2.3.1 Encephalocele

Depending on the age of the patient and the location of the lesion, diagnosis of an encephalocele may be made by imaging prior to submitting histology. Frequently, encephaloceles extending into the nasal cavity or sinus include meninges and glial tissue associated with fibrosis.1 ^,​ 2

2.3.2 Nasal Glial Heterotopia

This is a congenital malformation in which ectopic glial tissue is found without connection to intracranial structures.3 Nasal glial heterotopia may present as an extranasal, intranasal, or mixed intranasal and subcutaneous mass. Patients may also present with symptoms and findings of nasal polyp, chronic sinusitis, and otitis media. Radiological confirmation of the lack of intracranial communication is stressed so as to avoid complications such as cerebrospinal fluid leak. Generally these lesions present as smooth, homogenous tan soft tissue–mimicking brain parenchyma. Histologically, they are typically composed of neural tissue with fibrosis and astrocytic proliferation (Fig. 2.1).

2.3.3 Respiratory Epithelial Adenomatoid Hamartoma

Respiratory epithelial adenomatoid hamartoma (REAH), a benign proliferation of minor seromucinous glands of the sinonasal tract, occurs more commonly in men than women during the sixth decade of life. Major symptoms include nasal obstruction, epistaxis, and recurrent sinusitis. These lesions appear normally as polypoid tan to reddish brown, rubbery tissue nodules.4 ^,​ 5 ^,​ 6 Histologically, they are formed of numerous glandular structures lined by ciliated respiratory epithelium with thickened basement membrane and intervening fibrotic and/or edematous stroma (Fig. 2.2).

2.3.4 Seromucinous Hamartomas

In seromucinous hamartomas the underlying glandular component consists predominantly of seromucinous glands, in contrast to REAH. Smaller tubules, ducts, and glands are present in a lobular arrangement; the glands may be surrounded by stromal hyalinization, and a chronic lymphoplasmacellular infiltrate is typically present. By analogy, these resemble the microglandular adenosis of the breast.5 ^,​ 6

2.3.5 Ectopic Pituitary Adenoma

Pituitary adenomas may occur in the sphenoid bone and sinuses, either as a separate lesion or as an extension from a primary adenoma arising in the sella.7 ^,​ 8 Embryonic residue along the Rathke’s pouch formation is the presumed derivation. Females are more affected than males (2:1). Patients may present with nasal obstruction, headache, or epistaxis. Approximately half of patients exhibit hormonal abnormalities. Histologically, an ectopic pituitary adenoma is identical to that of a conventional pituitary adenoma with monotonous round cells (Fig. 2.3).

2.3.6 Inflammatory Pseudotumor

This is a benign reactive process in which a spindle cell tumor–like proliferation with inflammatory component is the cardinal feature.9 ^,​ 10 ^,​ 11 They may arise at any site in the skull base regions.

2.3.7 Sinonasal Polyps

These polypoid growths originate from the Schneiderian epithelial lining of the sinonasal cavities. They evolve as a result of fluid accumulation of the mucosa, most commonly as a result of nasal allergy and repeated sinusitis. Frequently, maxillary polyps may extend via the sinus openings into nasal or nasopharyngeal locations. The majority of polyps occurring in children are associated with asthma or cystic fibrosis (20–30%). In adult patients, they are often secondary to chronic sinusitis and allergy.12 ^,​ 13 ^,​ 14 Generally, sinonasal polyps grossly appear smooth, glistening, and translucent or opaque.

Histologically, the epithelium of nasal polyps is commonly respiratory, with or without mild hyperplasia or squamous metaplasia. The core is edematous, with numerous vessels and scattered inflammatory cells. In allergic polyps, the dominant cells are eosinophils, whereas inflammatory polyps feature chronic and a few acute inflammatory cells. Scattered minor salivary gland structures are also seen. Commonly, secondary changes due to infarction and organization are observed.

2.3.8 Sinonasal (Schneiderian) Papilloma

There are three histologic subtypes of this entity: (1) the exophytic, which is typically squamous in histology and almost always affects the nasal septum; (2) cylindrical cells, which are characterized by stratified columnar epithelial lining; and (3) the inverted papilloma, of which a transitional-like squamous proliferation in an inward growth is the cardinal feature.15 ^,​ 16 ^,​ 17 ^,​ 18 ^,​ 19 ^,​ 20 The latter types originate from the lateral nasal wall, middle meatus, and paranasal sinuses. Both cylindrical and inverted papillomas affect one side of the nasal and paranasal sinuses, with fewer than 5% occurring bilaterally.

