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Sinonasal tract pathology: an updated review of select entities
MINI-SYMPOSIUM: HEAD AND NECK PATHOLOGY
Sinonasal tract pathology: an updated review of select entities
LGNIA should be separated from other types of adenocarcinoma previously mentioned and benign proliferations due to differences in behaviour. Salivary type adenocarcinomas have distinct architectural and cytological morphologies with some subtypes demonstrating a dual population with basal cells, which are absent in LGNIA. Respiratory epithelial adenomatoid hamartoma (REAH) is characterized by a glandular proliferation commonly mimicking normal respiratory mucosa. The respiratory epithelium in REAH has a pseudostratified appearance and there is stromal hyalinization around glands which are usually distinguishable from the back to back arrangement of LGNIA. A closer differential is seromucinous hamartoma; a rare proliferation of small glands with serous differentiation; and criteria to consistently separate these two entities have not been tested in large series. Treatment of LGNIA is surgical excision with or without adjuvant radiation. Outcome is favourable with a few cases of distant metastasis and death reported in some papers that included salivary type and high-grade non-intestinal type adenocarcinomas in their subset. Two new tumour entities that remain unresolved in their distinction from the general group of LGNIA are sinonasal renal cell-like adenocarcinoma3 and ETV6 rearranged sinonasal adenocarcinoma. The former often shows clear cells with low grade nuclei and other features resembling renal cell carcinoma.4 They appear to represent a clear cell variant of LGNIA and demonstrate expression of CK7, CAIX, DOG-1 and SOX10 while they are negative for CK20 and PAX-8 with the latter aiding in distinguishing them from metastatic renal cell carcinoma. ETV6 rearranged sinonasal adenocarcinoma demonstrate predominantly back to back tubular proliferations with rare apocrine features and no evidence of secretions. These tumors are strongly positive for CK7, GCDFP-15, DOG-1 and SOX-10, weakly and focally positive for S100 and negative for markers of true mammary analogue secretory carcinoma (GATA-3 and mammoglobin). As named, these are associated with ETV6-NTRK3 gene fusions and a smaller subset of ETV6 with an unknown partner (ETV6-X) that could represent an ETV6-RET mutation.5 Both sinonasal renal cell-like adenocarcinoma and ETV6 rearranged sinonasal adenocarcinoma have shown an indolent behaviour similar to other types of LGNIA.
Ipshita Kak ~ez Bayardo Perez-Ordon
Abstract The sinonasal tract is host to numerous benign and malignant entities that can pose diagnostic challenges to pathologists as a result of limited exposure in daily practice. This review concentrates on certain key characteristics of select entities with focus on differential diagnosis, novel subtypes and/or molecular distinction. The aim of this review is to summarize current knowledge and shed light on diagnostically challenging and emerging entities in sinonasal tract pathology.
Keywords biphenotypic sinonasal sarcoma; esthesioneuroblastoma; ETV6 rearranged sinonasal adenocarcinoma; glomangiopericytoma; intestinal-type sinonasal adenocarcinoma; ITAC; low grade sinonasal adenocarcinoma; mucosal melanoma; olfactory neuroblastoma; sinonasal renal cell like adenocarcinoma
Low-grade sinonasal adenocarcinoma Adenocarcinomas in the sinonasal tract can be divided into salivary type and non-salivary type with the latter including intestinal type and non-intestinal type (low grade and high grade).1 Low-grade non-intestinal type adenocarcinomas (LGNIA) occur over a broad age range with no gender predilection or associated environmental or other risk factors. They encompass a heterogeneous morphologic array of presentations but usually present as exophytic masses with crowded back-to-back glandular complex configuration in papillary or microcystic patterns (Figure 1A, B and C). Squamous morules, psammoma bodies, clear cells and oncocytic cells have been described (Figure 1D and E). Absence of necrosis, increased mitotic activity and nuclear pleomorphism separate them from their high-grade counterparts. They are commonly immunoreactive for keratin 7 (CK7) (Figure 1F) and negative for keratin 20 (CK20), CDX2 and villin as well as basal cell markers (p63, 34BE12 etc). Staining for SOX10, S100 and DOG-1 has been described in few cases.2 Molecular pathogenesis is not well studied in these lesions with only a few reports describing abundant p53 expression and absence of Her-2, APC and beta-catenin mutations.
Intestinal-type sinonasal adenocarcinoma Intestinal-type sinonasal adenocarcinoma (ITAC) is one of the most common and better described epithelial malignancies occurring in the sinonasal tract. It can be divided into sporadic type which is commonly seen in women in the maxillary antrum or occupational type seen predominantly in males and affecting the ethmoid sinus with the latter being the most common form.6 Occupational forms have been linked to exposure to wood dust, leather and shoe dust. These tumors present with non-specific nasal symptoms and simulate inflammatory polyps on clinical and gross examination. Microscopically, ITACs emulate small and large bowel mucosa showing the breadth of changes from apparent "normal" mucosa to resembling dysplastic and malignant colonic proliferations (Figure 2A and B). ITACs have been classified
Ipshita Kak MBBS FRCPC Anatomical Pathologist, Department of Pathology, St. Joseph’s Healthcare, McMaster University, Hamilton, Ontario, Canada. Conflicts of interest: none declared. ~ ez MD FRCPC Staff Pathologist, Department of Bayardo Perez-Ordon Anatomic Pathology, University Health Network and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Conflicts of interest: none declared.
