells were positive for S100, calponin (Figure 3, E), and p63 (Figure 3, F).

Epithelial-myoepithelial carcinoma (EMC) is a rare, lowgrade neoplasm originating from the intercalated duct of salivary glands. It accounts for approximately 1% of all salivary gland tumors. It mostly occurs in the parotid gland, followed by the submandibular and minor salivary glands. Rare cases have also been reported in the upper aerodigestive tract and other parts of the body, such as lung and breast. There is a slight female predominance with a mean age of 60 years. (19,20) The prognosis is usually very good with a 10-year survival rate of up to 90.2%. (21) The tumor size appears to be an important prognostic factor. In a study of 207 cases, patients with tumors smaller than 2 cm; 2 to 4 cm; and larger than 4 cm have disease-specific survival rates of 96.8%, 85.9%, 58.8%, respectively, at 180 months. (19) The local recurrence rate is estimated to be approximately 36% (12 of 33 patients), (22) and distant metastasis is uncommon.

The classical presentation of patients with EMC consists of a slow-growing, unilateral parotid mass in middle-aged women. While patients with EMC are usually asymptomatic, sometimes they may have pain. (22) As implied by its name, EMC is characterized by a biphasic pattern of an outer layer of clear myoepithelial cells and an inner layer of epithelial ductal cells arranged in mixed tubular to solid patterns. However, histologic diagnosis can be challenging, since the composition of the 2 cell types may vary greatly (Figure 3). The differential diagnosis includes basaloid adenoma, cellular pleomorphic adenoma, adenoid cystic tumor, myoepithelioma, carcinoid tumor, and lymphoma.

The epithelial cells show strong positivity for pancytokeratin AE1/AE3, CAM 5.2, EMA, and c-Kit, while the myoepithelial cells are positive for p63, SMA, S100, and actin. Ki-67, a marker for cell proliferation, shows positive nuclear staining in 15% to 20% of the tumor cells. (22)


Example 4: Malignant Mucosal Melanoma of Nasal Cavity

This was a representative case of mucosal melanoma (MM) from posterior nasal sinus. Low magnification showed an epithelioid MM with overlying respiratory mucosa (Figure 4, A). Close view showed pigmented malignant melanocytes that were positive for SRY-related HMG-box 10 (SOX-10) (Figure 4, b), Melan-A (Figure 4, C), human melanoma black 45 (HMB-45) (Figure 4, D), S100 (Figure 4, E), and CD117 (Figure 4, F).

Malignant melanoma occurring at sites other than skin is usually a highly aggressive disease and carries a poor prognosis. Melanoma of the head and neck region is uncommon, and accounts for about 0.7% to 3.8% of all melanomas. (23) The most frequently involved sites are the nasal and oral cavities, (24) followed by nasopharynx, pharynx, larynx, middle ear, and upper esophagus. (23,25) It occurs more frequently in Asian patients (25) and accounts for about 0.5% of all oral cavity malignancies. (26) There is a wide age range, between the second and ninth decade of life, with a mean age of 59.2 years. (27) Several studies (27,28) have shown there is a slight male predominance.

Symptoms vary according to the involved sites, such as nasal obstruction, epistaxis, painful mass, hearing loss, hoarseness, and dysphagia. (29) The tumor appearance varies and presents as a friable or rubbery, polypoid or sessile lesion with or without ulceration, and also may appear to be brown, black, pink, or white. The malignant cells are epithelioid and spindled and are often the dominant cell types, (30) while other features including plasmacytoid, organoid, round blue cells, clear cells, pleomorphic cells with atypical mitotic figures, and giant cells may be observed within the tumor. Occasionally, MMs are amelanotic. (24,29) Figure 4 shows an epithelioid sinonasal malignant melanoma (SNMM) with confirmatory immunohistologic studies.

The list of differential diagnoses of MM is long and includes sinonasal undifferentiated carcinoma (SNUC), sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, primitive neuroectodermal tumor, rhabdomyosarco ma, and lymphoma. Immunohistochemistry will help to establish a diagnosis of mucosal melanoma. For example, SNUC shows diffuse positivity with pancytokeratin AE1/ AE3 and CAM 5.2 and is negative for all of the melanocytic markers. Mucosal melanoma is usually positive for S100, HMB-45, Melan-A, and melanogenesis-associated transcription factor (MITF), and negative for cytokeratins, CD99, desmin, myogenin, and CD45. For difficult cases, SOX-10 is a highly sensitive marker for SNMM (100%, 28 of 28 patients (25)) and it possesses great diagnostic value, especially in spindle cell and desmoplastic melanomas. (31) The proto-oncogene product c-Kit is also expressed in most SNMMs (85.7%, 24 of 28 patients) (25) and provides a promising therapeutic target for imatinib, a specific competitive inhibitor of tyrosine kinase.


Example 5: Basaloid Squamous Cell Carcinoma of Tonsil

A 63-year-old man presented with a left tonsil mass. Fine-needle aspiration (FNA) showed poorly differentiated carcinoma of epithelial origin. A level II lymph node was also positive for cancer cells. A biopsy was performed and demonstrated a poorly differentiated squamous cell carcinoma (SCC) with basaloid features such as peripheral palisading (Figure 5, A and B). P63 showed strong nuclear staining (Figure 5, C), and CK5/6 showed strong diffuse cytoplasmic staining (Figure 5, D). Recurrent tumor showed wild perineural invasion (Figure 5, E). Those tumor cells were strongly positive for p16 (Figure 5, F).

Squamous cell carcinoma is the most frequent malignant tumor of the head and neck region. The 2005 World Health Organization (WHO) classification of head and neck tumors introduced rare variants of SCC, including but not limited to verrucous, basaloid, papillary, spindle cell (sarcomatoid), acantholytic, and adenosquamous. (32)

Basaloid squamous cell carcinoma (BSCC) is the most common type of SCC in the head and neck region, (33) and it is a highly aggressive variant of SCC that was first described in 1986 by Wain et al. (34) It is usually diagnosed at an advanced stage with distant metastases consistent with a tumor of poor prognosis. The most frequent sites of occurrence in the upper aerodigestive tract are larynx, hypopharynx (pyriform sinus), oropharynx (base of tongue), and tonsils. It also can involve other sites, such as the oral cavity, nasopharynx, trachea, and very rarely, the sinonasal cavity. (35)

Head and neck BSCC (HNBSCC) frequently occurs in men in the sixth to seventh decade of life. (33) Smoking and alcohol are the 2 most important and synergistic risk factors identified in more than 80% of cases. (36) In recent years, human papillomavirus (HPV) has been implicated in HNBSCC. The HPV-positive cancer cases tend to occur with younger age at onset, and also occur in women with no history of smoking or alcohol consumption. They have a significantly better prognosis than HPV-negative HNBSCC.