2.3.9 Human Papillomavirus

Low- and high-risk human papillomavirus (HPV) subtypes have been identified in inverted and exophytic papillomas by in situ hybridizations and polymerase chain reactions. No clear association between HPV status and malignant transformation has been established.

2.3.10 Exophytic Sinonasal (Schneiderian) Papilloma

Generally, exophytic Schneiderian papilloma is a lobular mass composed histologically of bland squamous epithelium around fibrovascular cores.

2.3.11 Cylindrical Cell Papilloma

A generally exophytic papillomatous proliferation, histologically lined by multilayered columnar epithelium with and without oncocytic features. Microcysts with neutrophils within the epithelium are common (Fig. 2.4).

2.3.12 Inverted Sinonasal (Schneiderian) Papilloma

Grossly, inverted papillomas are typically tan to gray polypoid soft tissue having a mulberry appearance. These lesions affect more males than females and occur in older age. Keratinization may be present in some lesions, potentially indicating progression. Characteristic features of this lesion are inward invagination and presence of cellular structures formed of transitional-like epithelium having intraepithelial microcysts filled with macrophages, cellular debris, and mucinlike materials. Malignant transformation may occur in 10% of these lesions. Identifying dysplasia and carcinoma in situ in these lesions is critical for predicting the malignant progression of these lesions (Fig. 2.4).

2.4.1 Allergic Fungal Sinusitis

This entity results from an allergic reaction to persistent fungal organisms leading to mass formation.21 ^,​ 22 ^,​ 23 It may occur at any age, without gender predominance. The main symptoms are nasal discharge and rhinorrhea over a protracted period. The overall appearance of tissues from these lesions is that of tan butterlike material with debris.

The cardinal microscopic features include characteristic alternating layers of mucin and degenerating cells with eosinophilic materials and cells. Numerous intact and degenerating eosinophils and granules are present. Occasionally crystalloid eosinophilic deposition (Charcot–Leyden) crystals are found. Tissue invasion by hyphae is not identified in this disorder.

2.4.2 Invasive Fungal Sinusitis

Invasive fungal sinusitis is a potentially life-threatening condition characterized by fungal organisms that invade tissue and blood vessels, leading to massive tissue necrosis.24 ^,​ 25 Most commonly it is seen in immunocompromised patients and in patients who have poorly controlled diabetes mellitus. Infections spread rapidly to involve the central nervous system, which may lead to the patient’s death. Normally, tissue fragments are tan-gray, soft, and necrotic.

Histologically, fungal hyphae are identified with invading tissues and specifically with the blood vessels leading to massive necrosis (Fig. 2.5). Zygomycoses (Rhizopus/Rhizomucor) and Aspergillus are the most common organisms. Cultures should be taken for definitive species identification.

2.4.3 Rhinoscleroma

Rhinoscleroma is a chronic progressive granulomatous inflammation caused by Klebsiella rhinoscleromatis, a gram-negative bacterium.26 ^,​ 27 The disease is rare in the United States but is endemic in developing counties. Females are slightly affected more than males in the second to third decades of life. The natural history of the disease includes exudative, proliferative, and fibrotic phases. The exudative stage is characterized by purulent discharge, acute and chronic inflammation, and mucosal edema and congestion. The proliferative phase is characterized by granulomatous formation and multiple nodular inflammatory and ulcerating masses. The terminal phase is fibrotic, leading to stenosis.

The overall appearance of this lesion is that of polypoid and friable soft tissue in the proliferative phase. The histologic features are those of chronic inflammatory conditions, with extensive histiocytic cells that have vacuolation containing Klebsiella microorganisms (Mikulicz cells; Fig. 2.6). The fibrotic stage is nondiagnostic of the condition.

2.4.4 Granulomatosis with Polyangiitis

Formally known as Wegener’s granulomatosis, this destructive granulomatous condition is of unknown etiology. The disease, although systemic in nature, most commonly affects the upper respiratory tract, and it affects all ages and both genders. Common complaints are nasal stuffiness, rhinitis, and pain. Nasal septal destruction is common in young patients.28 ^,​ 29 ^,​ 30 ^,​ 31

Generally, tissues obtained from these lesions comprise fragments of necrotic-appearing materials. Histologically, the characteristic features include small vessel inflammation with granulomatous features, geographic necrosis, and basophilic debris as a result of cellular degeneration.

2.4.5 Histiocytosis-X (Eosinophilic Granuloma)

Histiocytosis-X (eosinophilic granuloma) is the most prevalent of these rare conditions, which also include two related conditions, Hand-Schüller-Christian syndrome and Lettere-Siwe disease. This disease can be localized or systemic and frequently involves head and neck sites, including the flat bones of the skull and sinonasal tract. Although age at presentation varies widely, this condition is most common in younger groups (< 20 years). Symptoms are nonspecific and include middle ear infections and destructive bony structures.32 ^,​ 33 ^,​ 34 ^,​ 35 ^,​ 36

The cardinal histologic features are proliferation of large histiocytes with cytoplasmic vacuolation and marked eosinophilic infiltrate. The characteristic electron-dense Birbeck granules are often seen on electron-optic examinations.

