Head and Neck Pathol (2016) 10:75–84 DOI 10.1007/s12105-016-0695-8 SPECIAL ISSUE: SINONASAL TRACT PATHOLOGY. GUEST EDITORS: JUSTIN BISHOP, MD AND ALESSANDRO FRANCHI, MD An Update on Sinonasal Round Cell Undifferentiated Tumors Alessandro Franchi1 Received: 13 August 2015 / Accepted: 5 October 2015 / Published online: 1 February 2016 Ó Springer Science+Business Media New York 2016 Abstract The sinonasal cavities host a wide variety of region from adjacent sites (oral cavity, nasopharynx, or skull undifferentiated malignancies with round cell morphology, base) or from distant sites, further complicating the approach including neoplasms of epithelial, mesenchymal, neuroecto- to the differential diagnosis. Thus, the clinical history and the dermal, and hematolymphoid lineage. The differential diag- results of imaging studies should be always available for an nosis may be difficult, especially in small biopsy material, due accurate differential diagnosis. to overlapping morphology, but their correct classification is Although no definitive data on the relative frequency of clinically relevant. The aim of this review is to provide undifferentiated sinonasal malignancies is available, it can practical guidelines for the differential diagnosis of these be expected that it should reflect the distribution of all his- malignancies, with emphasis on recently described entities totypes in the general population, where epithelial tumors are and special reference to the role of ancillary techniques. by far most frequent than non-epithelial tumors [1]. On the other hand, in the pediatric population rhabdomyosarcoma Keywords Nasal cavity Á Paranasal sinuses Á and olfactory neuroblastoma are the most frequent histo- Undifferentiated tumors Á Diagnosis Á types, followed by haematolymphoid malignancies, whereas Immunohistochemistry Á Molecular biology epithelial malignancies are extremely rare [2]. These dif- ferences should be taken into account when approaching the diagnosis of an undifferentiated sinonasal neoplasm. Introduction With the refinement of diagnostic criteria and the use of immunohistochemical and molecular markers, new sino- In the sinonasal tract, a wide range of malignancies may nasal malignancies with poorly differentiated morphology histologically appear as formed by neoplastic cell with no have recently been described. Moreover, several new definitive differentiation, round cell morphology with high immunohistochemical and molecular markers have been nuclear to cytoplasmic ratio, high mitotic and apoptotic tested on these neoplasms, and they facilitate, in combi- activity, and necrosis. The differential diagnosis is chal- nation with light and ultrastructural morphology, their lenging, particularly on small biopsy specimens, and includes correct classification. This review is focused on the dif- a whole range of neoplastic entities, both epithelial and non- ferential diagnosis of recently described entities in the epithelial. However, it is important to separate them because group of sinonasal undifferentiated/poorly differentiated their prognoses and management are different. Moreover, tumors with round cell morphology, with special reference poorly differentiated neoplasms may spread to the sinonasal to the role of ancillary techniques. & Alessandro Franchi Epithelial Neoplasms franchi@unifi.it Table 1 summarizes the immunohistochemical features of 1 Section of Anatomic Pathology, Department of Surgery and Translational Medicine, University of Florence, Largo sinonasal carcinomas that may present with undifferenti- Brambilla 3, 50134 Florence, Italy ated round cell morphology. 123 76 Head and Neck Pathol (2016) 10:75–84 Table 1 Summary of the diagnostic features of sinonasal poorly differentiated/undifferentiated carcinomas Histologic features CKa P63 P40 S100 Syn HPV EBV Diagnostic gene alterations SNUC Sheets, nests or ribbons of 7?; 5/6- --- - -(? in - ND small to medium-sized rare cells, no evidence of cases) squamous or glandular differentiation Lymphoepithelioma Syncitial growth pattern, 5/6?,13???-- - ? ND prominent lymphoid infiltrate NUT midline Sheets of monotonous 5/6?,7?, ??- - - - t(15;19) carcinoma undifferentiated round 20? in NUT ? by cells, foci of mature rare cases immunohistochemistry keratinized squamous cells occasionally seen Neuroendocrine Closely packed small cells 5/6 rarely?-/?- - ? - - ND carcinoma with scant cytoplasm, extensive necrosis, and brisk mitotic activity; in large cell NEC, cytoplasm is abundant, nuclei are vesicular with prominent nucleoli, moderate pleomorphism is present Basaloid squamous Nests of basaloid cells, 5/6?, ??- - ? - ND cell carcinoma peripheral palisading, 34bE12? comedo necrosis, foci of squamous differentiation Solid adenoid cystic Solid nests of basaloid cells 5/6?,7?, ?