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Figure 1 Low-grade non-intestinal type adenocarcinoma (LGNIA) composed of infiltrative dilated glands lined by a single layer of low cuboidal epithelium with minimal cytologic atypia (a). LGNIA with complex papillary architecture (b). LGNIA with a cribriform pattern of back-to-back glands (c). LGNIA with an oncocytic appearance (d). LGNIA with solid nests of clear cells (e). CK7 expression in a LGNIA (f).
morphologically by several groups with the initial description from Batsakis7 describing them as papillary, sessile, and alveolar emucoid neoplasms. Barnes8 expanded on this by dividing ITAC into five categories: tumours resembling colonic subtype (40%), tumours with solid architecture (20%), papillary tumours (18%), tumours resembling colonic mucinous or colloid carcinoma which can show focal signet ring cells (14%), and mixed type with combinations of these subtypes (8%). Kleinsasser and Schroeder9 listed four ITAC variants: papillary-tubular cylinder cell (further graded from I to III), signet-ring cell, alveolar goblet and transitional. On immunohistochemistry, these tumours strongly express intestinal type markers CK20, CDX2, villin, MUC2 and recently SATB2 (Figure 2C and D). Variable CK7 positivity may aid in differentiating from true colonic adenocarcinomas, which although uncommon can occur and therefore to definitively rule out metastatic gastrointestinal adenocarcinomas,
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endoscopy and associated investigations need to be performed. Non-intestinal sinonasal adenocarcinomas are usually strongly positive for CK7 and lack CK20, CDX2, villin and MUC2 expression. Mismatch repair proteins, beta catenin and E-cadherin show normal expression. A recent article reported PDL-1 positivity in 17% ITACs and although this did not correlate with prognosis they suggested that immunotherapy may be of benefit in this cohort.10 The similarity of ITAC to colon adenocarcinoma ends at a molecular level with KRAS and BRAF being uncommon in ITACs and unlike colon, MET gene amplification has been frequently reported. Loss of Annexin A1, diminished A2 expression and variable TP53 mutations have also been described. Overexpression of EGFR has been documented through immunohistochemistry but this has not correlated with detectable mutations. Hernandez et al. recently identified gains at 1q22-23, 3q28-
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Figure 2 Conventional intestinal-type sinonasal adenocarcinoma (ITAC) with cribriform architecture and so-called intraluminal “dirty” necrosis (a). ITAC showing pseudostratified epithelium and occasional Paneth cells with supranuclear granules in addition to enterochromaffin cells with infranuclear eosinophilic granules (b). CK20 and CDX2 expression characteristic of ITAC (c and d).
pattern with scant cytoplasm and salt and pepper chromatin (Figure 3A, B and C). The stroma is vascularized and usually contains neuropil or fibrillary tangles. Calcifications and Homer Wright pseudorosettes are occasionally seen in low grade tumours. The presence of nuclear atypia, nuclear pleomorphism (Figure 3D), necrosis, true annular rosettes with a lumen and secretion (FlexnereWintersteiner) and mitosis increases with increasing grade of tumour which is incorporated into the Hyams grading system.18 Hyams has been shown by multiple studies to be correlated with outcome.19 Rare descriptions of rhabdomyoblasts, ganglion cells, squamoid or true glandular differentiation and melanin pigment do exist. The neuroendocrine differentiation of ONB is highlighted by strong positivity for chromogranin and synaptophysin (Figure 3E) in addition to diffuse calretinin staining with variable intensity for CD56 and vimentin. S100 and GFAP (glial fibrillary acidic protein) highlight the sustentacular cells at the periphery of the lesion (Figure 3F). This helps to differentiate ONB from other tumours in the small round blue cell differential including negativity for CK5/6, p40, calcitonin, melanoma markers, CD45, CD117, pituitary hormone markers, desmin, myogenin, TTF-1, EBER, NUT-M1 and EWSR1. Cytokeratins and epithelial membrane antigen can be rarely positive. Proliferative index (Ki-67) can vary from 5 to 50%. Cytogenetic and comparative genomic hybridization studies (CGH) have implicated numerous chromosomal aberrations in ONB with gains more commonly found than losses. Of note, one report found that a specific deletion on chromosome 11 and gain on chromosome 1p was associated with metastasis and worse prognosis.20 Activation of Sonic Hedgehog pathway, expression of
29, 6p22, and 13q31-33, and losses at 4p15-16, 4q32-35, and 10q24 to be significantly associated with unfavorable clinical outcome.11 Other chromosomal and epigenetic findings continue to accumulate and add to the repertoire of knowledge in the field.12 ITACs are locally aggressive neoplasms with recurrences occurring in over half of affected patients. Lymph node and distant metastasis are uncommon; however death due to disease has been described. Occupational types show a slightly better prognosis than sporadic cases. Papillary subtype has been described to follow an indolent course whereas solid and mucinous subtypes are associated with a worse prognosis. The mainstay of treatment is surgery (open or endoscopic) followed by adjuvant intensity-modulated radiotherapy, although biological therapy is being explored with increasing knowledge of the molecular landscape of ITACs.13
Olfactory neuroblastoma Originally described by Berger et al.,14 olfactory neuroblastoma (ONB) is a rare malignant tumour most commonly seen in the 5th-6th decade as a superior nasal cavity mass causing nasal obstruction.15 Ectopic ONB is rare and is considered a diagnosis of exclusion.16 Imaging demonstrates a characteristic "dumbbell" shaped tumour arising from the cribriform plate on MRI with speckled calcifications and tumour cysts commonly seen on CT.17 Grossly, ONBs are reddish gray unilateral masses that demonstrate small rounds cells arranged in a lobular and nested
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Figure 3 Olfactory neuroblastoma (ONB) with typical nested pattern and prominent vascularity (a). ONB composed of small cells with relatively monotonous nuclei with finely dispersed chromatin (b). Higher power appearance of an ONB displaying small nucleoli (c). ONB with greater degree of nuclear variability (d). Diffuse chromogranin expression in a typical ONB (e). Sustentacular cells in ONB are highlighted by S100 (f).
subjective with better response seen in advanced stage and grade of tumor and unresectable or recurrent tumours.25 A recent article detailed the expression of somatostatin receptors, specifically SSTR2A and SSTR5 in ONB exclusive to other small round blue cell tumours, and their utility in the differential diagnosis and potential role of radioreceptor and somatostatin analogue treatment.26 ONB is a locally aggressive disease characterized by locoregional recurrence, however, the 5-year survival rates are excellent and distant metastasis is uncommon.