2.4.6 Myospherulosis

This is an iatrogenically induced lesion caused by reaction to petroleum, lanolin-based products, and fat necrosis.37 Typically patients present having undergone surgery with petroleum-based nasal packing. Symptoms include sinusitis, pain, and swelling.

The main histologic findings are pseudocystic formations containing nonrefractile small spherules and fibrosis.

2.5.1 Squamous Carcinoma

Squamous carcinoma typically occurs in elderly individuals who are in their sixth and seventh decades; it is more common in males (2:1). The most common sites are maxillary sinus, nasal cavity, ethmoid, frontal, and sphenoid sinus.40 ^,​ 41 ^,​ 42 ^,​ 43 Usually these carcinomas are typical ulcerated and indurate with exophytic features; sinus tumors are bulky and composed of friable light tan tumor tissues.

Histologically, squamous features should be identified and the extent of differentiation graded (well, moderately, or poorly). Tumors originating from the nasal cavity are generally keratinizing and well differentiated. Tumors of the paranasal sinuses and skull base are nonkeratinizing carcinomas with intermediate to poor differentiation (Fig. 2.7). The poorly differentiated carcinomas, also called Schneiderian carcinomas, most likely originate from preexisting inverted papillomas (Fig. 2.4c).

Differential Diagnosis

Squamous carcinoma may occasionally pose a diagnostic challenge on small biopsy specimens with sialometaplasia, pseudoepitheliomatous hyperplasia, and Schneiderian papilloma and should be differentiated from sinonasal undifferentiated carcinoma (SNUC).

2.5.2 Sinonasal Undifferentiated Carcinoma

SNUC was originally defined by Frierson et al44 as a “high-grade 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.” The World Health Organization (WHO) redefined SNUC as a highly aggressive and clinicopathologically distinct carcinoma of uncertain histogenesis that typically presents with locally extensive disease. SNUC is reputed to be refractory to even the most radical therapy and to carry a poor prognosis, particularly when the tumor transgresses the cranial base.

It seems likely that SNUC arises from Schneiderian epithelium and thus is of ectodermal derivation. In light of the overlapping clinical, anatomical, microscopic, and ultrastructural findings in olfactory neuroblastoma (ON) and neuroendocrine carcinoma (NEC), their origins may share both cells of Schneiderian mucosa and cells of olfactory neuroepithelium.45 ^,​ 46 It has also been proposed that SNUC would be best categorized as a large-cell NEC.45

SNUC is a high-grade, undifferentiated carcinoma characterized by primitive malignant epithelial cells with high mitotic figures and cellular necrosis.44 ^,​ 45 ^,​ 46 ^,​ 47 ^,​ 48 ^,​ 49 Patients are typically elderly males who present in a late stage of disease (Table 2.2). Tumors originate most commonly from the nasal cavity, ethmoid sinus, and maxillary sinus, but site of origin may be difficult to ascertain at presentation. These tumors are typically large, involving multiple adjacent structures that have ill-defined borders. They present as light tan soft tissue fragments.

Histologically, SNUC comprises sheets of undifferentiated cells having a low nuclear–cytoplasmic ratio, prominent nucleoli, and reticular and clear nuclei with high mitotic rate and necrotic features (Fig. 2.8). No squamous or glandular differentiation should be present.

2.5.3 SMARCB1 (INI1)-Deficient Sinonasal Carcinoma

Recently, a unique subset of sinonasal carcinomas was identified that is characterized by basaloid/rhabdoid tumor morphology and loss of expression of SMARCB1 (INI1). These tumors appear to be restricted to the sinonasal tract, and their unique clinical, morphological, and immunohistochemical features seem to warrant their inclusion as a separate new entity among the existing high-grade sinonasal neoplasms.50 ^,​ 51 ^,​ 52 Separation from the other types of sinonasal malignancies is important, for identification of SMARCB1 (INI1) deficiency may provide a new target for novel treatment approaches and could ultimately lead to improved patient survival. At the moment, these tumors are viewed as a subset of SNUCs.52

Morphologically these carcinomas are characterized by rounded or anastomosing nests of tumor cells set in a fibrous stroma. In some cases a prominent exophytic component with papillary fronds can be noted, but generally the tumors show a cohesive pattern of growth. Further characteristics include peripheral palisading as well as radial growth around blood vessels that impart a pseudorosette-like pattern. The tumors are highly infiltrative and often show invasion of the underlying bone. Cytologically, the cells have large round nuclei and prominent nucleoli (Fig. 2.9). The cytoplasm can vary and ranges from scant (basaloid) to more abundant with prominent eccentric eosinophilic cytoplasm (rhabdoid). Necrosis and a high mitotic rate are common findings. Isolated cases contained scattered ductlike spaces, but squamous or glandular differentiation is not a feature of reported SMARCB1-deficient sinonasal carcinomas.

