Lester D.R. Thompson AAOMP Unknowns P a g e | 1

Case 1 Oral cavity

13 year old boy presented with a left tongue lesion, reported to “pop” after growing rapidly. It was 3.2 cm. Diagnosis: Alveolar Soft Part Sarcoma

Malignant neoplasm showing pseudoalveolar growth of large, eosinophilic cells characterized by a specific fusion gene (ASPSCR1-TFE3)

Clinical Issues A rare malignant soft tissue neoplasm (0.5-0.9%) 5% of ASPS arising in the oral cavity In children: 25% of H&N ASPS involve tongue/oral cavity Age: Wide range: Strong predilection for adolescents Sex: Female > Male (~2:1) Site: Childhood tumors have a predilection for ENT sites Painless mass, occasionally bleeding Local recurrences common (44%), up to 9 yr after presentation Indolent with 80-85% 5-year survival (especially in children)

Microscopic Uninvolved surface with vascular invasion nearly always seen Multinodular growth of organoid, nested, compact cords to solid architecture, separated by variably thick septa of vascularized dense connective tissue Without intercellular cohesion, the neoplastic cells create a pseudo-alveolar pattern—slough into the alveolus Abundant, granular, eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli

Ancillary Tests Positive: MYOD1 (cytoplasmic); NSE, Desmin, TFE3 (nuc) t(X;17)(p11.2;q25): ASPSCR1/TFE3 fusion

Differential Diagnoses Granular cell tumor, rhabdomyoma (adult), rhabdomyosarcoma, oncocytoma, hibernoma, crystal storing histiocytosis References: Pediatr Blood Cancer. 2018 Apr;65(4) (PMID: 29286582); Head Neck Pathol. 2013 Mar;7(1):40-9 (PMID: 22961078)

Lester D.R. Thompson AAOMP Unknowns P a g e | 2

Case 2 Oral Cavity

78 year old female presented with a mass in the palate identified during vocalization efforts. Imaging seems to show extension into the sinus. Diagnosis: Polymorphous adenocarcinoma: Cribriform carcinoma (Cribriform adenocarcinoma of minor salivary glands (CAMSG) or Cribriform adenocarcinoma of tongue (CATS) Minor salivary gland adenocarcinoma showing cribriform

architecture, open nuclear chromatin, and paradoxical propensity for metastatic disease, considered spectrum of polymorphous adenocarcinoma, low grade (PLGA). Clinical Issues Range: 21-85 years (mean: 57 years) Vast majority affect tongue (usually base) 30% have cervical lymph node metastases at time of diagnosis Managed with wide excision, often accompanied by neck lymph node dissection Microscopic Invasive periphery (muscle, bone, vessels, nerves) Solid, cribriform to microcribriform and papillary structures Fibrous septa separate solid mass into irregularly shaped and variably sized nodules Central comedonecrosis Mucinous-spindle cell myofibroblastic stromal septa Nuclei are ovoid to irregular, with pale, optically clear to ground-glass vesicular chromatin Nucleoli are small and often peripherally located Ancillary Tests All neoplastic cells positive: AE1/AE3, CAM5.2, CK7, SOX10, S100 protein. Focal-negative: p40, p63, SMA PRKD fusions or rearrangements Differential Diagnoses Pleomorphic adenoma, polymorphous adenocarcinoma, low grade, metastatic carcinoma, basal cell adenocarcinoma, adenoid cystic carcinoma References: Am J Surg Pathol. 2020 Jan 7 (PMID: 31917707); Mod Pathol. 2020 Jan;33(1):65-73 (PMID: 31492931); Nat Genet. 2014 Nov;46(11):1166-9 (PMID: 25240283); Genes Chromosomes Cancer. 2014 Oct;53(10):845-56 (PMID: 24942367)

Dr. Sook-Bin Woo Case #3 Primordial Odontogenic Tumor This rare odontogenic tumor was first described by Mosqueda-Taylor et al when he and his colleagues presented 6 cases in 2014; to-date, 16 cases have been reported. All 16 cases occurred in patients below age 20 with M:F of 9:7. The majority (88%) occurred in the posterior mandible and present as well-delineated radiolucencies, usually unilocular with most (71%) being larger than 3 cm, and ¾ being associated with the third molar. Grossly, they are multilobulated, glossy, discrete, solid tumors without cystic spaces. It comprises abundant fibromyxoid tissue that is delicately collagenous resembling the dental papillae, surrounded at the periphery by cuboidal-to-columnar cells resembling enamel epithelium, sometimes with stellate reticulum-like areas. The surface of the tumor often has a characteristic undulating character, often with deep invaginations. Sub-epithelial mesenchymal hypercellularity similar to a cambium layer is noted. The epithelium is positive for CD14 and CK19, amelogenin, ameloblastin and dentin sialophosphoprotein precursor, but other markers including vimentin are variably expressed. The subepithelial condensation is usually positive for CD34 and syndecan-1. Proliferative index is < 5%. In rare cases, there is an abundance of epithelium and abortive tooth-like structures as well as deposition of enameloid and even calcifications. The differential diagnoses include ameloblastic fibroma because of the presence of both epithelial and mesenchymal components but the distinctive peripheral layer of epithelium and the hypercellular cambium layer distinguish this tumor. The peripheral layer of epithelium which is not seen in any other odontogenic tumor also distinguishes POT from odontogenic myxoma. This case, unlike previously reported cases, presented with a massive recurrence requiring a mandibulectomy. It is also one of the few cases that contained many abortive tooth-like structures. As such, one may speculate that this epithelium-rich variant of the POT may behave more aggressively than the ones that do not display this feature. References