The frequency of HPV positivity varies by the site of involvement. Oropharynx is the most common site, where HPV positivity is 57% to 76% (34 of 60 cases (37) and 16 of 21 cases (38)). (39) Basaloid squamous cell carcinoma usually presents as firm to hard, tan to brown exophytic nodular masses. The "basaloid" cells are small, monomorphic, with hyperchromasia with scant cytoplasm. This entity often has a lobular growth configuration and typically has prominent peripheral palisading that resembles the basal layer of stratified squamous epithelium (Figure 5). Sometimes, central comedo-type necrosis is present. Another morphologic "basaloid" feature is the presence of small cystic spaces that contain periodic acid-Schiff (PAS)- and Alcian bluepositive materials. (32) A conventional SCC component located superficially or focal squamous differentiation within the basaloid lobules is almost always present.

Basaloid squamous cell carcinomas are positive for cytokeratins, such as AE1/AE3, and EMA with variable degree of positivity. (32) High-molecular-weight cocktail CK5/ 6, 34pE12 (CK903), p40, and p63 show diffuse positivity in BSCC, while S100, CK7, CK14, and vimentin usually show negativity. (40-43)

The main differential diagnoses include poorly differentiated SCC, neuroendocrine carcinoma, and adenoid cystic carcinoma (AdCC). Although BSCC (14 cases) and AdCC (16 cases) are both nearly 100% positive for p63, the staining pattern is remarkably different. The p63 staining is diffusely positive in BSCC. In AdCC, there is a compartmentalized staining pattern within the tumor nests in that p63-positive cells surround or intersperse with p63-negative cells. (44)


Example 6: Spindle Cell Carcinoma of Glottis

A 67-year-old man presented with a polypoid tumor of glottis (Figure 6, A). Microscopically the mass showed spindle cell features (Figure 6, B), and foci of squamous cells intermingled with multinucleated giant cells (Figure 6, C). Some areas exhibited sarcomatoid component (Figure 6, D). Immunostain for CK5/6 demonstrated epithelial positivity (Figure 6, E); immunostain for p63 highlights the positive nuclei of the spindle cells (Figure 6, F). The immunoprofile was confirmatory of spindle cell carcinoma.

Spindle cell carcinoma or sarcomatous carcinoma (SC) is a rare and highly malignant variant of SCC with epithelial and mesenchymal biphasic morphology. In the head and neck region, about 50% of the SCs occur in the larynx and constitute approximately 2% of laryngeal neoplasms. Other common sites are the oral cavity, sinonasal sinus, and pharynx, and they rarely occur in the trachea. (45-47) In the larynx, it usually affects older patients, with a median age of 65.6 years (187 patients). (48) In sinonasal tract and oral cavity, the patients are a decade younger; most patients are male. (46,48)

The most significant risk factors for SC are smoking and alcohol abuse. (48) Ten to thirty percent of SC cases are associated with previous radiation in the region, and most cases lack an association with HPV infection. (45) Most tumors present as a bulky pedunculated mass, often with an ulcerated surface, (49) with a mean size of 1.8 cm (187 patients). (48) Microscopically, it is biphasic, with a squamous cell component at the surface that may be dysplastic, in situ, or invasive. The sarcomatous spindle cell component may occasionally contain osteosarcomatous, chondrosarcomatous, or rhabdomyosarcomatous elements. Cases with a history of resection or radiation are more likely to contain a sarcomatoid component (Figure 6, G through I). (50)

Pure spindle cell tumor is uncommon and could be misdiagnosed as sarcoma. (32) Previously, it was considered a "collision tumor" from epithelial and mesenchymal cell lineages owing to the biphasic phenotype. However, molecular evidence has established that it originates from monoclonal epithelial cells, with metaplasia of a mesenchymal morphology. (48) Wide spectrum and high-molecular-weight cytokeratins such as AE1/AE3 and CK903 are the most sensitive markers for SC. They show strong positivity for the SCC component, while vimentin usually shows strong positivity in the spindle cell component. The mesenchymal filaments, such as SMA, and muscle-specific actin, are variably expressed in the spindle cell component. (47) S100 protein and melanocytic markers show negativity. P63 and p40 staining can also aid in the diagnosis of spindle cell carcinoma versus sarcoma or reactive stroma. (51)


Example 7: Sinonasal Undifferentiated Carcinoma

A 59-year-old woman presented with a history of left-sided nasal obstruction and hyposmia. Computed tomography scan revealed a left nasopharyngeal mass, extending to the lateral nasal wall (Figure 7, A). Sections of the biopsy showed a pink polypoid cellular malignant neoplasm (Figure 7, B). High power revealed nests and sheets of pleomorphic tumor cells with vesicular nuclei and prominent nucleoli, high mitotic rate with tumor necrosis and apoptosis (Figure 7, C). Angiolymphatic invasion was easily identified (Figure 7, D). The tumor cells were positive for cytokeratin CAM 5.2 (Figure 7, E). They were also diffusely positive for AE1/AE3, while negative for melanocytic, neuroendocrine, and Epstein-Barr virus (EBV) markers. Immunostain for Ki-67 showed high proliferative rate (Figure 7, F). Final diagnosis was SNUC.

SNUC is a rare malignant neoplasm of the sinonasal cavities or paranasal sinuses. It progresses rapidly despite aggressive multidisciplinary therapies. The tumor typically presents at an advanced stage, has a very poor prognosis, and lacks squamous or glandular differentiation. The incidence in the United States is 0.2 per million, with a male to female ratio of 2:1 to 3:1. (52) There is a wide age range from 8 to 85 years at the time of diagnosis. The mean age is 57.8 years.