SMARCB1 (INI1) is a tumor suppressor gene located on chromosome 22q11.2. Its gene product, SMARCB1 (INI1), is ubiquitously expressed in nuclei of all normal tissues. SMARCB1 gene inactivation has been implicated in the pathogenesis of a diverse group of malignant neoplasms that tend to share rhabdoid cytomorphology.

2.5.4 Nasopharyngeal Carcinoma

These tumors are classified into keratinizing and nonkeratinizing phenotypes and correspond to WHO type I and II/III grades.48 ^,​ 53 ^,​ 54 ^,​ 55 ^,​ 56 ^,​ 57 ^,​ 58 Pathogenesis is strongly linked to Epstein-Barr virus (EBV) infection and a diet high in nitrosamines, including salted fish and fermented food (Table 2.3).

The histopathologic characteristics of these tumors vary by WHO classification. The keratinizing type (WHO-I) is composed of tumor nests with squamous features, including keratinization and intercellular bridges. The nonkeratinizing type (WHO-II/III) is composed of sheets of undifferentiated malignant epithelial cells intimately intermingled with chronic inflammatory infiltrate, which is often EBV-positive (Fig. 2.10).

2.5.5 Nuclear Protein in Testis Carcinoma

Nuclear protein in testis (NUT) carcinomas are rare, clinically aggressive carcinomas. They are characterized by a translocation involving the NUT gene on chromosome 15q14 and, in most cases, the bromodomain-containing 4 (BRD4) gene on chromosome 19p13.1, resulting in a BRD4-NUT fusion gene.59 ^,​ 60 ^,​ 61

NUT carcinomas are composed of undifferentiated basaloid cells with focal, often abrupt, squamous differentiation (Fig. 2.11). NUT carcinomas can mimic other undifferentiated neoplasms, such as pediatric small blue cell tumors, germ cell tumors, Ewing’s sarcoma, lymphoma, and SNUC.57 ^,​ 58 ^,​ 59 ^,​ 60 ^,​ 61 ^,​ 62 NUT carcinomas have an epithelial immunophenotype and focally express keratin, p63, CK7, CK20, and CK34, which reflect varying degrees of squamous differentiation. An extensive panel of immunostains (e.g., desmin, myoglobin, smooth muscle actin, muscle actin, chromogranin, synaptophysin, leukocyte common antigen, placental alkaline phosphatase, S-100 protein, alpha fetoprotein, neuron-specific enolase, CD57, CD99, HMB45) are not expressed in NUT carcinomas. Oncoviruses, such as EBV and HPV, have never been identified in NUT carcinomas; their presence would likely exclude this diagnosis. Demonstration of the NUT translocation is required for the diagnosis of NUT carcinomas; this can be achieved by karyotyping, reverse transcription polymerase chain reaction, or fluorescence in situ hybridization.

A monoclonal antibody to NUT was developed for use in immunohistochemistry (IHC) and has a sensitivity of 87%, a specificity of 100%, a negative predictive value of 99%, and a positive predictive value of 100% when tested in a large panel of carcinoma tissues.63 The use of this antibody helps distinguish NUT carcinomas from other poorly differentiated sinonasal carcinomas, thereby contributing to their clinicopathological characterization.63 In view of the anecdotal favorable responses of NMCs to certain treatment regimens, including chemotherapy according to Ewing’s sarcoma protocols or docetaxel and radiotherapy,64 ^,​ 65 the distinction of NUT carcinomas from other sinonasal carcinomas appears to be of clinical relevance. Any poorly differentiated midline carcinoma or head and neck tumor lacking lineage-specific differentiation markers should be considered for immunostaining for NUT or rearrangement testing.

2.5.6 Sinonasal Adenocarcinoma

These tumors originate from either the respiratory epithelium or the underlying seromucinous glands (Fig. 2.12; Table 2.3). Tumors of respiratory epithelial derivation are frequently located in the nasal cavity and the ethmoid sinus, whereas those arising from the subepithelial glands frequently affect the nasal cavity and the maxillary sinus.6 Salivary-type tumors appear as large, nodular, light tan soft masses, whereas intestinal-type adenocarcinomas tend to be bulky, friable, and soft with ulcerated surface.