1. Mosqueda-Taylor A, Pires FR, Aguirre-Urizar JM et al. Primordial odontogenic tumour: clinicopathological analysis of six cases of a previously undescribed entity. Histopathol 2014; 65:606-612

2. Bologna-Molina, Pereira-Prado V, Sanchez-Romero C, Ganzalez-Gonalez R, Mosqueda-Taylor A. Primordial odontogenic tumor: A systemic review. Med Oral Patol orl Cir Bucal 2020. In press.

3. Almazyad A, Li CC, Tapia ROC, Robertson JP, Collette D, Woo SB. Primordial odontogenic tumour: report of two cases. Histopathol 2018; 72:1221-1227

4. Poomsawat S, Ngamsom S, Nonpassopon N. Primordial odontogenic tumor with prominent calcifications: A rare case. J Clin Exp Dent 2019; 11:e952-6

5. Bomfim BB, Prado R, Sampalo RK et. Primordial Odontogenic Tumor: Report of a New Case and Literature. Head Neck Pathol 2019; 13:125-130.

6. Mikami T, Ohashi Y, Bologna-Molina R et al. Primordial odontogenic tumor; A case report with histopathological analyses. Pathol Int 2017:67:638-43.

7. Mikami T, Bologna-Molina R, Mosqueda-Taylor A et al. Pathogenesis of primordial odontogenic tumour based on tumorigenesis and odontogenesis. Oral Dis 2018; 24:1226-34.

Dr. Sook-Bin Woo Case #4: KRAS-positive oral histiocytosis of uncertain etiology and biology, not further classified This unusual condition is not further classifiable. In brief, this otherwise healthy patient in his third decade of life presented with a histiocytic disorder worsening over four years in spite of immunosuppressive therapy, that was positive for KRAS mutation, with complete resolution after local radiation therapy with 10 Gy. The histiocytes in this case were positive for CD163 while the PU.1 study for monocyte-macrophage transcription factor (SPI-1 gene) was diffusely positive within the nuclei. The lack of positivity for S100 protein, langerin, EBER, ALK, CD15, CD30, the usual markers for infectious agents and strong positivity for macrophages and histiocytes ruled our Langerhans cell histiocytosis, EBV-mucocutaneous ulcer and lymphomas. Interestingly, histiocytic disorders often show BRAF mutations and these include Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and some cases of cranial and intracranial xanthogranuloma. One unusual and interesting differential diagnosis is follicular dendritic cell sarcoma (FDCS) which exhibits large cells but with less cytoplasm, and nuclei with irregular outlines and coarse chromatin and that is positive for CD21, CD23 and CD35. Extranodal FDCS in the head neck occurs mostly in the oropharynx and especially in the tonsils, and because they are p16 positive, may be mistaken for p16+ squamous cell carcinoma, if there is no suspicion for FDCS. References

1. Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood 2020; 135:1319-1331. 2. Emile J-F, Abla O, Fraitag S, et al. Histiocyte Society. Revised classification of histiocytoses and

neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127: 2672-2681. 3. Bubolz AM, Weissinger SE, Stenzinger A et al. Potential clinical implications of BRAF mutations in

histiocytic proliferations. Oncotarget 2020; 5: 4061-4070 4. Abla O, Jacobsen E, Picarsic J et al. Consensus recommendations for the diagnosis and clinical

management of Rosai-Dorfman-Destombes disease. Blood. 2018 Jun 28;131:2877-2890 5. Techavichit P, Sosothikul D, Chaichana T et al. BRAF V600E mutation in pediatric intracranial

and cranial juvenile xanthogranuloma. Hum Pathol 2017;69:118-122 6. Hutchinson B, Sadigh S, Ferry JA et al. Tonsillar p16-Positive Follicular Dendritic Cell Sarcoma

Mimicking HPV-Related Oropharyngeal Squamous Cell Carcinoma: A Case Report and Review of Reported Cases. Head Neck Pathol 2020; epub ahead of print.