ASH-1, alteration in mTOR/PI3K and amplifications of CCND1 and FGFR3 have been recently discovered in next generation studies.21 Capper et al. recently published a DNA methylation based reclassification of ONB into 4 distinct groups: core ONB, sinonasal tumors with IDH2 mutation, sinonasal tumors with high methylation and others. They suggested following an algorithmic approach with low Hyams grade tumours (I-II) divided based on chromogranin and cytokeratin expression and high Hyams grade tumours (III-IV) investigated with IDH2 sequencing.22 Due to some difficulty in applying the traditional AJCC TNM staging23 in this particular region, numerous staging systems have been proposed from Kadish to Morita and Dulguerov based on local extension to including cervical nodal involvement and distant metastasis in a TNM format. With the exception for very early disease, multimodality treatment with gross total resection and adjuvant radiotherapy is the accepted norm at most institutions.24 The role and type of chemotherapy is more
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Mucosal melanoma Mucosal melanomas (MM) represent a rare subset of melanomas which unlike cutaneous and ocular types are not associated with sun exposure. The majority of them are found in the head and neck region and show ethnic differences. They are uncommon before the age of 30 and typically peak in the 6th to 7th decade in
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Figure 4 Sinonasal malignant melanoma with epithelioid appearance displaying significant nuclear pleomorphism and rhabdoid cells (a) and diffuse HMB45 expression (b).
proposed,28 AJCC is the commonly used staging system.29 SMM are distinct molecular entities with more prevalent NRAS and KIT alterations along with loss of p16/INK4a and frequent gains of chromosome 1q, 6p and 8q rather than BRAF mutations.15,30 Additionally, GNAQ/GNA11 was not identified in SMM. Due to its rarity, there are no agreed upon optimal management strategies for SMM with options ranging from aggressive surgery with or without adjuvant radiation, with the latter showing no effect on overall survival, to systemic traditional or personalized chemotherapy regimens including Imatinib, MEK inhibitors and PD/PDL1 inhibitors.31 While patients with nasal MM have the most favourable outcomes among mucosal sites, most patients progress with lymph node and distant metastasis and eventually death within 5 years.
both genders with some reports of a slight male predominance. Although sinonasal mucosal melanomas (SMM) may present as pigmented masses causing nasal bleeding and obstructive symptoms and can be mistaken for nasal polyps, the majority of MM present as aggressive locally advanced masses. Similar to their cutaneous counterparts, SMM can show varied morphology from epithelioid, spindled, plasmacytoid to desmoplastic (Figure 4A). A significant proportion are devoid of pigment (amelanotic) and therefore immunohistochemistry (S100, Melan A, HMB45 etc.) (Figure 4B) is commonly employed to differentiate them from other poorly differentiated neoplasms. Distinction from metastatic melanoma can be made by the presence of in situ mucosal disease.27 Clark and Breslow staging are difficult to apply to the mucosal and although classification system has been
Figure 5 Sinonasal glomangiopericytoma comprised of monotonous spindle cells arranged in short fascicles. Note a subepithelial “Grenz” zone (a). Glomangiopericytoma composed of cellular fascicles of bland spindle cells (b) with expression of actin (c) and beta-catenin (d).
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MIR143-NOTCH-1/2/3 fusion genes not found in GPC.40 GPC can occasionally show a whorled architecture where meningiomas can enter the differential but immunoreactivity for EMA and Claudin-1 helps differentiate the two diagnoses. Also in the differential is monophasic synovial sarcoma, however, keratin, Bcl2, TLE-1 and CD99 expression can distinguish it from glomangiopericytoma.41 In terms of clinical behaviour, these tumours are generally indolent with a 90% 5 year survival rate.37,38 Rates of recurrence up to 40% have been described and are dependent on adequate margins on the initial wide surgical excision,36 for which endoscopic sinus surgery with pre-operative embolization is becoming increasingly popular. Multiple recurrences are commonly associated with and precede metastasis.38 Poor prognostic factors include: bony invasion, size >5 cm, mitotic activity >4/10 high-power fields, Ki-67 index of more than 10%, necrosis and prominent nuclear pleomorphism.34
Glomangiopericytoma Distinct from the prevalent nomenclature change to solitary fibrous tumour in other sites,32,33 the World Health Organization has retained the use of the term hemangiopericytoma/glomangiopericytoma (GPC) in the sinonasal tract34 which describes a rare indolent neoplasm composed of bland epithelioid or spindle cells with perivascular arrangement and myoid differentiation.32,35 These tumours show a wide age range (3 months e87 years), slight female predominance and typically produce non-specific symptoms with occasional reports of osteomalacia associated with a unilateral nasal mass causing obstruction.36,37 Clinical examination and imaging reveal a polypoid lesion, commonly less than 5 cm in size,38 with no surface ulceration. Microscopically, these are unencapsulated well-demarcated submucosal spindle cell lesions with a "grenz" zone composed of monotonous epithelioid or spindle cells within a rich vascular network showing staghorn vessels32,34 (Figure 5A and B). Perivascular hyalinization is quite characteristic and an inflammatory cell infiltrate with extravasated red blood cells is commonly seen. Occasionally degenerative changes with fibrous, myxoid and giant cell rich areas have been described.35 Mitoses are low and necrosis is unusual. The tumour cells are strongly immunoreactive for actin and beta-catenin (nuclear) (Figure 5C and D), focally and weakly positive for CD34 and negative for S100, desmin, CD117 and Bcl-2. Recurrent CTNNB1 gene mutations leading to nuclear accumulation of beta-catenin and resultant upregulation of Cyclin D1, c-MYC and LEF-1, in the absence of NAB2-STAT6 gene fusion is the molecular hallmark of this lesion. GPC can be separated from its close mimics solitary fibrous tumour and glomus tumour by the rarity of the latter two entities in the sinonasal tract. Solitary fibrous tumour shows a patternless pattern with dense collagen and strong immunohistochemical staining for CD34, Bcl-2 and STAT-6 and negativity for actin39. Glomus tumours have recently been described to have
Biphenotypic sinonasal sarcoma Biphenotypic sinonasal sarcoma (BPSS) is a relatively new addition to the WHO classification of Head and Neck tumours42 that typifies a low-grade sarcoma with neural and myogenic phenotype exclusive to the sinonasal tract. Initial reports described fibrosarcomas and neurogenic sarcomas of the sinonasal tract with divergent differentiation that were difficult to classify, however, a recent case series described this distinct entity based on its characteristic histological, immunohistochemical and molecular characteristics.43 Commonly found in the superior nasal cavity and ethmoid sinus, these are tumours that occur over a wide age range (24e85 years) and predominantly affect females.44 Histology shows a poorly circumscribed cellular bland spindle cell lesion with infiltration demonstrating herring-bone and hemangiopericytoma like patterns with surface respiratory epithelium proliferation and entrapment (Figure 6A and B). The
Figure 6 Biphenoptypic sinonasal sarcoma (BPSS) composed of bland spindle cells surrounded by normal nasal serous glands (a). Note the absence of mitoses, necrosis or significant nuclear pleomorphism in this BPSS (b). BPSS with typical co-expression of S100 (c) and actin (d).