2.5.7 Salivary-Type Adenocarcinomas

The most frequent phenotype affecting the minor salivary gland of the skull base is ACC. Less frequent subtypes are mucoepidermoid, acinic cell, and low-grade papillary adenocarcinoma.6 The histopathologic features are those of their primary salivary counterparts.

2.5.8 Human Papillomavirus–Related Carcinoma with Adenoid Cystic–Like Features

As in conventional ACC, HPV-related carcinoma with ACC-like features demonstrates a dual population of ductal and basal cells with solid and cribriform growth (Fig. 2.13). Squamous dysplasia may be seen in the overlying surface epithelium but without infiltrating squamous carcinoma.64 ^,​ 65 The biphasic phenotype mirrors ACC, with CK7 and c-kit in epithelial cells, whereas p63 and p40 SMA decorate the abluminal cells. These tumors strongly express p16 and HPV types 31 and 33.6 ^,​ 66 ^,​ 67 ^,​ s. Literatur

2.5.9 Nonsalivary Gland Adenocarcinoma

Tumors in this category are divided into intestinal and nonintestinal (seromucinous) adenocarcinomas. The intestinal adenocarcinoma is identical to those arising in the intestinal tract. These tumors arise in patients who have a history of exposure to hardwoods, leather, and certain chemical manufacturing processes. They tend to occur in the ethmoid sinus and nasal cavity. The nonintestinal adenocarcinomas are typically seromucinous adenocarcinoma and affect the ethmoid and maxillary sinuses.6 ^,​ 69 ^,​ 70 ^,​ 71 ^,​ 72 ^,​ 73 ^,​ s. Literatur

Histologically, the intestinal type is typically that of the colonic adenocarcinoma phenotype but may show mucinous and signet ring features (Fig. 2.14). The seromucinous type is usually low-grade, with back-to-back cuboidal-lined glands and cords (Fig. 2.15a). Some cases may be composed of clear cells and resemble renal cell carcinoma (RCC; Fig. 2.15b), staining with antibodies to CA-IX but less reliably with antibodies to CD10 and RCC.75

2.6.1 Benign Tumors

Various benign tumors similar to those originating in other soft tissues may arise in the skull base region.

2.6.2 Lobular Capillary Hemangioma (Pyogenic Granuloma)

This relatively common benign vascular lesion represents approximately 25% of the nonepithelial neoplasms of the sinonasal tract and skull base region. This entity is frequently found in the nasal septum (60%) and is most commonly identified in adolescent boys and young women. Local trauma and hormonal factors may play an etiologic role in the development of this entity. Intermittent painless epistaxis is the most common symptom.76 ^,​ 77

Usually a polypoid red to purple nodular growth is identified with mucosal ulceration. Histologically, lobular capillary hemangiomas are composed of fairly organized vascular proliferations with lobular formation (Fig. 2.16). An inflammatory infiltrate may be present.

2.6.3 Glomangiopericytoma (Sinonasal Hemangiopericytoma)

An uncommon nonepithelial neoplasm is composed of spindle cell proliferation of hybrid pericyte and myxoid differentiation. The tumor can present at any age, and patients most commonly complain of nasal obstruction epistaxis and pain. The nasal cavity and the paranasal sinuses are typically affected.67 ^,​ 68 ^,​ 69 ^,​ 70

In general, these tumors appear typically as a polypoid gray to red soft, fleshy tissue mass. Histologically, these lesions manifest as subepithelial spindled to round, markedly compacted cell proliferation with complex vascularity (Fig. 2.17). The cells may form a variety of patterns, including fascicular, storiform, and palisading morphology with interspersed vascular spaces in different size and forms; mitosis and mild cellular pleomorphism may also be seen.

2.6.4 Nasopharyngeal Angiofibroma

This benign, highly vascular mesenchymal neoplasm arises predominantly in young males. Lesions arise in the roof of the nasopharynx, and patients’ symptoms typically include nasal obstruction, epistaxis and drainage, and, less commonly, facial deformities, proptosis, deafness, sinusitis, and palliative swelling.73 ^,​ 74 ^,​ 75

Usually angiofibroma presents as rounded, nonencapsulated, gray-white soft tissue masses covered with smooth mucosa and spongy cut surface appearance. The cardinal histologic features of these lesions are richly thin-walled vascular formations in fibrotic connective background with stromal cell proliferation (Fig. 2.18).