Dr. Marino Leon CASE #5 DIAGNOSIS: OROPHARYNGEAL MUCOEPIDERMOID CARCINOMA, HIGH-GRADE, CILIATED VARIANT WITH A SPINDLE CELL COMPONENT. Mucoepidermoid carcinoma (MEC) is the most common tumor of minor salivary glands [1, 2]. A large subset of these MECs harbor gene fusions involving MAML2 [3, 4]. Most MECs are easy to identify; uncommon variants may cause some diagnostic difficulty [5, 6]. Mucoepidermoid carcinoma, along with other salivary gland tumors, may involve the oropharynx [7, 2] with mucoepidermoid and adenoid cystic carcinomas being the most common [8, 9, 2, 1]. MEC of the oropharynx affects females more than males [7]; and the age of presentation ranges from 31 to 88 years, with a median of 61 [7]. Most arise in the base of tongue and are associated with a high rate of lymph node metastasis. Histologically, 88% are classified as low to intermediate grade and 12% as high-grade [7]; however, neither grading nor MAML-2 status predicts the risk of metastasis [7]. This case is a ciliated variant of MEC (CV-MEC) with a MAML2 fusion which has recently been described by Bishop et al [5]. CV-MECs show cystic spaces lined by a mixture of intermediate cells, epidermoid cells, mucocytes and ciliated columnar cells [5]. Conventional MEC, when present, represents a minor component [5]. Most cases are positive for the break-apart fluorescence in situ hybridization (FISH) for MAML2 [5]. Interestingly, this tumor also showed a focal spindle cell pattern. A case of MEC with a predominant spindle cell component has been described involving the palatine tonsil [10]. The spindle cell pattern showed bland spindled to fusiform cells arranged in organoid-like nests with scattered goblet cells [10]. FISH revealed the presence of a t(11;19) CRTC1-MAML2 gene fusion [10]. MAML2 rearrangement was identified our case. This finding establishes a clear connection to the MEC group of tumors and is a valuable ancillary test in establishing the diagnosis [5] . The differential diagnosis includes polymorphous adenocarcinoma, epithelial-myoepithelial carcinoma, adenoid cystic carcinoma, secretory carcinoma, salivary duct carcinoma, basaloid squamous cell carcinoma and human papillomavirus (HPV)-related squamous cell carcinoma and HPV-related multiphenotypic carcinoma (HPV-MC). Polymorphous adenocarcinoma (PAC), previously known as polymorphous low-grade adenocarcinoma (PLGA)[11], is rare in the oropharynx [12]. The cells of PAC are monomorphic (ductal cell type) [13], show ovoid, vesicular nuclei with inconspicuous and peripherally located nucleoli, and have scant to moderate, lightly eosinophilic cytoplasm [13]. There is a wide range of morphologic patterns (hence the term polymorphous) including tubular, fascicular, solid, cribriform and papillary [14-16]. PAC cells may be arranged in single files or narrow trabeculae forming concentric whorls (targetoid appearance) around nerves [16]. These tumors may be focally positive for p63 but are negative for p40 [16]; PAC does not show MAML-2 rearrangements. Epithelial-myoepithelial carcinoma (EMC) is a biphasic tumor [17] which contain abluminal clear polygonal myoepithelial cells and luminal ductal cells with scant cytoplasm [18, 13, 17]. EMC may have ancient and Verocay-like changes [17]; sebaceous differentiation may be present [17, 19]. Variants such dedifferentiated, oncocytic, myoepithelial anaplasia and double-clear add to

the histologic diversity [20, 19]. Mucocytes and epidermoid cells are not present in these tumors. p63, along with other standard myoepithelial markers, highlight the myoepithelial cells. Adenoid cystic carcinoma (ACC) of the base of the tongue has been reported in the literature [21, 22]. ACCs show myoepithelial cells with high nuclear to cytoplasmic ratios. These cells have angulated hyperchromatic nuclei and may be associated with variable amounts of basal lamina and stromal material, contributing to the morphologic diversity of these tumors. A glandular component is also present. Altogether, these features yield the tubular, cribriform and solid patterns characteristic of ACC. In challenging cases, testing for fusions of MYB, MYBL1 or NFIB can be helpful [23]. MYB-NFIB fusion positive ACCs are more likely to arise from minor salivary glands [24]. ACCs lack mucocytes and epidermoid cells. Secretory carcinoma (SC), previously known as mammary analogue secretory carcinoma [25] has rarely been reported in the base of the tongue [26]; SCs are circumscribed and divided by thin septa with a lobular-like architecture [25]. SCs may show microcystic, papillary-cystic, “follicular” and solid patterns [27]. A cystic glandular pattern lined by cells with a cuboidal appearance with “bubbly” secretions is common [25]. SCs may have focal areas of mucin-containing cells that may stain with mucicarmine [27]. SCs are positive for mammaglobin and S100 protein and are negative for p63 [27]; SC show rearrangement of the ETV6 gene by fluorescence in situ hybridization [27]. MEC is negative for S100 protein. A carcinoma ex-pleomorphic adenoma with invasive micropapillary SDC and ACC components involving hard and soft palate has been reported [28]. SDCs are histologically similar to high-grade invasive and in-situ ductal carcinoma of breast [29, 30]; SDCs show pleomorphic cuboidal to polygonal cells arranged in clusters, sheets and invasive irregular glandular formations within a desmoplastic stroma [30]. SDCs may show cribriform, solid or micropapillary patterns with comedo necrosis [30]. This morphology is not seen in the current case. SDC lacks mucocytes and p63 positive epidermoid cells. Most HPV-related carcinomas arise in the oropharynx and show a basaloid morphology [31-35]. The epithelium is arranged in sheets and ribbons of basaloid cells with high-nuclear to cytoplasmic rations. In these tumors, focal definitive squamous differentiation is noted; these tumors do not show cystic formations and lack mucocytes and cystic spaces. The cells stain with p63 [36], p40 and cytokeratin 5/6 [37]. They are both positive for p16 [38] and in situ hybridization for high-risk types of HPV, either DNA ISH or RNA ISH [39, 40]. HPV-related multiphenotypic carcinoma (HPV-MC) are described in the nasal cavity; an oropharyngeal primary has not be described in the literature [41]. Histologically, HPV-MC grow in solid nests of basaloid cells and have apparent mitoses and necrosis [41]. HPV-MC cells show histologic and immunohistochemical evidence of myoepithelial differentiation [41]. They may also show squamous and sarcomatoid differentiation [41]. HPV-MC cases are positive for p16 by immunohistochemistry and HPV by DNA or RNA in situ hybridization [41]. HPV-MC are negative for fusions involving MYB, MYBL, and NFIB genes [41]. Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma [42, 34, 43, 44]. HPV-related squamous cell carcinoma is frequently confused with this tumor [43]; however, BSCC is frequently associated with tobacco smoking and alcohol abuse [45, 46]. BSCCs arise frequently in the larynx, hypopharynx and oropharynx [34, 46]. BSCCs also have nests of small crowded cells with scant cytoplasm, basaloid cells, with a “jigsaw” puzzle pattern. The cells also form cords [45] and peripheral palisading may be seen [46]. The tumor stroma shows varying amounts of basal lamina; this feature has been called “stromal pericellular