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Differential diagnosis of biphenotypic sinonasal sarcoma Diagnosis
S100 SMA MSA SOX10
Desmin MYOD1 Cytokeratins CD34 Other differentiating features
Biphenotypic Sinonasal Sarcoma
þ/Fþ þ/Fþ þ/Fþ e
þ/Fþ
Rþ
Rþ
Rþ
Fibrosarcoma Cellular schwannoma Malignant peripheral nerve sheath tumor Leiomyosarcoma Solitary fibrous tumour Rhabdomyosarcoma Monophasic synovial sarcoma
e Fþ þ e þ/Fþ e
Fþ e e
e þ þ/Fþ
e e Rþ
e e Rþ
e e e
þ e e
e e e Rþ
þ e e e
e e e e
þ e þ/Fþ e
e e þ/Fþ Rþ
e e Rþ þ/Fþ
e þ e e
þ e e Rþ
PAX3-MAML3, PAX3-FOXO1 and PAX3NCOA1 fusion Prominent collagen matrix Diffuse and strong S100 positivity Varying degrees of nuclear pleomorphism and necrosis Nuclear atypia and necrosis Characteristic ropey collagen and STAT6 Dominant histology is rhabdoid TLE1 and SS18eSSX fusion diagnostic
Key: þ strongly and diffusely positive, Fþ focally positive, Rþ rare positive, e negative.
Table 1
myogenic markers in the absence of SOX-10 is usually sufficient to render the diagnosis. Table 1 further highlights the essential features that help differentiate BPSS from other histological mimics.41 A
low grade nature of the lesion is illustrated by the lack of necrosis and rare mitosis. On immunohistochemistry, the lesional cells are positive for S100 and smooth muscle markers (SMA, MSA etc.) (Figure 6C and D) but negative for SOX-10. Rhabdomyoblastic45,46 and epithelial differentiation43 with expression of desmin, myogenin and MYOD1 in the former and focal EMA/ keratins in the latter have also been reported. Beta-catenin staining has been described in a recent subset of BPSS. This also corresponds at a molecular level with most BPSS harbouring the characteristic t (2;4)(q35; q31.1) PAX3-MAML3 fusion while those with rhabdomyoblastic features on histology and immunohistochemistry yielding PAX3-FOXO1 and PAX3-NCOA1 fusion genes.45,46 Reports of PAX3 with an unknown partner and MAML3 without PAX3 are on record.47,48 A recent publication described a biphenotypic sarcoma in the oropharynx with similar histology and immunohistochemical characteristics but novel RREB1eMKL2 fusion transcript, raising questions about the spectrum of fusion negative BPSS.49 Clinically, BPSS can present with facial pressure, laboured breathing or nasal congestion which on examination and imaging reveal polypoid lesions that are frequently infiltrative.43,47 Resection, with or without adjuvant radiation, is the most common treatment modality and recurrence can develop in up to 40 e50% of patients. There have been no reports of distant metastasis from these tumours.43 Only one case of death from disease has been reported, however, FISH for PAX3 failed in the mentioned case.48 One patient died from perioperative complications of tumour resection. Depending on the histology and variant immunohistochemistry, the differential diagnosis can range from fibrous (fibrosarcoma), neural (malignant peripheral nerve sheath tumor, cellular schwannoma), myogenic (leiomyosarcoma), hemangiopericytoma-like (solitary fibrous tumour, glomangiopericytoma) to rhabdomyosarcoma and monophasic synovial sarcoma. However, the unique dual expression of neural and
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Practice points C
C
C
C
C
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Non-salivary sinonasal adenocarcinomas include non-intestinal type which are typified by immunoreactivity for CK7 and negativity for CK20, CDX2 and villin with the latter differentiating them from intestinal type adenocarcinomas (ITACs). Non-salivary nonintestinal sinonasal adenocarcinomas are further subdivided into low and high grade. Olfactory neuroblastoma can be distinguished from other mimics in the small round blue cell tumours category by its characteristic histology, strong positivity for neuroendocrine markers in addition to S100 and GFAP staining of sustentacular cells. Mucosal melanomas are distinct from cutaneous and ocular melanomas in location, molecular characteristics and behavior and should be kept in the differential of poorly differentiated malignancies in the sinonasal tract. They can be recognized by immunopositivity for melanoma markers. Glomangiopericytoma is an uncommon indolent tumour of the sinonasal tract characterized by bland epithelioid cells highlighted by actin and nuclear beta-catenin with negativity for NAB2-STAT6 gene fusion. Biphenotypic sinonasal sarcoma is a recently described entity with exclusive sinonasal location of a low grade sarcoma with neural (S100 positive but SOX10 negative) and myogenic immunohistochemical expression.
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analysis of 104 cases showing perivascular myoid differentiation. Am J Surg Pathol 2003; 27: 737e49. Catalano PJ, Brandwein M, Shah DK, Urken ML, Lawson W, Biller HF. Sinonasal hemangiopericytomas: a clinicopathologic and immunohistochemical study of seven cases. Head Neck 1996; 18: 42e53. Park ES, Kim J, Jun SY. Characteristics and prognosis of glomangiopericytomas: a systematic review. Head Neck 2017; 39: 1897e909. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013; 45: 180e5. Mosquera JM, Sboner A, Zhang L, et al. Novel MIR143-NOTCH fusions in benign and malignant glomus tumors. Genes Chromosomes Cancer 2013; 52: 1075e87. Miettinen M, Limon J, Niezabitowski A, Lasota J. Patterns of keratin polypeptides in 110 biphasic, monophasic, and poorly differentiated synovial sarcomas. Virchows Arch 2000; 437: 275e83. Lewis JEOA. In: El-Naggar AKCJ, Grandis JR, Takata T, Slootweg PJ, eds. Tumours of the nasal cavity, paranasal sinuses and skull base: malignant soft tissue Tumours: biphenotypic sinonasal sarcoma. 4th ed. Lyon, France: IARC, 2017.