2.6.5 Myxoma

These intraosseous, ill-defined lesions comprise mucomyxoid stroma with scattered stellate cells. If a fibrous component is visible, they are called myxofibroma. Although they most commonly present in the jaw, the maxilla may be affected. These lesions affect females more than they do males.76 ^,​ 77 Usually they appear as unencapsulated, well-circumscribed, nodular, tan to white gelatinous lesions. Histologically, they are characterized by sparsely scattered, stellate-shaped mesenchymal cells in a myxoid background.

2.6.6 PEComa (Perivascular Epithelioid Cell Tumor)

The perivascular epithelioid cell tumors (PEComa) family includes mesenchymal tumors that consist of perivascular epithelioid cells. The most common tumors in the PEComa family are renal angiomyolipoma and pulmonary lymphangioleiomyomatosis (both of which are more common in patients who have tuberous sclerosis).78 ^,​ 79 ^,​ 80

Histologically, the tumor shows a trabecular and nested architecture, composed of epithelioid cells having clear to granular eosinophilic cytoplasm (Fig. 2.19). Some PEComas are dominated by spindle cells and show a sheetlike grown pattern. Marked nuclear atypia, prominent nucleoli, high mitotic activity, and necrosis are features of malignant transformation. On IHC, the tumor cells are positive for smooth muscle actin and desmin, as well as for the melanocytic markers HMB-45 and microphthalmia transcription factor.

The majority of PEComas harbor TSC1/TSC2 (tuberous sclerosis complex) mutations. Inactivation of TSC2 releases the inhibition of Rheb, resulting in mTOR activation—hence the use of mTOR inhibitors (sirolimus, temsirolimus) for this class of tumors, with demonstrated clinical efficacy. A large subset of PEComas lack the TSC2 mutations and instead harbor TFE3 gene rearrangements. TFE3 gene rearrangements also define alveolar soft part sarcomas as a consequence of the translocation t(X; 17).78 ^,​ 79 ^,​ 80 Differential diagnosis includes leiomyosarcoma, melanoma, and alveolar soft part sarcoma.

2.7.1 Rhabdomyosarcoma

Though a relatively uncommon mesenchymal malignancy of the skull base region, rhabdomyosarcoma is the most common sarcoma of the head and neck and is the most frequent childhood sarcoma. The sinonasal tract and the nasopharynx are the most commonly affected sites. The embryonal type is the most common type in children, whereas the alveolar subtype predominates in an older age group. Patients present with swelling, bleeding, visual symptoms, and sinusitis (Table 2.4).73 ^,​ 81 ^,​ 82 ^,​ s. Literatur Normally the tumor may be either small gray/red or large, polypoid, and fleshy. The botryoid variant exhibits grapelike features.

Histologically, these tumors are classified into the embryonal phenotype for the vast majority of skull base rhabdomyosarcomas and are composed of primitive small round to spindled monotonous cell proliferation in sheets. A myxoid stroma may be present, giving rise to the botryoid variant. The alveolar phenotype is less common and is composed of tumor cells with eosinophilic cytoplasm in clusters separated by fibrous septa (Fig. 2.20). Rhabdomyoblasts and multinucleated giant cells may be seen.

Ancillary Markers

Immunohistochemical markers, including desmin, myo-D, and myogenin, are necessary for diagnosis, especially of the embryonal form.

Differential Diagnosis

Tumors that may be confused with embryonal rhabdomyosarcoma include lymphoma, neuroblastoma, Ewing’s sarcoma/PNET, and melanoma. Immunophenotyping is critical for diagnosis (Fig. 2.21; Table 2.5).

Table 2.5 Clinicohistopathologic and genetic features of small round cell tumors of the sinonasal area