The survival data for SNUC in the literature show a low 5-year survival rate of about 34.9% (318 patients). (52) The etiology and the molecular changes of SNUC are poorly understood. Various occupational exposures such as wood dust, leather tanning, chromium and nickel refining, and other industrial fumes are associated with an increased risk of sinonasal malignant tumors. Wood dust and leather dust are strong risk factors for adenocarcinoma. Smoking is not considered to be a significant risk factor. (53)

A few genetic changes have been identified in SNUC, including nucleotide polymorphism of the promoter region of vascular endothelial growth factor. (54) Proto-oncogene c-Kit protein product was overexpressed in SNUC by immunohistochemistry, but there is no genetic mutation or amplification. No HER2 overexpression was identified in the 11 SNUC cases examined, although it was reported in one study using an animal model. (55,56) SOX-2 amplification was shown in about one-third of SNUCs and other sinonasal cancers, such as SCC, and this may be associated with relapse after primary therapy. (57) There are also variable results regarding SNUC and HPV infection. Wadsworth et al (58) showed strong and diffuse p16 expression in SNUC, but no HPV DNA was identified in any of these cases. Therefore, the p16 expression may represent residual epithelial staining that normally is present in the sinonasal tract. In 2015, Gray et al (59) demonstrated that 11 of 14 SNUCs (78.6%) were strongly positive for p16, and 9 (81.8% of p16+ SNUCs, 64.3% of all cases) were associated with expression of high-risk HPV subtypes. (59)

Patients with SUNC often present with epistaxis, nasal obstruction, proptosis, diplopia, and other symptoms. Histologically, SNUC is hypercellular and has a solid to trabecular growth pattern, small to moderate amount of eosinophilic cytoplasm, hyperchromatic and large nuclei, and inconspicuous to prominent nucleoli (Figure 7). The morphologic diagnosis of SNUC can be very challenging, as it is one of the so-called small round blue cell tumors with a long list of differential diagnoses including poorly differentiated SCC, nasopharyngeal undifferentiated carcinoma, small cell undifferentiated neuroendocrine carcinoma, rhabdomyosarcoma, MM, olfactory neuroblastoma, high-grade lymphoma, recently identified NUT midline carcinoma, and SMARCB1 (INI1)-deficient sinonasal carcinoma. The latter entity was recently distinguished from sinonasal carcinoma by the loss of INI1 and the basaloid/rhabdoid morphology. Only 7 cases have been reported. (60) Unlike nasopharyngeal undifferentiated carcinoma, SNUC is not associated with EBV.

A panel of immunohistochemical markers must be used to rule out the above differential diagnoses. SNUC is positive for pancytokeratin, CK19, EMA, and neuronspecific enolase, and negative for synaptophysin, S100, HMB-45, CD45, and desmin. Pancytokeratin is the most helpful diagnostic immunostain. Immunomarkers that are important for differentiating the most common considerations of small round blue cell tumors are shown in Table 2. (61-64)


Example 8: Nasopharyngeal Carcinoma

A 46-year-old man presented with a left-sided neck mass. Biopsy demonstrated a metastatic high-grade undifferentiated carcinoma, and imaging revealed a left-sided nasopharyngeal mass. Sections of the mass showed nasopharyngeal mucosa (Figure 8, A) with submucosal infiltrating undifferentiated carcinoma (Figure 8, B) and extensive lymphovascular tumor invasion (Figure 8, C). Immunostain confirmed positivity for AE1/AE3 (Figure 8, D) and diffuse nuclear staining for Ki-67 (Figure 8, E). In situ hybridization with EBV yielded a positive result (Figure 8, F).

Nasopharyngeal carcinomas (NPCs) are squamous cell carcinomas originating from the squamous mucosa of nasopharynx. The original classification of NPC by WHO in 1978 showed 3 histologic subtypes: (1) squamous cell carcinoma, (2) nonkeratinizing carcinoma, and (3) undifferentiated carcinoma. In 1991, NPC was reclassified into 2 major subtypes, namely, squamous cell carcinoma and nonkeratinizing carcinoma. The latter includes differentiated carcinoma and undifferentiated carcinoma. The current WHO classification includes: (1) nonkeratinizing carcinoma (differentiated carcinoma and undifferentiated carcinoma), (2) keratinizing carcinoma, and (3) basaloid SCC.

Nasopharyngeal carcinoma is an uncommon disease in the United States. However, the incidence is high in Southeast Asia, North Africa, the Arctic region, and especially in Southern China. (32) In these regions, the incidence is about 80 cases per 100 000 of the population. (65) Nasopharyngeal carcinoma affects more men than women, and it occurs most commonly in the fourth to sixth decade of life. (32) Cigarette smoking and alcohol consumption are the major risk factors for NPC. In Southern China, diet containing salty fish is also a major risk factor. (66) Epstein-Barr virus infection is strongly associated with NPC in endemic regions, where most cases are nonkeratinizing undifferentiated carcinomas. Epstein-Barr virus induces neoplastic transformation of epithelial cells of the nasopharynx by activation of oncogenes and inactivation of tumor-suppressor genes. (67) Keratinizing squamous cell carcinomas are most common in Western countries. In nonendemic Western countries, HPV has been reported in nasopharyngeal carcinomas of keratinizing and nonkeratinizing types. Nonviral infection cases have worse prognosis. (68)

Nasopharyngeal carcinoma often is indolent and presents as an asymptomatic cervical neck mass, typically localized to the posterior cervical region. Symptoms may include nasal obstruction, nasal discharge or epistaxis, serous otitis media, otalgia, hearing loss, headache, and cranial nerve involvement. Histologically, the keratinizing type of NPC is well to poorly differentiated with intercellular bridges, keratinization, invasive growth, and a desmoplastic stromal response. In contrast, nonkeratinizing differentiated-type NPC is a well-delineated lesion without a desmoplastic response in the surrounding stroma. The growth pattern is stratified cellular proliferation. Keratinization is absent or may be focally present. Nonkeratinizing undifferentiated-type NPC shows round nuclei, prominent nucleoli, increased nuclear to cytoplasmic ratio, and mitotic activity (42) (Figure 8).