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43 Lewis JT, Oliveira AM, Nascimento AG, et al. Low-grade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases. Am J Surg Pathol 2012; 36: 517e25. 44 Wang X, Bledsoe KL, Graham RP, et al. Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet 2014; 46: 666e8. 45 Huang SC, Ghossein RA, Bishop JA, et al. Novel PAX3-NCOA1 fusions in biphenotypic sinonasal sarcoma with focal rhabdomyoblastic differentiation. Am J Surg Pathol 2016; 40: 51e9. 46 Wong WJ, Lauria A, Hornick JL, Xiao S, Fletcher JA, MarinoEnriquez A. Alternate PAX3-FOXO1 oncogenic fusion in biphenotypic sinonasal sarcoma. Genes Chromosomes Cancer 2016; 55: 25e9. 47 Fritchie KJ, Jin L, Wang X, et al. Fusion gene profile of biphenotypic sinonasal sarcoma: an analysis of 44 cases. Histopathology 2016; 69: 930e6. 48 Rooper LM, Huang SC, Antonescu CR, Westra WH, Bishop JA. Biphenotypic sinonasal sarcoma: an expanded immunoprofile including consistent nuclear beta-catenin positivity and absence of SOX10 expression. Hum Pathol 2016; 55: 44e50. 49 Siegfried A, Romary C, Escudie F, et al. RREB1-MKL2 fusion in biphenotypic "oropharyngeal" sarcoma: new entity or part of the spectrum of biphenotypic sinonasal sarcomas? Genes Chromosomes Cancer 2018; 57: 203e10.
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Sinonasal tract pathology: an updated review of select entities
LGNIA should be separated from other types of adenocarcinoma previously mentioned and benign proliferations due to differences in behaviour. Salivary type adenocarcinomas have distinct architectural and cytological morphologies with some subtypes demonstrating a dual population with basal cells, which are absent in LGNIA. Respiratory epithelial adenomatoid hamartoma (REAH) is characterized by a glandular proliferation commonly mimicking normal respiratory mucosa. The respiratory epithelium in REAH has a pseudostratified appearance and there is stromal hyalinization around glands which are usually distinguishable from the back to back arrangement of LGNIA. A closer differential is seromucinous hamartoma; a rare proliferation of small glands with serous differentiation; and criteria to consistently separate these two entities have not been tested in large series. Treatment of LGNIA is surgical excision with or without adjuvant radiation. Outcome is favourable with a few cases of distant metastasis and death reported in some papers that included salivary type and high-grade non-intestinal type adenocarcinomas in their subset. Two new tumour entities that remain unresolved in their distinction from the general group of LGNIA are sinonasal renal cell-like adenocarcinoma3 and ETV6 rearranged sinonasal adenocarcinoma. The former often shows clear cells with low grade nuclei and other features resembling renal cell carcinoma.4 They appear to represent a clear cell variant of LGNIA and demonstrate expression of CK7, CAIX, DOG-1 and SOX10 while they are negative for CK20 and PAX-8 with the latter aiding in distinguishing them from metastatic renal cell carcinoma. ETV6 rearranged sinonasal adenocarcinoma demonstrate predominantly back to back tubular proliferations with rare apocrine features and no evidence of secretions. These tumors are strongly positive for CK7, GCDFP-15, DOG-1 and SOX-10, weakly and focally positive for S100 and negative for markers of true mammary analogue secretory carcinoma (GATA-3 and mammoglobin). As named, these are associated with ETV6-NTRK3 gene fusions and a smaller subset of ETV6 with an unknown partner (ETV6-X) that could represent an ETV6-RET mutation.5 Both sinonasal renal cell-like adenocarcinoma and ETV6 rearranged sinonasal adenocarcinoma have shown an indolent behaviour similar to other types of LGNIA.
Ipshita Kak ~ez Bayardo Perez-Ordon
Abstract The sinonasal tract is host to numerous benign and malignant entities that can pose diagnostic challenges to pathologists as a result of limited exposure in daily practice. This review concentrates on certain key characteristics of select entities with focus on differential diagnosis, novel subtypes and/or molecular distinction. The aim of this review is to summarize current knowledge and shed light on diagnostically challenging and emerging entities in sinonasal tract pathology.
Keywords biphenotypic sinonasal sarcoma; esthesioneuroblastoma; ETV6 rearranged sinonasal adenocarcinoma; glomangiopericytoma; intestinal-type sinonasal adenocarcinoma; ITAC; low grade sinonasal adenocarcinoma; mucosal melanoma; olfactory neuroblastoma; sinonasal renal cell like adenocarcinoma
Low-grade sinonasal adenocarcinoma Adenocarcinomas in the sinonasal tract can be divided into salivary type and non-salivary type with the latter including intestinal type and non-intestinal type (low grade and high grade).1 Low-grade non-intestinal type adenocarcinomas (LGNIA) occur over a broad age range with no gender predilection or associated environmental or other risk factors. They encompass a heterogeneous morphologic array of presentations but usually present as exophytic masses with crowded back-to-back glandular complex configuration in papillary or microcystic patterns (Figure 1A, B and C). Squamous morules, psammoma bodies, clear cells and oncocytic cells have been described (Figure 1D and E). Absence of necrosis, increased mitotic activity and nuclear pleomorphism separate them from their high-grade counterparts. They are commonly immunoreactive for keratin 7 (CK7) (Figure 1F) and negative for keratin 20 (CK20), CDX2 and villin as well as basal cell markers (p63, 34BE12 etc). Staining for SOX10, S100 and DOG-1 has been described in few cases.2 Molecular pathogenesis is not well studied in these lesions with only a few reports describing abundant p53 expression and absence of Her-2, APC and beta-catenin mutations.
Intestinal-type sinonasal adenocarcinoma Intestinal-type sinonasal adenocarcinoma (ITAC) is one of the most common and better described epithelial malignancies occurring in the sinonasal tract. It can be divided into sporadic type which is commonly seen in women in the maxillary antrum or occupational type seen predominantly in males and affecting the ethmoid sinus with the latter being the most common form.6 Occupational forms have been linked to exposure to wood dust, leather and shoe dust. These tumors present with non-specific nasal symptoms and simulate inflammatory polyps on clinical and gross examination. Microscopically, ITACs emulate small and large bowel mucosa showing the breadth of changes from apparent "normal" mucosa to resembling dysplastic and malignant colonic proliferations (Figure 2A and B). ITACs have been classified
Ipshita Kak MBBS FRCPC Anatomical Pathologist, Department of Pathology, St. Joseph’s Healthcare, McMaster University, Hamilton, Ontario, Canada. Conflicts of interest: none declared. ~ ez MD FRCPC Staff Pathologist, Department of Bayardo Perez-Ordon Anatomic Pathology, University Health Network and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Conflicts of interest: none declared.