-/?? - - - t(6;9)(q22–23;p23–24) carcinoma 34bE12?, 20- HPV-related Similar to adenoid cystic AE1/AE3?? ND ?- ? -ND carcinoma with carcinoma; myoepithelial adenoid cystic- differentiation, squamous like features differentiation in surface epithelia SMARCB1 (INI-1)- Nests of basaloid cells with 5??? Focal?- - SMARCB1 gene deficient sinonasal peripheral palisading and alterations; carcinoma variable amounts of SMARCB1 negative rhabdoid cells by immunohistochemistry CK cytokeratin, Syn synaptophysin, ND not determined a All carcinomas are positive for pan-cytokeratins, only specific classes are reported Sinonasal undifferentiated carcinoma (SNUC) is a rare epithelial membrane antigen (EMA) [7]. Variable reactiv- clinically aggressive neoplasm, which more frequently ity can be seen with neuron specific enolase (NSE), chro- originates from the ethmoid region and invades the mogranin, and synaptophysin. SNUC usually shows only adjacent sinonasal structures, the orbit, the skull base, and limited positivity for p63 and p40 [8–11], and this is a the brain [3]. Histologically, it is composed of sheets, useful feature to separate it from poorly differentiated SCC nests or ribbons of small to medium-sized cells, which and lymphoepithelioma. SNUC is typically negative for according to the original description should lack evidence Epstein–Barr virus (EBV) [5, 6], while association with of squamous or glandular differentiation [4] (Fig. 1), HPV has been reported with variable, generally low, fre- whereas neuroendocrine features have been repeatedly quency [12, 13]. However, a recent study reported a higher reported [5, 6]. frequency of p16 positivity in SNUC (78.6 %) with Immunohistochemically, SNUC is positive for epithelial detection of HPV DNA in 64.3 %, and p16 positive tumors markers, such as simple epithelia cytokeratins (CKs) and had a significantly improved survival [14]. 123 Head and Neck Pathol (2016) 10:75–84 77 specific in the distinction of NMC from other carcinomas [18]. In addition, NMC stains for cytokeratins, p63, CD34 (in approximately half of the cases), while it is negative for S100, HMB45, desmin, myoglobin, smooth muscle actin, muscle actin, chromogranin, synaptophysin, CD45, pla- cental alkaline phosphatase, alphafetoprotein, neuron specific enolase, CD57, and CD99 [16]. HPV and EBV were also negative in all cases tested. Sinonasal neuroendocrine carcinoma is a rare and aggressive tumor type, which is similar to the pulmonary counterpart. It occurs over a wide age range, and it has an aggressive clinical course with frequent local recurrences and metastatic spread to lymph nodes, lung, liver, and to Fig. 1 Sinonasal undifferentiated carcinoma. a The tumor consists of the skeleton. Histologically, it may present with ‘‘small a proliferation of undifferentiated round cells, with a high nuclear/cy- cell’’ or ‘‘large cell’’ morphology (Fig. 2). It is positive for toplasmic ratio. Mitotic figures and apoptotic bodies are present. pan-cytokeratins and neuroendocrine markers, including Tumor cells are positive for cytokeratin 8 (b) CD56, synaptophysin, and chromogranin, although with variable frequency. CD56 or neuron-specific enolase Being mainly a diagnosis of exclusion and due to the (NSE) immunoreactivity alone is not considered sufficient lack of specific criteria for the diagnosis, it is likely that the to demonstrate neuroendocrine differentiation. Cytokeratin diagnosis of SNUC may have been applied to a heteroge- 5/6, p63 and p40 are either negative or focally positive. The neous group of carcinomas, and further refinement in differential diagnosis with atypical carcinoid (i.e., moder- diagnostic criteria and the availability of new molecular ately differentiated neuroendocrine tumor), which is markers may lead in the future to the separation of specific extremely rare in this anatomic site, is mainly based on tumor types from this group of tumors. mitotic count [19]. Positivity for cytokeratins allows the Lymphoepithelial-like carcinoma primarily involving distinction from other undifferentiated tumors, which may the sinonasal tract is extremely rare, while an extension of show neuroendocrine differentiation, including olfactory a nasopharyngeal lesion is more frequent [15]. The dis- neuroblastoma and melanoma. Finally, sinonasal neuroen- tinction from SNUC can usually be done on morphological docrine carcinoma may occur in combination with squa- grounds, because neoplastic cells grow in a syncytial mous cell carcinoma or adenocarcinoma [20, 21]. growth pattern, with indistinct borders, and have markedly A group of poorly differentiated sinonasal carcinomas vesicular nuclei with prominent nucleoli. A prominent may present with a ‘‘basaloid’’ morphology, being formed lymphoplasmacytic cell infiltrate is