hyalinization” or “hyalinosis” [46]. Additionally, stromal material is produced in “cystic spaces” producing a cribriform-like pattern that may be confused with ACC [46, 45, 34]. Focal necrosis may be encountered [44, 46]. BSCCs show focal conventional squamous cell carcinoma or dysplasia [45, 44] and lack mucocytes and “true” cystic spaces. Additionally, the differential diagnosis includes cystic lesions with cilia such as ciliated HPV-related carcinomas and ciliated adenoquamous carcinoma [47, 5]. Ciliated HPV-related carcinomas show nonkeratinizing squamous epithelium and cystic/microcystic formations lined by “pseudostratified/multilayered-appearing” ciliated columnar cells [48]; these squamous cells and ciliated cells are positive for high-risk HPV by in situ hybridization [48]. Ciliated HPV-related adenosquamous carcinoma (CHAC) involves the palatine tonsil and the base of tongue [47]. CHACs show microcystic formations or nonkeratinizing squamous nests with glandular elements, including cuboidal to columnar cells and mucous cells that resemble MEC [47] with ciliated cells being present in all cases [47]. CHACs may present as cystic lymph node metastasis similar to ciliated MEC [5]. Focal keratinization and atypia are usually seen [47]. These tumors are positive for p16 and are also positive for HPV in situ hybridization [47]. MAML2 rearrangements are not present [47]. MEC may be p16 positive, potentially creating confusion [5]; therefore, testing should include MAML2 and HPV testing [5]. Additionally, mucoepidermoid carcinoma “arising in a possible bronchogenic cyst” in the thymic region has been described [49]. The presence of ciliated cells in a lateral neck mass may therefore be interpreted as a benign lesion such as a branchial cleft cyst [5]. The treatment of MEC is individualized with surgery alone, radiation alone or a combination of surgery and radiation therapy [8, 9, 50, 1]; High-grade MECs may be treated with adjuvant radiation [1]. However, in a study of radiation therapy of minor salivary gland malignancies, sinonasal and oropharyngeal primaries seem to be associated with poorer local control [51] The 5-year and 10-year predicted overall survival for tumors of minor salivary glands is 86% and 69%, respectively [1]. In the oropharynx, minor salivary gland carcinomas show 5-year and 10-year rates of disease-specific survival of 75.1% and 61.6%, respectively [2]. In this group, independent prognostic factors include tumor grade, T stage, N stage, and age of more than 70 years. Regarding survival, as the number of reported MEC variants is low, additional studies may be performed to further clarify this issue. References 1. Hay AJ, Migliacci J, Karassawa Zanoni D, McGill M, Patel S, Ganly I. Minor salivary gland tumors of the head and neck-Memorial Sloan Kettering experience: Incidence and outcomes by site and histological type. Cancer. 2019;125(19):3354-66. doi:10.1002/cncr.32208. 2. Goel AN, Badran KW, Braun APG, Garrett AM, Long JL. Minor Salivary Gland Carcinoma of the Oropharynx: A Population-Based Analysis of 1426 Patients. Otolaryngol Head Neck Surg. 2018;158(2):287-94. doi:10.1177/0194599817735309. 3. Seethala RR, Dacic S, Cieply K, Kelly LM, Nikiforova MN. A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am J Surg Pathol. 2010;34(8):1106-21. doi:10.1097/PAS.0b013e3181de3021.