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Figure 1 Low-grade non-intestinal type adenocarcinoma (LGNIA) composed of infiltrative dilated glands lined by a single layer of low cuboidal epithelium with minimal cytologic atypia (a). LGNIA with complex papillary architecture (b). LGNIA with a cribriform pattern of back-to-back glands (c). LGNIA with an oncocytic appearance (d). LGNIA with solid nests of clear cells (e). CK7 expression in a LGNIA (f).
morphologically by several groups with the initial description from Batsakis7 describing them as papillary, sessile, and alveolar emucoid neoplasms. Barnes8 expanded on this by dividing ITAC into five categories: tumours resembling colonic subtype (40%), tumours with solid architecture (20%), papillary tumours (18%), tumours resembling colonic mucinous or colloid carcinoma which can show focal signet ring cells (14%), and mixed type with combinations of these subtypes (8%). Kleinsasser and Schroeder9 listed four ITAC variants: papillary-tubular cylinder cell (further graded from I to III), signet-ring cell, alveolar goblet and transitional. On immunohistochemistry, these tumours strongly express intestinal type markers CK20, CDX2, villin, MUC2 and recently SATB2 (Figure 2C and D). Variable CK7 positivity may aid in differentiating from true colonic adenocarcinomas, which although uncommon can occur and therefore to definitively rule out metastatic gastrointestinal adenocarcinomas,
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endoscopy and associated investigations need to be performed. Non-intestinal sinonasal adenocarcinomas are usually strongly positive for CK7 and lack CK20, CDX2, villin and MUC2 expression. Mismatch repair proteins, beta catenin and E-cadherin show normal expression. A recent article reported PDL-1 positivity in 17% ITACs and although this did not correlate with prognosis they suggested that immunotherapy may be of benefit in this cohort.10 The similarity of ITAC to colon adenocarcinoma ends at a molecular level with KRAS and BRAF being uncommon in ITACs and unlike colon, MET gene amplification has been frequently reported. Loss of Annexin A1, diminished A2 expression and variable TP53 mutations have also been described. Overexpression of EGFR has been documented through immunohistochemistry but this has not correlated with detectable mutations. Hernandez et al. recently identified gains at 1q22-23, 3q28-
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Figure 2 Conventional intestinal-type sinonasal adenocarcinoma (ITAC) with cribriform architecture and so-called intraluminal “dirty” necrosis (a). ITAC showing pseudostratified epithelium and occasional Paneth cells with supranuclear granules in addition to enterochromaffin cells with infranuclear eosinophilic granules (b). CK20 and CDX2 expression characteristic of ITAC (c and d).
pattern with scant cytoplasm and salt and pepper chromatin (Figure 3A, B and C). The stroma is vascularized and usually contains neuropil or fibrillary tangles. Calcifications and Homer Wright pseudorosettes are occasionally seen in low grade tumours. The presence of nuclear atypia, nuclear pleomorphism (Figure 3D), necrosis, true annular rosettes with a lumen and secretion (FlexnereWintersteiner) and mitosis increases with increasing grade of tumour which is incorporated into the Hyams grading system.18 Hyams has been shown by multiple studies to be correlated with outcome.19 Rare descriptions of rhabdomyoblasts, ganglion cells, squamoid or true glandular differentiation and melanin pigment do exist. The neuroendocrine differentiation of ONB is highlighted by strong positivity for chromogranin and synaptophysin (Figure 3E) in addition to diffuse calretinin staining with variable intensity for CD56 and vimentin. S100 and GFAP (glial fibrillary acidic protein) highlight the sustentacular cells at the periphery of the lesion (Figure 3F). This helps to differentiate ONB from other tumours in the small round blue cell differential including negativity for CK5/6, p40, calcitonin, melanoma markers, CD45, CD117, pituitary hormone markers, desmin, myogenin, TTF-1, EBER, NUT-M1 and EWSR1. Cytokeratins and epithelial membrane antigen can be rarely positive. Proliferative index (Ki-67) can vary from 5 to 50%. Cytogenetic and comparative genomic hybridization studies (CGH) have implicated numerous chromosomal aberrations in ONB with gains more commonly found than losses. Of note, one report found that a specific deletion on chromosome 11 and gain on chromosome 1p was associated with metastasis and worse prognosis.20 Activation of Sonic Hedgehog pathway, expression of
29, 6p22, and 13q31-33, and losses at 4p15-16, 4q32-35, and 10q24 to be significantly associated with unfavorable clinical outcome.11 Other chromosomal and epigenetic findings continue to accumulate and add to the repertoire of knowledge in the field.12 ITACs are locally aggressive neoplasms with recurrences occurring in over half of affected patients. Lymph node and distant metastasis are uncommon; however death due to disease has been described. Occupational types show a slightly better prognosis than sporadic cases. Papillary subtype has been described to follow an indolent course whereas solid and mucinous subtypes are associated with a worse prognosis. The mainstay of treatment is surgery (open or endoscopic) followed by adjuvant intensity-modulated radiotherapy, although biological therapy is being explored with increasing knowledge of the molecular landscape of ITACs.13
Olfactory neuroblastoma Originally described by Berger et al.,14 olfactory neuroblastoma (ONB) is a rare malignant tumour most commonly seen in the 5th-6th decade as a superior nasal cavity mass causing nasal obstruction.15 Ectopic ONB is rare and is considered a diagnosis of exclusion.16 Imaging demonstrates a characteristic "dumbbell" shaped tumour arising from the cribriform plate on MRI with speckled calcifications and tumour cysts commonly seen on CT.17 Grossly, ONBs are reddish gray unilateral masses that demonstrate small rounds cells arranged in a lobular and nested
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Figure 3 Olfactory neuroblastoma (ONB) with typical nested pattern and prominent vascularity (a). ONB composed of small cells with relatively monotonous nuclei with finely dispersed chromatin (b). Higher power appearance of an ONB displaying small nucleoli (c). ONB with greater degree of nuclear variability (d). Diffuse chromogranin expression in a typical ONB (e). Sustentacular cells in ONB are highlighted by S100 (f).
subjective with better response seen in advanced stage and grade of tumor and unresectable or recurrent tumours.25 A recent article detailed the expression of somatostatin receptors, specifically SSTR2A and SSTR5 in ONB exclusive to other small round blue cell tumours, and their utility in the differential diagnosis and potential role of radioreceptor and somatostatin analogue treatment.26 ONB is a locally aggressive disease characterized by locoregional recurrence, however, the 5-year survival rates are excellent and distant metastasis is uncommon.