In all types of NPC, the tumor shows strong reactivity with cytokeratins, such as OSCAR, AE1/AE3, CAM 5.2, CK5/6, and EMA. P63 is also diffusely strongly positive. The assay for EBV-encoded small RNAs (EBERs) is the gold standard to detect EBV infection. Stains for other EBV viral proteins, such as latent membrane protein 1 (LMP-1), are also used. Differential diagnoses include large cell neuroendocrine carcinoma, SNUC, and lymphoepithelioma-like carcinoma. The latter two are histologically similar to nonkeratinizing undifferentiated NPC but occur at different sites. SNUC is located at the sinonasal tract, and lymphoepithelioma-like carcinoma is an undifferentiated carcinoma outside the nasopharynx with or without a lymphoplasmacytic infiltrate. The most frequent site is the parotid gland. (69)

Many ongoing molecular studies have been developed to elucidate new markers that correlate NPC with clinical stage, metastasis, and prognosis. For example, SOX-4 overexpression is correlated with poor survival rate, (70) and overexpression of chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) may promote disease progression and predicts metastasis and prognosis. (71) Upregulation of hypoxia upregulated 1 (HYOU1) is also associated with a poor prognosis. (72) Loss of heterozygosity and comparative genomic hybridization also have identified potential biomarkers that could be used in the diagnosis and staging of NPC.


Example 9: A Monophasic Synovial Sarcoma at Base of the Tongue and Mandible

An 18-year-old man presented with a 2.0-cm mass at the base of the tongue and mandible. The mass infiltrated skeletal muscle (Figure 9, A). Histologic features showed monophasic spindle cells arranged in herringbone pattern (Figure 9, B). The tumor cells were focally positive for EMA (Figure 9, C), diffusely positive for transducin-like enhancer of split 1 (TLE-1) (Figure 9, D) and B-cell lymphoma 2 (BCL-2) (Figure 9, E), and also positive for CD99 immunostain. They were positive for cytogenetic synovial sarcoma translocation-synovial sarcoma X gene fusion (SYT-SSX) (not shown).

Head and neck primary sarcomas are uncommon. They account for 5% to 15% of all sarcomas in adults, as reported in 2003 by the MD Anderson Cancer Center (Houston, Texas). In the same report, 3.6% (29 of 802 patients) were synovial sarcomas (SS) afflicting the head and neck. (73) The study also showed that the parotid gland was the most frequent site of involvement, followed by the scalp and the upper aerodigestive tract (such as tongue, soft palate, larynx, and hypopharynx; Figure 9, F, shows a nasopharynx SS of a 47-year-old man). Unusual locations, such as the thyroid gland (74) and temporomandibular joints, also have been reported. (75) Fewer than 100 cases of SS in unusual locations have been reported in the English literature. (76) Other common head and neck sarcomas are osteosarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, and angiosarcoma. It should be mentioned that rhabdomyosarcomas in the head and neck region are the most common primary sarcomas in the pediatric population.

Synovial sarcoma may present as a rapidly growing firm mass in the neck region. The unusual location often makes its recognition difficult, especially the monophasic SS. It could be misdiagnosed as an epithelial tumor, or a soft tissue tumor such as fibrosarcoma, hemangiopericytoma, and malignant peripheral nerve sheath tumor. (76) Microscopically, SS consists of primitive spindle cells of mesenchymal origin. The cells form fascicles with focal hyalinization. Figure 9, A through E, shows a monophasic SS at the base of the tongue. The tumor cells are tightly packed and have scant cytoplasm. The nuclei are irregular and hyperchromatic. The cells have high nuclear to cytoplasmic ratio. Hemangiopericytomatous vasculature could be seen. In the biphasic tumor, epithelial cells are plump with abundant cytoplasm, with round nuclei and fine chromatin.

The tumor cells are positive for CK7, CK19, EMA, vimentin, BCL-2, CD99, and protein gene product 9.5 (PGP 9.5). Positive staining with TLE-1 will confirm the diagnosis. Cytogenetic testing for the signature t(X; 18)(p11.2; q11.2) translocation that results in the SYTSSX1/2 gene fusion in more than 90% of the cases confirms the diagnosis. (74,76-78)


Example 10: Parathyroid Carcinoma

A 34-year-old man with a medical history of parathyroid gland neoplasm presented with a sternocleidomastoid muscle mass. The mass was composed of monotonous cells with minimal atypia and mitotic activity, and separated by dense irregular fibrous bands (Figure 10, A). It invaded into adjacent muscle and soft tissue (Figure 10, B and C). Angiovascular invasion (Figure 10, D), intramuscular lymphovascular invasion (Figure 10, E), and tumor thrombi in the adjacent fibroconnective tissue (Figure 10, F) were seen. Several lymph nodes were completely replaced by metastatic carcinoma. The patient had a recurrent mass 1.5 years later.

Parathyroid carcinoma (PC) is an extremely rare endocrine neoplasm. The incidence is about 3.58 to 5.73 cases per 10 million a year, and its occurrence is increasing. (79) It affects males and females equally, with a median age of 59 years. Its benign counterpart, parathyroid adenoma, is more frequent in women. Although parathyroid adenoma has been associated with radiation of the neck region, the risk factor of PC has not been well established. (80)

There is an increased incidence of PC in association with several genetic syndromes. The prevalence of PC in multiple endocrine neoplasia 1 (MEN1) syndrome is 0.28% (1 of 348 cases) (81) and is much higher than in the general population. The risk of developing PC is approximately 15% in patients with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder characterized by the germline mutation in the hypoxanthine phosphoribosyltransferase 2 (HRPT2), which encodes protein parafibromin. (82) In multiple studies, (83,84)

HRPT2 mutations have been identified in sporadic PC, but not in adenoma or hyperplasia.

Most of the tumors are functional with high serum parathyroid hormone and serum calcium levels. These features may be similarly seen in primary hyperparathyroidism caused by parathyroid hyperplasia and adenoma; therefore, it is very difficult to distinguish PC from primary hyperparathyroidism clinically. Pathologically, it is also very difficult to differentiate a PC from its benign counterpart. Although grossly, PC may present as a mass that is larger than parathyroid adenoma and is adherent to adjacent structure, a definite diagnosis of carcinoma can only be made with evidence of invasion, and/or metastasis of local lymph nodes or distal organs. Microscopically, PC shares similar morphology with parathyroid adenoma, consisting of solid sheets of monomorphic round chief cells with moderate amount of eosinophilic cytoplasm, often with little to no atypia. Although increased mitotic activity and thick fibrous bands may indicate carcinoma, atypia and mitotic activity may be variable in carcinoma and overlap with adenoma and hyperplasia.