4. Behboudi A, Enlund F, Winnes M, Andren Y, Nordkvist A, Leivo I et al. Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer. 2006;45(5):470-81. doi:10.1002/gcc.20306. 5. Bishop JA, Cowan ML, Shum CH, Westra WH. MAML2 Rearrangements in Variant Forms of Mucoepidermoid Carcinoma: Ancillary Diagnostic Testing for the Ciliated and Warthin-like Variants. Am J Surg Pathol. 2018;42(1):130-6. doi:10.1097/PAS.0000000000000932. 6. Goepfert H, Giraldo AA, Byers RM, Luna MA. Salivary gland tumors of the base of the tongue. Arch Otolaryngol. 1976;102(7):391-5. doi:10.1001/archotol.1976.00780120039002. 7. Navale P, Rooper LM, Bishop JA, Westra WH. Mucoepidermoid carcinoma of the oropharynx: a tumor type with a propensity for regional metastasis unrelated to histologic grade. Hum Pathol. 2019;93:1-5. doi:10.1016/j.humpath.2019.08.014. 8. de Vries EJ, Johnson JT, Myers EN, Barnes EL, Jr., Mandell-Brown M. Base of tongue salivary gland tumors. Head Neck Surg. 1987;9(6):329-31. doi:10.1002/hed.2890090604. 9. Ellis ER, Million RR, Mendenhall WM, Parsons JT, Cassisi NJ. The use of radiation therapy in the management of minor salivary gland tumors. Int J Radiat Oncol Biol Phys. 1988;15(3):613-7. doi:10.1016/0360-3016(88)90302-1. 10. Goh GH, Lim CM, Vanacek T, Michal M, Petersson F. Spindle Cell Mucoepidermoid Carcinoma of the Palatine Tonsil With CRTC1-MAML2 Fusion Transcript: Report of a Rare Case in a 17-Year-Old Boy and a Review of the Literature. Int J Surg Pathol. 2017;25(8):705-10. doi:10.1177/1066896917714890. 11. Evans HL, Batsakis JG. Polymorphous low-grade adenocarcinoma of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Cancer. 1984;53(4):935-42. doi:10.1002/1097-0142(19840215)53:4<935::aid-cncr2820530420>3.0.co;2-v. 12. Pittman CB, Zitsch RP, 3rd. Polymorphous low-grade adenocarcinoma of the tonsil: report of a case and review of the literature. Am J Otolaryngol. 2002;23(5):297-9. doi:10.1053/ajot.2002.124194. 13. Simpson RH, Clarke TJ, Sarsfield PT, Gluckman PG. Epithelial-myoepithelial carcinoma of salivary glands. J Clin Pathol. 1991;44(5):419-23. doi:10.1136/jcp.44.5.419. 14. Perez-Ordonez B, Linkov I, Huvos AG. Polymorphous low-grade adenocarcinoma of minor salivary glands: a study of 17 cases with emphasis on cell differentiation. Histopathology. 1998;32(6):521-9. doi:10.1046/j.1365-2559.1998.t01-2-00410.x. 15. Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999;86(2):207-19. 16. Xu B, Aneja A, Ghossein R, Katabi N. Predictors of Outcome in the Phenotypic Spectrum of Polymorphous Low-grade Adenocarcinoma (PLGA) and Cribriform Adenocarcinoma of Salivary Gland (CASG): A Retrospective Study of 69 Patients. Am J Surg Pathol. 2016;40(11):1526-37. doi:10.1097/PAS.0000000000000705. 17. Seethala RR, Barnes EL, Hunt JL. Epithelial-myoepithelial carcinoma: a review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract. Am J Surg Pathol. 2007;31(1):44-57. doi:10.1097/01.pas.0000213314.74423.d8. 18. Luna MA, Ordonez NG, Mackay B, Batsakis JG, Guillamondegui O. Salivary epithelial-myoepithelial carcinomas of intercalated ducts: a clinical, electron microscopic, and immunocytochemical study. Oral Surg Oral Med Oral Pathol. 1985;59(5):482-90. doi:10.1016/0030-4220(85)90089-1. 19. Shinozaki A, Nagao T, Endo H, Kato N, Hirokawa M, Mizobuchi K et al. Sebaceous epithelial-myoepithelial carcinoma of the salivary gland: clinicopathologic and immunohistochemical analysis of 6 cases of a new histologic variant. Am J Surg Pathol. 2008;32(6):913-23. doi:10.1097/PAS.0b013e318160852a. 20. Seethala RR, Richmond JA, Hoschar AP, Barnes EL. New variants of epithelial-myoepithelial carcinoma: oncocytic-sebaceous and apocrine. Arch Pathol Lab Med. 2009;133(6):950-9. doi:10.1043/1543-2165-133.6.950.