ASH-1, alteration in mTOR/PI3K and amplifications of CCND1 and FGFR3 have been recently discovered in next generation studies.21 Capper et al. recently published a DNA methylation based reclassification of ONB into 4 distinct groups: core ONB, sinonasal tumors with IDH2 mutation, sinonasal tumors with high methylation and others. They suggested following an algorithmic approach with low Hyams grade tumours (I-II) divided based on chromogranin and cytokeratin expression and high Hyams grade tumours (III-IV) investigated with IDH2 sequencing.22 Due to some difficulty in applying the traditional AJCC TNM staging23 in this particular region, numerous staging systems have been proposed from Kadish to Morita and Dulguerov based on local extension to including cervical nodal involvement and distant metastasis in a TNM format. With the exception for very early disease, multimodality treatment with gross total resection and adjuvant radiotherapy is the accepted norm at most institutions.24 The role and type of chemotherapy is more
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Mucosal melanoma Mucosal melanomas (MM) represent a rare subset of melanomas which unlike cutaneous and ocular types are not associated with sun exposure. The majority of them are found in the head and neck region and show ethnic differences. They are uncommon before the age of 30 and typically peak in the 6th to 7th decade in
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Figure 4 Sinonasal malignant melanoma with epithelioid appearance displaying significant nuclear pleomorphism and rhabdoid cells (a) and diffuse HMB45 expression (b).
proposed,28 AJCC is the commonly used staging system.29 SMM are distinct molecular entities with more prevalent NRAS and KIT alterations along with loss of p16/INK4a and frequent gains of chromosome 1q, 6p and 8q rather than BRAF mutations.15,30 Additionally, GNAQ/GNA11 was not identified in SMM. Due to its rarity, there are no agreed upon optimal management strategies for SMM with options ranging from aggressive surgery with or without adjuvant radiation, with the latter showing no effect on overall survival, to systemic traditional or personalized chemotherapy regimens including Imatinib, MEK inhibitors and PD/PDL1 inhibitors.31 While patients with nasal MM have the most favourable outcomes among mucosal sites, most patients progress with lymph node and distant metastasis and eventually death within 5 years.
both genders with some reports of a slight male predominance. Although sinonasal mucosal melanomas (SMM) may present as pigmented masses causing nasal bleeding and obstructive symptoms and can be mistaken for nasal polyps, the majority of MM present as aggressive locally advanced masses. Similar to their cutaneous counterparts, SMM can show varied morphology from epithelioid, spindled, plasmacytoid to desmoplastic (Figure 4A). A significant proportion are devoid of pigment (amelanotic) and therefore immunohistochemistry (S100, Melan A, HMB45 etc.) (Figure 4B) is commonly employed to differentiate them from other poorly differentiated neoplasms. Distinction from metastatic melanoma can be made by the presence of in situ mucosal disease.27 Clark and Breslow staging are difficult to apply to the mucosal and although classification system has been
Figure 5 Sinonasal glomangiopericytoma comprised of monotonous spindle cells arranged in short fascicles. Note a subepithelial “Grenz” zone (a). Glomangiopericytoma composed of cellular fascicles of bland spindle cells (b) with expression of actin (c) and beta-catenin (d).
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MIR143-NOTCH-1/2/3 fusion genes not found in GPC.40 GPC can occasionally show a whorled architecture where meningiomas can enter the differential but immunoreactivity for EMA and Claudin-1 helps differentiate the two diagnoses. Also in the differential is monophasic synovial sarcoma, however, keratin, Bcl2, TLE-1 and CD99 expression can distinguish it from glomangiopericytoma.41 In terms of clinical behaviour, these tumours are generally indolent with a 90% 5 year survival rate.37,38 Rates of recurrence up to 40% have been described and are dependent on adequate margins on the initial wide surgical excision,36 for which endoscopic sinus surgery with pre-operative embolization is becoming increasingly popular. Multiple recurrences are commonly associated with and precede metastasis.38 Poor prognostic factors include: bony invasion, size >5 cm, mitotic activity >4/10 high-power fields, Ki-67 index of more than 10%, necrosis and prominent nuclear pleomorphism.34
Glomangiopericytoma Distinct from the prevalent nomenclature change to solitary fibrous tumour in other sites,32,33 the World Health Organization has retained the use of the term hemangiopericytoma/glomangiopericytoma (GPC) in the sinonasal tract34 which describes a rare indolent neoplasm composed of bland epithelioid or spindle cells with perivascular arrangement and myoid differentiation.32,35 These tumours show a wide age range (3 months e87 years), slight female predominance and typically produce non-specific symptoms with occasional reports of osteomalacia associated with a unilateral nasal mass causing obstruction.36,37 Clinical examination and imaging reveal a polypoid lesion, commonly less than 5 cm in size,38 with no surface ulceration. Microscopically, these are unencapsulated well-demarcated submucosal spindle cell lesions with a "grenz" zone composed of monotonous epithelioid or spindle cells within a rich vascular network showing staghorn vessels32,34 (Figure 5A and B). Perivascular hyalinization is quite characteristic and an inflammatory cell infiltrate with extravasated red blood cells is commonly seen. Occasionally degenerative changes with fibrous, myxoid and giant cell rich areas have been described.35 Mitoses are low and necrosis is unusual. The tumour cells are strongly immunoreactive for actin and beta-catenin (nuclear) (Figure 5C and D), focally and weakly positive for CD34 and negative for S100, desmin, CD117 and Bcl-2. Recurrent CTNNB1 gene mutations leading to nuclear accumulation of beta-catenin and resultant upregulation of Cyclin D1, c-MYC and LEF-1, in the absence of NAB2-STAT6 gene fusion is the molecular hallmark of this lesion. GPC can be separated from its close mimics solitary fibrous tumour and glomus tumour by the rarity of the latter two entities in the sinonasal tract. Solitary fibrous tumour shows a patternless pattern with dense collagen and strong immunohistochemical staining for CD34, Bcl-2 and STAT-6 and negativity for actin39. Glomus tumours have recently been described to have
Biphenotypic sinonasal sarcoma Biphenotypic sinonasal sarcoma (BPSS) is a relatively new addition to the WHO classification of Head and Neck tumours42 that typifies a low-grade sarcoma with neural and myogenic phenotype exclusive to the sinonasal tract. Initial reports described fibrosarcomas and neurogenic sarcomas of the sinonasal tract with divergent differentiation that were difficult to classify, however, a recent case series described this distinct entity based on its characteristic histological, immunohistochemical and molecular characteristics.43 Commonly found in the superior nasal cavity and ethmoid sinus, these are tumours that occur over a wide age range (24e85 years) and predominantly affect females.44 Histology shows a poorly circumscribed cellular bland spindle cell lesion with infiltration demonstrating herring-bone and hemangiopericytoma like patterns with surface respiratory epithelium proliferation and entrapment (Figure 6A and B). The
Figure 6 Biphenoptypic sinonasal sarcoma (BPSS) composed of bland spindle cells surrounded by normal nasal serous glands (a). Note the absence of mitoses, necrosis or significant nuclear pleomorphism in this BPSS (b). BPSS with typical co-expression of S100 (c) and actin (d).