When a definite diagnosis of PC cannot be excluded, the term atypical parathyroid adenoma may be used to describe a mass with certain degree of atypia, but lacking the apparent invasion or metastasis. To address this diagnostic challenge, extensive research has been suggested recently in an effort to make the diagnosis of PC, based on immunohistochemical profiles. Loss of parafibromin has been shown to be a feature of carcinoma, in combination with galectin-3 overexpression, increased Ki-67 index, and expression of PGP 9.5. Loss of adenomatous polyposis coli is also a useful additional marker to aid in the diagnosis of carcinoma versus adenoma. (85-87) Rarely, PC or normal parathyroid tissue may involve or occupy the thyroid gland and mimic papillary carcinoma of the thyroid; thyroid transcription factor-1 (TTF-1) could be used in such cases to exclude the thyroid origin (Figure 10, G through I). The overall survival is low, with 5- and 10-year overall survival rates of 85% and of 49% to 77%, respectively. (88)


Example 11: Two Paragangliomas

A 54-year-old man presented with a recurrent left carotid body tumor. Computed tomography scan showed an enlarged mass of the left carotid (Figure 11, A). Sections of the carotid mass showed Zellballen architecture type I cells (Figure 11, B) that were positive for neuron-specific enolase (Figure 11, C), chromogranin (Figure 11, D), and synaptophysin (Figure 11, E). Type II supporting cells were positive for S100 (Figure 11, F).

The second example described a pigmented paraganglioma in a 33-year-old man who presented with a nasal polypoid mass and bleeding. Sections of the mass showed pigmented large cells (Figure 11, G); the pigment melanin was bleached (Figure 11, H). Those large cells were positive for chromogranin (Figure 11, I) and synaptophysin. Scattered peripheral cells were positive for S100. Other melanocytic markers showed negativity, including Melan-A and HMB-45.

Paragangliomas (PGs) are uncommon neuroendocrine tumors that develop in the extra-adrenal paraganglion neurocrest tissue. Approximately 3% of all PGs occur in the head and neck area. They account for about 0.6% of all head and neck tumors. The most common site is the carotid body at the bifurcation of the common carotid artery, followed by the jugular bulb, tympanic plexus, and vagus nerve. It is rarely observed in the larynx and paranasal sinuses. (89,90) It usually affects women in their fourth or fifth decade of life with a female to male ratio of from 3 to 6:1. (91) Most PGs are unicentric, unilateral, benign, and sporadic. Only fewer than 5% of PGs are malignant. Since morphologic alterations in malignant PGs are minimal, malignancy is often determined by the presence of regional or distant metastases. One-third of the familial carotid body PGs are bilateral, as opposed to 4% in the sporadic nonfamilial cases. In addition, only 2% to 5% of PGs produce catecholamines. (90)

The tumor typically presents as an asymptomatic, painless, slow-growing neck mass. Small masses sometimes display side-to-side movement, but not vertical movement (Fontaine sign). Large masses often invade the adjacent structures, such as cranial nerves and brainstem, resulting in cranial nerve paresis or paralysis, dysphagia, hoarseness, headache, Horner syndrome, and syncope. (89,91-93)

Paragangliomas are highly vascular, blue or red submucosal lesions. They are invested by a thin, sometimes focally thickened fibrous capsule. On section, the cut surface has a variegated yellow, tan, pink, red, or brown appearance with areas of fibrosis and hemorrhage. The chief cells are arranged into characteristic large oval to round cell nests (Zellballen). The cells are polygonal with eosinophilic, granular cytoplasm and large vesiculated nuclei. The periphery of the cell nests or Zellballen is lined by spindle-shaped sustentacular cells. Local or distant metastasis is the only definite criterion for malignancy. Features such as infiltration of surrounding tissue, vessels, and neurons, and necrosis do not always define malignancy (90) (Figure 11).

The chief cells are positive for synaptophysin and chromogranin, and the sustentacular cells are positive for S100. There is recent awareness of a genetic basis of PGs.

Thirty to forty percent of PGs are proposed to be part of the autosomal dominant hereditary tumor syndrome. Most head and neck cases are associated with mutation of succinate dehydrogenase genes. (94,95)


Example 12: Castleman Disease in the Parapharyngeal Space, Hyaline Vascular Type

A 40-year-old Asian woman presented with a right-sided parapharyngeal space mass. She reported mild symptoms while swallowing. Magnetic resonance imaging demonstrated a bulky right poststyloid parapharyngeal lesion with mild mass effect. (96) Microscopic examination of the right parapharyngeal lymph node demonstrated a markedly enlarged lymph node with a nodular growth pattern. Low magnification showed atretic follicles and several hyalinized vessels with markedly enlarged lymphoid follicles with a nodular growth pattern (Figure 12, A). Lymphoid follicles showing parafollicular cells were markedly increased in number and arranged in an onion-skin appearance (Figure 12, B and C). Immunostain for CD10 highlighted positivity of the follicular lymphoid cells (Figure 12, D).

Castleman disease (CD) is a nonmalignant lymphoproliferative disorder of lymph node that usually occurs in young adults and children, with no sex predilection. Head and neck region is the second most common site of involvement after mediastinum. Six to fourteen percent of CD cases occur in the head and neck region, (97) especially in children. Approximately 30 pediatric cases were reported in the literature. (98)

According to the new classification, CD is subdivided into hyaline vascular, plasma cell, HHV-8 associated, and multicentric CD not otherwise specified. (99) From the extent of lymph node involvement, CD can also be classified into multicentric and unicentric. The latter is more common and usually has a better prognosis. (100) Castleman disease that involves the head and neck is often unicentric, asymptomatic, or presents as an enlarged mass associated with mild symptoms while swallowing, but not dysphagia. (96) Most lesions are between 5 and 10 cm in diameter. Multicentric CD is associated with HHV-8 infection, especially in patients infected with human immunodeficiency virus. It has systemic manifestations such as generalized lymphadenopathy, malaise, night sweats, and weight loss and has an aggressive clinical course 99