21. Namazie A, Alavi S, Abemayor E, Calcaterra TC, Blackwell KE. Adenoid cystic carcinoma of the base of the tongue. Ann Otol Rhinol Laryngol. 2001;110(3):248-53. doi:10.1177/000348940111000308. 22. Kirke DN, Chitguppi C, Rubin SJ, Truong MT, Jalisi S. Adenoid cystic carcinoma of the base of tongue: A population-based study. Am J Otolaryngol. 2017;38(3):279-84. doi:10.1016/j.amjoto.2017.01.010. 23. Fujii K, Murase T, Beppu S, Saida K, Takino H, Masaki A et al. MYB, MYBL1, MYBL2 and NFIB gene alterations and MYC overexpression in salivary gland adenoid cystic carcinoma. Histopathology. 2017;71(5):823-34. doi:10.1111/his.13281. 24. Rettig EM, Tan M, Ling S, Yonescu R, Bishop JA, Fakhry C et al. MYB rearrangement and clinicopathologic characteristics in head and neck adenoid cystic carcinoma. Laryngoscope. 2015;125(9):E292-9. doi:10.1002/lary.25356. 25. Skalova A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol. 2010;34(5):599-608. doi:10.1097/PAS.0b013e3181d9efcc. 26. Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands. Histopathology. 2012;61(3):387-94. doi:10.1111/j.1365-2559.2012.04232.x. 27. Connor A, Perez-Ordonez B, Shago M, Skalova A, Weinreb I. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol. 2012;36(1):27-34. doi:10.1097/PAS.0b013e318231542a. 28. Sedassari BT, da Silva Lascane NA, Tobouti PL, Pigatti FM, Franco MI, de Sousa SC. Carcinoma ex pleomorphic adenoma of the palate composed of invasive micropapillary salivary duct carcinoma and adenoid cystic carcinoma components: an unusual case with immunohistochemical approach. Medicine (Baltimore). 2014;93(27):e146. doi:10.1097/MD.0000000000000146. 29. Luk PP, Weston JD, Yu B, Selinger CI, Ekmejian R, Eviston TJ et al. Salivary duct carcinoma: Clinicopathologic features, morphologic spectrum, and somatic mutations. Head Neck. 2016;38 Suppl 1:E1838-47. doi:10.1002/hed.24332. 30. Delgado R, Vuitch F, Albores-Saavedra J. Salivary duct carcinoma. Cancer. 1993;72(5):1503-12. doi:10.1002/1097-0142(19930901)72:5<1503::aid-cncr2820720503>3.0.co;2-k. 31. El-Mofty SK, Patil S. Human papillomavirus (HPV)-related oropharyngeal nonkeratinizing squamous cell carcinoma: characterization of a distinct phenotype. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(3):339-45. doi:10.1016/j.tripleo.2005.08.001. 32. El-Mofty SK. Human papillomavirus (HPV) related carcinomas of the upper aerodigestive tract. Head Neck Pathol. 2007;1(2):181-5. doi:10.1007/s12105-007-0021-6. 33. El-Mofty SK, Zhang MQ, Davila RM. Histologic identification of human papillomavirus (HPV)-related squamous cell carcinoma in cervical lymph nodes: a reliable predictor of the site of an occult head and neck primary carcinoma. Head Neck Pathol. 2008;2(3):163-8. doi:10.1007/s12105-008-0066-1. 34. Chernock RD, Lewis JS, Jr., Zhang Q, El-Mofty SK. Human papillomavirus-positive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Hum Pathol. 2010;41(7):1016-23. doi:10.1016/j.humpath.2009.11.015. 35. El-Mofty SK. HPV-related squamous cell carcinoma variants in the head and neck. Head Neck Pathol. 2012;6 Suppl 1:S55-62. doi:10.1007/s12105-012-0363-6. 36. Bishop JA, Montgomery EA, Westra WH. Use of p40 and p63 immunohistochemistry and human papillomavirus testing as ancillary tools for the recognition of head and neck sarcomatoid carcinoma and its distinction from benign and malignant mesenchymal processes. Am J Surg Pathol. 2014;38(2):257-64. doi:10.1097/PAS.0000000000000119.

37. Lewis JS, Jr., Chernock RD, Bishop JA. Squamous and Neuroendocrine Specific Immunohistochemical Markers in Head and Neck Squamous Cell Carcinoma: A Tissue Microarray Study. Head Neck Pathol. 2018;12(1):62-70. doi:10.1007/s12105-017-0825-y. 38. Begum S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am J Surg Pathol. 2008;32(7):1044-50. doi:10.1097/PAS.0b013e31816380ec. 39. Bishop JA, Ma XJ, Wang H, Luo Y, Illei PB, Begum S et al. Detection of transcriptionally active high-risk HPV in patients with head and neck squamous cell carcinoma as visualized by a novel E6/E7 mRNA in situ hybridization method. Am J Surg Pathol. 2012;36(12):1874-82. doi:10.1097/PAS.0b013e318265fb2b. 40. Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer. 2010;116(9):2166-73. doi:10.1002/cncr.25033. 41. Bishop JA, Andreasen S, Hang JF, Bullock MJ, Chen TY, Franchi A et al. HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features. Am J Surg Pathol. 2017;41(12):1690-701. doi:10.1097/PAS.0000000000000944. 42. Altavilla G, Mannara GM, Rinaldo A, Ferlito A. Basaloid squamous cell carcinoma of oral cavity and oropharynx. ORL J Otorhinolaryngol Relat Spec. 1999;61(3):169-73. doi:10.1159/000027665. 43. Lewis JS, Jr., Chernock RD. Human papillomavirus and Epstein Barr virus in head and neck carcinomas: suggestions for the new WHO classification. Head Neck Pathol. 2014;8(1):50-8. doi:10.1007/s12105-014-0528-6. 44. Wain SL, Kier R, Vollmer RT, Bossen EH. Basaloid-squamous carcinoma of the tongue, hypopharynx, and larynx: report of 10 cases. Hum Pathol. 1986;17(11):1158-66. doi:10.1016/s0046-8177(86)80422-1. 45. Banks ER, Frierson HF, Jr., Mills SE, George E, Zarbo RJ, Swanson PE. Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol. 1992;16(10):939-46. doi:10.1097/00000478-199210000-00003. 46. Ereno C, Gaafar A, Garmendia M, Etxezarraga C, Bilbao FJ, Lopez JI. Basaloid squamous cell carcinoma of the head and neck: a clinicopathological and follow-up study of 40 cases and review of the literature. Head Neck Pathol. 2008;2(2):83-91. doi:10.1007/s12105-008-0045-6. 47. Radkay-Gonzalez L, Faquin W, McHugh JB, Lewis JS, Jr., Tuluc M, Seethala RR. Ciliated Adenosquamous Carcinoma: Expanding the Phenotypic Diversity of Human Papillomavirus-Associated Tumors. Head Neck Pathol. 2016;10(2):167-75. doi:10.1007/s12105-015-0653-x. 48. Bishop JA, Westra WH. Ciliated HPV-related Carcinoma: A Well-differentiated Form of Head and Neck Carcinoma That Can Be Mistaken for a Benign Cyst. Am J Surg Pathol. 2015;39(11):1591-5. doi:10.1097/PAS.0000000000000521. 49. Tanaka M, Shimokawa R, Matsubara O, Aoki N, Kamiyama R, Kasuga T et al. Mucoepidermoid carcinoma of the thymic region. Acta Pathol Jpn. 1982;32(4):703-12. doi:10.1111/j.1440-1827.1982.tb02072.x. 50. Kokemueller H, Brueggemann N, Swennen G, Eckardt A. Mucoepidermoid carcinoma of the salivary glands--clinical review of 42 cases. Oral Oncol. 2005;41(1):3-10. doi:10.1016/j.oraloncology.2004.01.017. 51. Le QT, Birdwell S, Terris DJ, Gabalski EC, Varghese A, Fee W, Jr. et al. Postoperative irradiation of minor salivary gland malignancies of the head and neck. Radiother Oncol. 1999;52(2):165-71. doi:10.1016/s0167-8140(99)00084-5.