Diagnosis	Age (y)/location	Histopathology/architecture	Mitotic activity/necrosis	Cytomorphology	Anaplasia or marked atypia	Cytogenetic/molecular	Immunohistochemistry
Malignant epithelial sinonasal small round blue cell tumors
Small cell carcinoma, neuroendocrine type	26–77/superior or posterior nasal cavity, maxillary, ethmoid sinuses	Sheets, ribbons, or nests of closely packed cells with nuclear molding	Frequent/common	Monotonous small cells with hyperchromatic nuclei, inconspicuous or absent nucleoli, and minimal cytoplasm	Variable		CD56 Cytokeratin (punctate perinuclear) Chromogranin (variable) NSE (variable) Synaptophysin (variable) TTF-1 (variable)
Sinonasal undifferentiated carcinoma	20–80/nasal cavity, maxillary antrum, ethmoid sinuses, often with extension into adjacent sites	Tumor cells may be arranged in nests, lobules, trabeculae, or sheets	Frequent/common	Medium-sized nuclei with prominent nucleoli surrounded by scant eosinophilic cytoplasm	Common	No recurrent cytogenetic change No c-kit activating mutations or gene amplification	Pankeratin CK7 CK8 CK19 Ki-67 (most cells, variable intensity) NSE (occasional) EMA (occasional) CD99 (rare) Synapthophysin (rare) S-100 protein (rare) Chromogranin (rare)
Squamous cell carcinoma (nonkeratinizing)	55–65/maxillary sinus, nasal cavity, ethmoid sinus, sphenoid, and frontal sinuses	Ribbons, nests, or strands; underlying tissue invasion often features well-delineated border	Variable/limited	Poorly differentiated form most difficult to distinguish from other undifferentiated small round cell tumors, such as neuroendocrine carcinoma and olfactory neuroblastoma	Common		Pankeratin EMA CK5/6 CK8 CK13 CK14 CK19
Neuroectodermal sinonasal small round blue cell tumors
Ewing’s sarcoma/primitive neuroectodermal tumor	< 30/maxillary sinus, nasal fossa	Sheets, lobules (less commonly cords or trabeculae may cause dx difficulty with carcinoid or undifferentiated carcinoma) of uniformly round cells; ± Homer-Wright rosettes	Variable/common	Small to intermediate-sized cells with poorly defined, scant, or vacuolated cytoplasm and round nuclei with fine chromatin	Infrequent	t(11;22)(q24;q12) EWSR1-FLI1 (~ 95%) t(21;22)(q22;q12) EWSR1-ERG (~ 5%) Other EWSR1 or FUS variants (< 5%)	CD99 (membranous pattern) Vimentin FLI1 NSE (variable) Synaptophysin (variable) AE1/AE3 and CAM5.2 (occasional)
Mucosal malignant melanoma	40–70/nasal septum, paranasal sinuses (particularly maxillary)	Commonly deeply infiltrative with ulceration and frequent pseudopapillary architecture.	Frequent/common	Amelanotic small round cell or larger melanotic epithelioid or spindle-shaped cells; nuclear molding and/or prominent eosinophilic nucleoli possibly present	Common	CDKN2A/p16 (9p21) PTEN (10q23) 1q + ,6p + ,8q + 	S-100 protein Vimentin HMB45 (usually) Melan-A (usually) Microphthalmia transcription factor (variable) Tyrosinase (variable)
Olfactory neuroblastoma	Broad age range (< 10 to > 80)/roof of nasal cavity, cribriform plate	Localized to submucosa; lobular to solid growth pattern in higher-grade neoplasms; rosettes (Homer-Wright and Flexner-Wintersteiner) may be present	Variable/variable	Uniformly, small cells having scant cytoplasm and round nuclei with fine to coarse granular chromatin and occasional small nucleoli (grade-dependent)	Variable (more common in high-grade tumors)	Complex with aCGH studies demonstrating gain of 13q, 20q, and loss of Xp as most frequent in high-stage tumors	Neuron-specific enolase CD56 Synaptophysin (usually) S-100 protein (supporting sustentacular cells) CD57 (Leu7) (variable) Chromogranin (variable) GFAP (variable) Keratin (occasional)
Mesenchymal sinonasal small round blue cell tumors
Desmoplastic small round blue cell	15–35/sinonasal case report 1	Nests of undifferentiated cells embedded in a prominent desmoplastic stroma	Frequent/common	Small, round–oval cells with scant-moderate cytoplasm and hyperchromatic nuclei with inconspicuous nucleoli; intracytoplasmic inclusions or vacuoles may be seen	Infrequent	t(11;22)(p13;q12) EWSR1-WT1	Desmin (perinuclear dotlike pattern) Pankeratin, EMA, AE1/AE3, CAM5.2 Vimentin WT1 NSE (usually) CD57 (usually) Synaptophysin (occasional) CD99 (occasional)
Rhabdomyosarcoma	< 20 y/nasopharynx[sinonasal tract	Embryonal subtype (ERMS): alternating hyper- and hypocellular areas with myxoid or sparsely collagenized stroma Alveolar subtype (ARMS): collagenous fibrous septa separate nests of tumor cells with loss of central cohesion Solid ARMS: sheets of tumor cells without fibrous septa	Variable/limited	Small round cells with scant cytoplasm ± scattered cells with eosinophilic cytoplasm and cross-striations	Common	ERMS: gain of all or portions of chromosomes 2, 7, 8, 11, 12, 13, and/or 20 with or without loss of 22 11p15 LOH ARMS: t(2;13)(q35;q14) PAX3-FOXO1 (50–60%) t(1;13)(p36;q14) PAX7-FOXO1 (*20%) Other PAX3 variants (\1%) Fusion neg. (20–30%)	Desmin Myogenin (nuclear) myo-D1 (nuclear) Myoglobin (cytoplasmic) Vimentin (usually) CD56 (usually) Myosin (variable)
Synovial sarcoma (poorly differentiated)	< 50/maxillary, sphenoid, ethmoid, and frontal sinuses	Often solidly packed small round cells with richly vascular hemangiopericytoma-like pattern; may be focal within a typical biphasic or monophasic synovial sarcoma or may represent the predominant pattern; other poorly differentiated forms include large (epithelioid) cell and high-grade spindle cell	Variable/variable	Poorly differentiated small cell pattern composed of small cells with high nuclear-to-cytoplasmic ratios may be exceedingly difficult to distinguish from other small round cell tumors	Infrequent	t(X;18)(p11.2;q11.2) SYT-SSX1 or SYT-SSX2 (> 99%)	EMA BCL2 TLE1 Vimentin Cytokeratin (variable) CD99 (variable) S-100 (occasional)
Hematolymphoid sinonasal small round blue cell tumors
Extramedullary plasmacytoma	35–75/nasal cavity, paranasal sinuses, nasal cavity	Diffuse infiltrate of uniform (well-differentiated) to pleomorphic (anaplastic) neoplastic plasma cells Amyloid deposits (11–38%)	Variable/uncommon	Small to large (well to poorly differentiated) cells with fine to coarse nuclear chromatin and prominent nucleoli; intracytoplasmic crystals, Dutcher bodies, and perinuclear hof may be present	Occasional	14q32 (IGH) [although unlike multiple myeloma lacks t(11;14)] -13 or 13q-	Light chain restriction CD138 CD38 CD45 VS38 EMA (variable) CD79a (variable) CD31 (occasional) CD56 (occasional)
Extranodal NK/T cell lymphoma, nasal	50–75/nasal cavity, paranasal sinuses, nasopharynx	Diffuse neoplastic lymphoid proliferation with angiocentric/angiodestructive growth pattern, mucosal ulceration, pseudoepitheliomatous hyperplasia, and frequent associated inflammatory infiltrate	Frequent/common	Small or medium-sized cells to large transformed cells with round, oval, or irregular nuclei and azurophilic cytoplasmic granules	Common	del(6)(q21–25) i(6)(p10) EBV (ISH) 10% with T cell receptor gene rearrangement, no immunoglobulin light or heavy chain rearrangements	CD2 CD3e (cytoplasmic) Granzyme B Perforin CD45 CD56 (cytoplasmic) (usually) TIA-1 (usually)
Abbreviations: TLE1, Transducer-like enhancer of split 1; TIA-1, Tcell intracellular antigen 1