Microscopically, the disorder shows markedly enlarged lymph nodes with follicular hyperplasia. (96) The germinal center classically has a lollipop pattern, with marked vascular proliferation and hyalinization. The mantle zone is expanded with a concentric arrangement, showing onionskin-like growth pattern (Figure 12). Clinically, CD may appear as a parotid mass. Fine-needle aspiration biopsies show normal or reactive lymphoid tissue. (101) The differential diagnosis includes salivary gland neoplasm, neurogenic neoplasm, lipoma, lymphoma, sarcoma, and metastasis. (96) Immunohistochemical staining with CD3, CD20, CD21/ CD23, k and k, and other markers is used to illustrate a hyperplastic/reactive lymph node pattern and to rule out lymphoma. The unicentric type of CD is negative for EBER and HHV8. (98) The treatment for unicentric CD is complete surgical excision. Radiation therapy may be used for unresectable lesions. (102)


Example 13: Sinonasal Extranodal Rosai-Dorfman Disease

A 61-year-old man had complaints of nasal obstruction. He presented with a bilateral polypoid sinonasal mass involving the nasal cavity floor, anterior septum, lateral nasal wall (Figure 13, A), and paranasal sinuses (Figure 13, B). Low magnification of the mass showed spindle lesion (Figure 13, C) with large atypical spindle cells admixed with inflammatory cells (Figure 13, D). Immunostain for CD68 demonstrated many histiocytes (Figure 13, E), with some large histiocytes containing multiple lymphocytes (Figure 13, F). Immunostain for S100 (Figure 13, G) highlighted those large histiocytes with emperipolesis, confirming the diagnosis.

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, benign proliferation of histiocytes of unknown etiology.

About 43% of the patients with RDD have extranodal disease. Head and neck region is the most common extranodal site of involvement. The disorder affects males and females equally. (103,104) The typical clinical presentation is a neck mass and painless massive bilateral cervical lymphadenopathy. (105) Sinus involvement and salivary gland involvement are also seen. Laryngeal involvement rarely results in recurrent dysphonia and airway obstruction. Although it is usually a self-limiting benign process, persistence and recurrence of the disorder may occur. In one report, (106) 4.8% (6 of 126 cases) of patients eventually succumbed to the disease.

Definitive diagnosis depends on histopathologic examination, which shows a significant proliferation of sinus histiocytes, admixed with lymphocytes and plasma cells. Therefore, infectious processes such as EBV, tuberculosis, and cytomegalovirus must be excluded. The characteristic feature of "emperipolesis" (lymphocytes and erythrocytes phagocytized by histiocytes or neutrophils) is diagnostically helpful. According to the current hypothesis on the pathogenesis of RDD, the histiocytes are derived from the monocytes of peripheral blood. They are recruited into lymph nodal sinuses or extranodal sites where they are transformed into histiocytes, with evidence of emperipolesis. These histiocytes release cytokines that cause fever and other systemic symptoms. (107) Rosai-Dorfman disease may also exhibit fibrosis and nonspecific inflammatory changes, which render morphologic diagnosis difficult. Sometimes multiple biopsies at different times are required. In addition to infectious diseases, other differential diagnoses include inflammation, reactive hyperplasia, immunoglobulin G4-related sclerosing disease, sarcoidosis, granulomatosis with polyangiitis (formerly called Wegener granulomatosis), leukemia, Hodgkin lymphoma, and Langerhans cell histiocytosis. Rosai-Dorfman disease is strongly positive for S100 and variably positive for CD68 (Figure 13) but negative for CD1a. (106,108) The latter could differentiate RDD from Langerhans cell histiocytosis. (109)

Please Note: Illustration(s) are not available due to copyright restrictions.


Here we reviewed the commonly used immunohistochemical and molecular markers for differentiating unusual neoplasms of the head and neck regions. Most entities are high-grade malignancies that are challenging owing to their poor differentiation. Some entities are low grade and less aggressive, but bear diagnostic challenges partially because of the rarity. We discussed the potential pitfalls to aid the diagnostic differentials of these diseases. Owing to the ongoing research efforts, our knowledge of immunohistochemical markers and molecular alterations continues to be updated. Meanwhile, histologic features still serve as the foundation for pathologists' daily work.

We would like to express our genuine gratitude to Fritz Lin, MD, emeritus professor of Pathology and Cytopathology, University of California, Irvine, for his contribution to reviewing and editing the manuscript.


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Chun-Hui Yi, MD, PhD; Qihui (Jim) Zhai, MD; Beverly Y. Wang, MD

Accepted for publication February 13, 2017.

From the Department of Pathology, Mount Sinai Health System, St. Luke's-Roosevelt Hospital and Beth Israel Medical Centers, New York, New York (Dr Yi); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida (Dr Zhai); the Department of Pathology and Laboratory Medicine, University of California, School of Medicine at Irvine Campus and UC Irvine Medical Center, Orange, California (Dr Wang).

The authors have no relevant financial interest in the products or companies described in this article.

This manuscript was presented at the First Chinese American Pathologists Association (CAPA) Diagnostic Pathology Course: Best Practices in Immunohistochemistry in Surgical Pathology and Cytopathology; August 22-24, 2015; Flushing, New York.

Reprints: Beverly Y. Wang, MD, Department of Pathology and Laboratory Medicine, University of California, School of Medicine at Irvine Campus, UC Irvine Medical Center, 101 The City Dr, South Orange, CA 92868 (email:

Caption: Figure 1. Mammary analogue secretory carcinoma. A 59-year-old woman presented with a left parotid mass by computerized tomography scan (A, arrow); cross-section of excised specimen (B). The mass was well circumscribed with secretory cells, adjacent to parotid gland (C) (photo courtesy of Levine et al (1) and reprinted with permission by John Wiley and Son). Some areas of the carcinoma exhibited features similar to ductal carcinoma in situ of breast (D). A ductal cystic area with intraductal papillae (E). Carcinoma morphology appears to be low grade, however with vascular invasion (F). Carcinoma was positive for cytokeratin (CK) 7 (G), CKI8, mammaglobin (H), S100 (I), and STAT5a; focally positive for p63; and negative for gross cystic disease fluid protein 15 (GCDFP-15), discovered on GIST-1 (DOG1), smooth muscle actin, calponin, and estrogen receptor/progesterone receptor. The ETS variant 6-neurotrophic tyrosine receptor kinase 3 gene fusion (ETV6-NTRK3) by fluorescence in situ hybridization was diagnostic (J) (photo courtesy of Skalova et al (2) and reprinted with permission from Wolters Kluwer) (hematoxylin-eosin, original magnification X100 [C through F]; original magnifications X200 [G and H] and X400 [I]).