Dr. James Lewis, Case # 6: Adenosquamous Carcinoma

Adenosquamous carcinoma (AdSCC) is one of the more confusing of the variants of squamous cell carcinoma (SCC) when arising in the head and neck. In its most basic definition, it consists of a biphasic tumor composed of SCC with a component of gland forming tumor with “punched out” luminal spaces. In the head and neck, three peculiar characteristics should be noted. The WHO does not require the presence of mucin but, in this author’s experience, it is virtually always present. In addition, unlike some other organ systems such as the lung, there is no % cutoff for the amount of gland formation/adenocarcinoma so it can range from very focal to extensive. The third, and most interesting and controversial characteristic, is that the gland component may contain tumor cells with cilia.

Based on the largest descriptive studies, it constitutes ~1-2% of all head and neck SCC. It most commonly arises in the larynx and oral cavity, then is evenly distributed amongst all other mucosal sites. Patients have similar demographics to conventional SCC, with no obvious differences in the largest studies in the literature. Nodal metastases are similar in frequency to conventional CC as well. There is no grading system so a differentiation status should not be reported. As AdSCC is rare, no specific treatments have been defined and so it is managed largely in the same manner as conventional SCC. Prognosis is the most controversial feature and has been addressed by a few case matching studies in the literature. Although numbers are small, in a study controlling for HPV status for oropharyngeal cases, AdSCC had worse prognosis than conventional SCC1,2 with hazard ratios for disease free and disease specific survival of 2.21 and 1.493. It is generally considered, across oncologic practice, as a “high risk” form of SCC. Where clinical treatment is unclear, should be managed more aggressively, akin to other “high risk” forms of head and neck SCC.

AdSCC morphologically consists of overt SCC with associated gland formation. The latter is usually in the deeper aspects of the tumors and typically is associated with cells with higher nuclear to cytoplasmic ratios and more rounded nuclei. The glands have smooth contours, rounded profiles and are distinct. Their lumina contain lightly basophilic mucin with eosinophilic globules in it and intracytoplasmic mucin globules are sometimes seen. The gland spaces characteristically have degenerating neutrophils and nuclear debris within them. True cilia, when present, are usually focal and must have clear, crisp morphology with terminal bars, rather than the “fuzzy” borders that mimic cilia.

The most important aspects for AdSCC involve the pathologic diagnosis and not misdiagnosing it as something else. One must consider conventional SCC invading in and around non-neoplastic salivary gland tissue, conventional SCC with “gland like” and adenoid nests or artifactual basophilic mimicking mucin, and finally mucoepidermoid carcinoma. Conventional SCC, particularly of the supraglottic larynx, but at an anatomic subsite, invades into the normal salivary gland tissue. When it degenerates, one tends to get ductal differentiation so that these are intimately admixed with the SCC. The key is noting the cytology around the glands/ducts as it is reactive, not neoplastic. Typically it lacks the same degree of atypia as the carcinoma. The nests of conventional SCC often degenerated where squamous cells fall apart from each other (acantholysis) so that irregular spaces form centrally. The key is that these spaces are highly variable and irregular in shape, not punched out with rounded shapes and very smooth borders of the cells with the lumen, as is seen with true gland formation. Mucin production in AdSCC is usually obvious. The key is basophilic material with intraluminal eosinophilic globules. Mucicarmine special staining can be very helpful but it not required for diagnosis. Mucin like degenerative material in acantholytic squamous nests lacks the globules and is much more irregular and inconsistent. AdSCC is most often confused with mucoepidermoid carcinoma. That latter, almost by definition, should not have bonafide squamous differentiation, nor should it have surface involvement. There is usually cystic change that is absent in AdSCC as well. Nuclei in the solid, squamoid/epidermoid nests of MEC are typically round, and there is less pleomorphism than in AdSCC.