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Differential diagnosis of biphenotypic sinonasal sarcoma Diagnosis
S100 SMA MSA SOX10
Desmin MYOD1 Cytokeratins CD34 Other differentiating features
Biphenotypic Sinonasal Sarcoma
þ/Fþ þ/Fþ þ/Fþ e
þ/Fþ
Rþ
Rþ
Rþ
Fibrosarcoma Cellular schwannoma Malignant peripheral nerve sheath tumor Leiomyosarcoma Solitary fibrous tumour Rhabdomyosarcoma Monophasic synovial sarcoma
e Fþ þ e þ/Fþ e
Fþ e e
e þ þ/Fþ
e e Rþ
e e Rþ
e e e
þ e e
e e e Rþ
þ e e e
e e e e
þ e þ/Fþ e
e e þ/Fþ Rþ
e e Rþ þ/Fþ
e þ e e
þ e e Rþ
PAX3-MAML3, PAX3-FOXO1 and PAX3NCOA1 fusion Prominent collagen matrix Diffuse and strong S100 positivity Varying degrees of nuclear pleomorphism and necrosis Nuclear atypia and necrosis Characteristic ropey collagen and STAT6 Dominant histology is rhabdoid TLE1 and SS18eSSX fusion diagnostic
Key: þ strongly and diffusely positive, Fþ focally positive, Rþ rare positive, e negative.
Table 1
myogenic markers in the absence of SOX-10 is usually sufficient to render the diagnosis. Table 1 further highlights the essential features that help differentiate BPSS from other histological mimics.41 A
low grade nature of the lesion is illustrated by the lack of necrosis and rare mitosis. On immunohistochemistry, the lesional cells are positive for S100 and smooth muscle markers (SMA, MSA etc.) (Figure 6C and D) but negative for SOX-10. Rhabdomyoblastic45,46 and epithelial differentiation43 with expression of desmin, myogenin and MYOD1 in the former and focal EMA/ keratins in the latter have also been reported. Beta-catenin staining has been described in a recent subset of BPSS. This also corresponds at a molecular level with most BPSS harbouring the characteristic t (2;4)(q35; q31.1) PAX3-MAML3 fusion while those with rhabdomyoblastic features on histology and immunohistochemistry yielding PAX3-FOXO1 and PAX3-NCOA1 fusion genes.45,46 Reports of PAX3 with an unknown partner and MAML3 without PAX3 are on record.47,48 A recent publication described a biphenotypic sarcoma in the oropharynx with similar histology and immunohistochemical characteristics but novel RREB1eMKL2 fusion transcript, raising questions about the spectrum of fusion negative BPSS.49 Clinically, BPSS can present with facial pressure, laboured breathing or nasal congestion which on examination and imaging reveal polypoid lesions that are frequently infiltrative.43,47 Resection, with or without adjuvant radiation, is the most common treatment modality and recurrence can develop in up to 40 e50% of patients. There have been no reports of distant metastasis from these tumours.43 Only one case of death from disease has been reported, however, FISH for PAX3 failed in the mentioned case.48 One patient died from perioperative complications of tumour resection. Depending on the histology and variant immunohistochemistry, the differential diagnosis can range from fibrous (fibrosarcoma), neural (malignant peripheral nerve sheath tumor, cellular schwannoma), myogenic (leiomyosarcoma), hemangiopericytoma-like (solitary fibrous tumour, glomangiopericytoma) to rhabdomyosarcoma and monophasic synovial sarcoma. However, the unique dual expression of neural and
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Practice points C
C
C
C
C
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Non-salivary sinonasal adenocarcinomas include non-intestinal type which are typified by immunoreactivity for CK7 and negativity for CK20, CDX2 and villin with the latter differentiating them from intestinal type adenocarcinomas (ITACs). Non-salivary nonintestinal sinonasal adenocarcinomas are further subdivided into low and high grade. Olfactory neuroblastoma can be distinguished from other mimics in the small round blue cell tumours category by its characteristic histology, strong positivity for neuroendocrine markers in addition to S100 and GFAP staining of sustentacular cells. Mucosal melanomas are distinct from cutaneous and ocular melanomas in location, molecular characteristics and behavior and should be kept in the differential of poorly differentiated malignancies in the sinonasal tract. They can be recognized by immunopositivity for melanoma markers. Glomangiopericytoma is an uncommon indolent tumour of the sinonasal tract characterized by bland epithelioid cells highlighted by actin and nuclear beta-catenin with negativity for NAB2-STAT6 gene fusion. Biphenotypic sinonasal sarcoma is a recently described entity with exclusive sinonasal location of a low grade sarcoma with neural (S100 positive but SOX10 negative) and myogenic immunohistochemical expression.
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