Caption: Figure 2. Salivary duct carcinoma of the parotid from an 85-year-old man (A) with areas of tumor necrosis (B), solid area showing high-grade invasive tumor (C), with perineural and intraneural invasion (D). Immunostains showed tumor cells were positive for CK18 (E) and androgen receptor (F) (hematoxylin-eosin, original magnifications x 100 [A, B, and D] and 3200 [C]; original magnification x 100 [E and F]).

Caption: Figure 3. Epithelial-myoepithelial carcinoma (A) showing a biphasic pattern of outer layer of clear myoepithelial cells and inner layer of epithelial ductal cells arranged in mixed tubular to solid patterns (B). The epithelial cells show strong positivity for Oscar keratin (OSCAR) (C), cytokeratin AE1/ AE3 (D), epithelial membrane antigen, and proto-oncogene c-Kit protein product, while the myoepithelial cells are positive for S100, calponin (E), andp63 (F) (hematoxylin-eosin, original magnification X200 [B]; original magnification X100 [C through F]).

Caption: Figure 4. Morphology and immunostaining of mucosal malignant melanoma (MM). An epithelioid MM of posterior nasal sinus with overlying respiratory mucosa (A), showing-positivity to SRY-related HMG-box 10 (SOX-10) (B), Melan-A (C), human melanoma black 45 (HMB-45) (D), S100 (E), and CD117 (F) (hematoxylin-eosin, original magnification X40 [A]; original magnification X100 [B through F]).

Caption: Figure 5. Basaloid squamous cell carcinoma (SCC) of tonsil. Poorly differentiated SCC with basaloid feature, such as peripheral palisading (A and B). P63 showed strong nuclear staining (C). Cytokeratin 5/6 showed strong diffuse cytoplasmic staining (D). Recurrent basaloid SCC with wild perineural invasion: cross-section of nerve surrounded by tumor cells (E, arrows). Those tumor cells were strongly positive for p16 (F, arrows) (hematoxylin-eosin, original magnifications X40 [A], X200 [B], and X100 [E]; original magnifications X40 [C and D] and X100 [F]).

Caption: Figure 6. A through F, Spindle cell carcinoma from a 67-year-old man with a polypoid tumor of glottis (A) with spindle cell features (B). Foci of squamous cells intermingled with multinucleated giant cells (C, arrows), some areas exhibit sarcomatoid component (D). Immunostain for cytokeratin 5/6 demonstrated epithelial positivity (E); immunostain for p63 highlights the positive nuclei of the spindle cells (F). Immunoprofile was confirmatory for spindle cell carcinoma. G through I, Recurrent squamous cell carcinoma with sarcomatoid features. A 51 year-old man had a highgrade, right-sided squamous cell carcinoma of the tongue. It was excised. Two year later, recurrent subcutaneous tumor (G) extended to the right cheek, showing spindle and pleomorphic morphology (H) resembling sarcomatoid neoplasm such as angiosarcoma. A panel of immunostains revealed that all markers showed negativity, except p63, which showed diffuse positivity (I) (hematoxylin-eosin, original magnifications X100 [B and D], X200 [C and H], and X40 [G]; original magnifications X100 [E and F] and X40 [I]).

Caption: Figure 7. Sinonasal undifferentiated carcinoma from a 59-year-old woman who presented with a history of left-sided nasal obstruction and hyposmia. Computerized tomography scan revealed a left-sided nasopharyngeal mass, extending to the lateral nasal wall (A, arrow). Sections of tissue showed pink polypoid cellular malignant neoplasm (B), nests and sheets of pleomorphic tumor cells with vesicular nuclei and prominent nucleoli, high mitotic rate with tumor necrosis and apoptosis (C). Angiolymphatic invasion was easily identified (D). The tumor cells were positive for cytokeratin CAM 5.2 (E), diffusely positive for cytokeratin AE1/AE3, and negative for melanocytic, neuroendocrine, and Epstein-Barr virus markers. Immunostain for Ki-67 showed high proliferative rate (F) (hematoxylin-eosin, original magnifications X40 [B], X200 [C], and X100 [D]; original magnification X100 [E and F]).

Caption: Figure 8. Nasopharyngeal carcinoma from a 46-year-old man who presented with a left-sided neck mass. Biopsy demonstrated a metastatic highgrade undifferentiated carcinoma, and imaging revealed a left-sided nasopharyngeal mass. Sections of the mass showing nasopharyngeal mucosa (A) with submucosa-infiltrating undifferentiated carcinoma (B), with extensive lymphovascular tumor invasion (C). Immunostain confirmed positivity for cytokeratin AE1/AE3 (D) and diffuse nuclear staining for Ki-67 (E). Result from in situ hybridization of Epstein-Barr virus was positive (F) (hematoxylin-eosin, original magnification X100 [A through C]; original magnification X200 [D through F]).

Caption: Figure 9. Synovial sarcoma (SS). A through E, A monophasic SS from an 18-year-old man at base of the tongue and mandible, FNCLCC (French Federation of Cancer Centers Sarcoma Group) grade 3 (2 cm). Mass-infiltrated skeletal muscle (A). Monophasic spindle cells arranged in herringbone pattern (B). The tumor cells were focally positive for epithelial membrane antigen (EMA); (C); diffusely positive for transducin-like enhancer of split 1 (TLE-1) (D), B-cell lymphoma 2 (BCL-2) (E), and CD99; and also positive for the cytogenetic synovial sarcoma translocationsynovial sarcoma X gene fusion (SYT-SSX) (not shown). F, Nasopharynx SS from a 47-year-old man (hematoxylin-eosin, original magnifications X40 [A] and X100 [B and F]; original magnification X100 [C through E]).

Caption: Figure 10. Parathyroid carcinoma. A through F, Lesion was composed of monotonous cells with minimal atypia and mitotic activity (A), and separated by dense irregular fibrous bands invading into adjacent muscle and soft tissue (B and C). Angiovascular invasion could be difficult to determine on frozen section (D, arrow). A foci of intramuscular lymphovascular invasion (E, arrow) and tumor thrombi in the adjacent fibroconnective tissue (F). In the absence of evident invasion or metastasis, it may be called atypical parathyroid adenoma and the interpretation needs to be communicated to the surgeon. G through I, A 37-year-old woman presented with a 1.6-cm left-sided thyroid mass on ultrasonography. Preoperative fine-needle aspiration showed papillary thyroid carcinoma. Total thyroidectomy was performed. Microscopically, a follicular nodule with oncocytic and papillary features was identified (G), showing areas of healing necrosis at the fine-needle aspiration site (arrow), the right side showing thyroid tissue. Immunostaining for parathyroid hormone was positive for parathyroid (H, arrow), while thyroid transcription factor-1 (TTF-1) showed positivity for thyroid follicles (I, arrow). The final diagnosis was intrathyroid parathyroid, instead of papillary thyroid carcinoma (hematoxylineosin, original magnifications X40 [A and G], X100 [B through D], X200 [E], and X400 [F]; original magnification X40 [H and I]).