Key References:

1. Kass JI, Lee SC, Abberbock S, Seethala RR, Duvvuri U. Adenosquamous carcinoma of the head and neck: Molecular analysis using CRTC-MAML FISH and survival comparison with paired conventional squamous cell carcinoma. The Laryngoscope. 2015;125(11):E371-376.

2. Keelawat S, Liu CZ, Roehm PC, Barnes L. Adenosquamous carcinoma of the upper aerodigestive tract: a clinicopathologic study of 12 cases and review of the literature. American journal of otolaryngology. 2002;23(3):160-168.

3. Mehrad M, Trinkaus K, Lewis JS, Jr. Adenosquamous Carcinoma of the Head and Neck: A Case-Control Study with Conventional Squamous Cell Carcinoma. Head and neck pathology. 2016;10(4):486-493.

Dr. James Lewis, Case 7: Basaloid Squamous Cell Carcinoma

Basaloid squamous cell carcinoma (BSCC) is perhaps the most confusing of all of the variants of SCC when arising in the head and neck, with what may be construed as a “Dr. Jekyll and Mr. Hyde” phenotype 1. First described by Wain et al. in 1986, it occurs across all head and neck mucosal anatomic subsites and has widely varied prognosis depending on HPV and/or EBV status in oropharyngeal and nasopharyngeal tumors.

BSCC has a predilection for the supraglottic larynx, oropharynx, and hypopharynx, but also occurs with regularity in the sinonasal tract and nasophopharynx, and occasionally in the oral cavity. It has not been convincingly described in the major salivary glands. In its most basic definition, it is a basaloid carcinoma with squamous differentiation usually on H&E examination, but by immunohistochemistry alone if necessary. The basaloid component consists of tightly circumscribed nests of cells in lobules with prominent peripheral palisading and comedonecrosis. Small pseudocystic/pseudoglandular spaces containing basophilic material that mimics true mucin are common as is stromal hyalinization, either as small nodules in the nests or as thin lines of stroma around and between the nests. Architecturally, a jigsaw puzzle pattern where the nests mold to one another is characteristic. The tumor cells are round with variably prominent nucleoli with brisk mitotic activity and apoptosis. The tumors can be overtly biphasic with a clear squamous component mixed with them, either keratinizing or nonkeratinizing, depending on the location. Sometimes, there is only SCC or surface squamous dysplasia. Metastases can hold either component.

The differential diagnosis is extensive and one of the reasons BSCC is so difficult for pathologists. It includes solid adenoid cystic carcinoma, neuroendocrine carcinoma, and adenosquamous carcinoma. When arising in the oral cavity, BSCC can be difficult to distinguish from the rare (but well described) oral basal cell carcinoma. BSCC is immunophenotypically squamous, with expression of high molecular weight cytokeratins (34betaE12 and 5/6) and diffuse positive expression of p63 and p40, although occasional tumors are focally positive only (or completely lacking) for the latter two markers. The tumor cells never express neuroendocrine or myoepithelial markers. Solid adenoid cystic carcinoma either completely lacks p63/p40 or, if retained in the solid nests, stains only at the periphery in a patchy, linear distribution. Basal cell carcinoma is EMA negative and is positive for BerEP4. It also lacks the stromal hyalinization, high mitotic activity, and necrosis so frequent in true BSCC.

What is the clinical significance of BSCC? When first described, it was considered a very high risk type of SCC, occurring mostly in older male smokers. Over time, however, as HPV (and EBV) related head and neck carcinomas have become more frequent (and more frequently detected), it has become apparent that BSCC is a mixed variant that probably can (and should be) divided into those that are viral-associated versus those that are not. Outcome studies, even those where BSCC patients are matched case for case with conventional SCC patients, have shown mixed results with some showing worse prognosis for BSCC, some no difference, and even some where BSCC is prognostically favorable. HPV likely explains these confusing findings. Begum and Westra and Chernock et al. found that the majority of oropharyngeal BSCC are related to transcriptionally-active high risk HPV while virtually all non-oropharyngeal cases are not2,3. These series had few or no nasopharyngeal or sinonasal cases. They suggest that the HPV-negative oropharyngeal BSCC and non-oropharyngeal BSCC are best considered as a group with very aggressive clinical behavior, worse than conventional SCC. Nasopharyngeal BSCC is rare. In the older versions of the WHO classification, it was not even listed as a numerical type, but in the 2017 blue book, it became a third type of nasopharyngeal carcinoma after keratinizing and nonkeratinizing (differentiated and undifferentiated). Constituting far less than 1% of all NPC, it has been shown that most nasopharyngeal BSCC are related to EBV, presumably with a prognosis similar to other EBV-positive nasopharyngeal carcinomas.

Key References:

1. Woolgar JA, Lewis JS, Jr., Devaney KO, et al. Basaloid squamous cell carcinoma of the upper aerodigestive tract: a single squamous cell carcinoma subtype or two distinct entities hiding under one histologic pattern? Eur Arch Otorhinolaryngol. 2011;268(2):161-164.

2. Begum S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am J Surg Pathol. 2008;32(7):1044-1050.

3. Chernock RD, Lewis JS, Jr., Zhang Q, El-Mofty SK. Human papillomavirus-positive basaloid squamous cell carcinomas of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma. Human pathology. 2010;41(7):1016-1023.