2.7.2 Fibrosarcoma

This is the most frequent mesenchymal malignancy of the sinonasal tract, affecting the maxillary sinus, nasal cavity, and ethmoid region most frequently.73 ^,​ 84 ^,​ 85 Normally the tumor presents as light tan and fleshy with a smooth surface having soft to firm consistency. Histologically, the tumor typically forms sweeping spindle cell interlacing bundles extending to surrounding tissue cells with moderate to low mitotic activity.

2.7.3 Synovial Sarcoma

Synovial sarcoma may involve the skull base region as extension from oropharynx or adjacent structures. The tumor affects the young age groups, having a median of 25 years and exhibiting male predominance.73 ^,​ 86 ^,​ 87 ^,​ 88 ^,​ 89 ^,​ 90 ^,​ s. Literatur

Histologically, synovial sarcoma may present as a pure spindle cell variant (monophasic) or in a biphasic form in which both spindle and epithelial components are present (Fig. 2.22). The epithelioid component is typically composed of cuboidal or columnar epithelial cells forming cords, nests, and pseudoglandular spaces intermingled with a spindle cell proliferation.

2.7.4 Hemangioendothelioma/Epithelioid Hemangioendothelioma

Epithelioid hemangioendothelioma (EHE) is a rare low- to intermediate-grade mesenchymal neoplasm characterized by short cords and nests of epithelioid tumor cells with endothelial differentiation set in a myxohyaline matrix (Fig. 2.13b,c; Fig. 2.23).92 ^,​ 93 ^,​ 94 Primary sites include skin, superficial and deep soft tissues, visceral organs, and bone. Anecdotal cases of primary hemangioendothelioma of the skull base have been described.92 ^,​ 93 Although the majority behave in an indolent fashion, there is an approximately 20% risk of widespread metastasis and death from disease.94 The diagnosis of EHE may be challenging, particularly on limited biopsy, with mimickers including metastatic carcinoma, myoepithelial, and chondroid neoplasms. EHE of the bone and extraskeletal sites has a highly specific recurrent translocation, t(1;3) (p36.3; q23–25), resulting in a WWTR1-CAMTA1 fusion transcript.94