Caption: Figure 11. Paragangliomas. A through F, A 54-year-old man with left carotid body tumor recurrence. Computerized tomography scan showing an enlarged mass of the left carotid (A). Sections of the carotid mass showing Zellballen architecture of type I cells (B) that were positive for neuronspecific enolase (C), chromogranin (D), and synaptophysin (E); type II supporting cells were stained by S100 (F, arrow). G through I, Pigmented paraganglioma from a 33-year-old man who presented with a nasal polypoid mass with bleeding. Sections of mass showed pigmented large cells (G), and after bleaching of melanin pigment (H). Those large cells were positive for chromogranin (I) and synaptophysin. Scattered peripheral cells were positive for S100. Other melanocytic markers showed negativity, including Melan-A and human melanoma black 45 (HMB-45). Case is provided courtesy of Honggang Liu, MD, Tonren Hospital, Beijing, China (hematoxylin-eosin, original magnification X400 [B, G, and H]; original magnification X400 [C through F, and I]).

Caption: Figure 12. Castleman disease, hyaline vascular type. Low magnification showing atretic follicles and several hyalinized vessels with markedly enlarged lymphoid follicles with nodular growth pattern (A). Lymphoid follicle showing that parafollicular cells were markedly increased in number and arranged in an onion-skin appearance (B and C). Immunostain for CD10 highlights positivity of the follicular lymphoid cells (D). (A) and (B) are reprinted from Clain et al (96) with permission from Springer (hematoxylin-eosin, original magnifications X100 [A] and X200 [B through D]).

Caption: Figure 13. Rosai-Dorfman disease. A 61-year-old man with complaints of nasal obstruction presented with a bilateral polypoid sinonasal mass involving the nasal cavity floor, anterior septum, lateral nasal wall (A), and paranasal sinuses (B). Low magnification of mass showing spindle lesion (C) with the large atypical spindle cells admixed with inflammatory cells (D). Immunostain for CD68 demonstrated many histiocytes (E), with some of the large histiocytes containing multiple lymphocytes (F). Immunostain for S100 highlights emperipolesis in those large histiocytes (G, arrow), confirming the diagnosis (hematoxylin-eosin, original magnifications X100 [C] and X200 [D]; original magnifications X100 [E] and X200 [F and G]).
Table 1. Immunohistochemical Markers in Normal Salivary Glands

                                   PASD   Amylase   Antichymotrypsin

Acini                               +        +             +
Duct (striated and interlobular)    -        -             -
Myoepithelial cells                 -        -             -

                                   CK   CEA   EMA   Calponin

Acini                              -     -     -       -
Duct (striated and interlobular)   +     +     +       -
Myoepithelial cells                +     -     -       +

                                     P63      S100

Acini                                 -        -
Duct (striated and interlobular)      -        -
Myoepithelial cells                   +        +

Abbreviations: CEA, carcinoembryonic antigen;CK, cytokeratin;EMA,
epithelial membrane antigen;PASD, periodic acid-Schiff-diastase;+,
positive;-, negative.

Table 2. The Small Round Blue Cell Tumors of the Head and Neck Region

           AE1/AE3   CK5    P16     P40     P63    S100    MyoD

EWS/PNET      -       -      -       -       -       V      -
MMM           -       -      -       -       -       +      -
ONB           R              -       -       -       S      -
DSRCT         +                                      V      -

RMS           -       -      -       -       R       -      +
SS            +
TNK           -       -      -       -       -       -      -

SCC           +       +      V       +       +       -      -
SNUC          +       -    Focal   Focal   Focal     R      -
AdCC          +                    Focal   Focal   Focal
Smcc        + PDP                  R, F    R, F

           CD45   EBER   Syn   Melan-A   Vim   Other

EWS/PNET    -      -      -       -       +    CD99, PAS, FLI1
MMM         -      -      -       +       -    HMB-45, MITF, SOX-10
ONB         -      -      +       -       V    NSE, CHR, CD56(V)
DSRCT                     V               +    WT-1, desmin, EMA,
RMS         -      -      R       -       V    Myogenin, desmin
SS                                        +    TLE-1, EMA, BCL-2
TNK         +      +      -       -       -    cCD3, CD56, EBV, TIA-
                                               1, cytotoxic granules
SCC         -      -      -       -       -
SNUC        -      -      R       -       -    EMA, CK8, CK19, NSE
AdCC                                           DOG1, CD117
Smcc                      V                    CD56, EMA

Abbreviations: AdCC, adenoid cystic carcinoma; BCL-2, B-cell
lymphoma 2; CK, cytokeratin; DOG1, discovered on GIST-1; DSRCT,
desmoplastic small round cell tumor; EBER, Epstein-Barr
virus-encoded small RNAs; EBV, Epstein-Barr virus; EMA, epithelial
membrane antigen; EWS/PNET, Ewing sarcoma/primitive neuroectodermal
tumor; F, few; HMB-45, human melanoma black 45; MITF,
microphthalmia-associated transcription factor; MMM, mucosal
malignant melanoma; NSE, neuron-specific enolase; ONB, olfactory
neuroblastoma; PAS, periodic acid-Schiff; PDP, perinuclear dot
pattern; R, rare; RMS, rhabdomyosarcoma; S, sustentacular cells;
SCC, squamous cell carcinoma; Smcc, small cell carcinoma; SNUC,
sinonasal undifferentiated carcinoma; SOX-10, SRY-related HMG-box
10; SS, synovial sarcoma; TLE-1, transducin-like enhancer of split
1; TNK, T-/NK-cell lymphoma; V, variable; +, positive; -, negative.
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Author:Yi, Chun-Hui; Zhai, Qihui; Wang, Beverly Y.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Sep 1, 2017
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