New/Emerging Entities in Salivary Gland Pathology

Transcription

1 New/Emerging Entities in Salivary Gland Pathology Alena Skalova, MD, PhD Professor of Pathology Charles University, Faculty of Medicine in Plzen, Czech Republic 2018 IAP Congress; Jordan, October 2018.

2 Outlines of the talk Diagnostically relevant molecular aberrations in salivary gland tumors Newly described salivary gland tumors New variants, reclassified old salivary entities Challenging and emerging salivary entities

3 Role of molecular testing Salivary gland neoplasms are a morphologically heterogeneous group diagnostically challenging discovery of tumor type-specific fusion oncogenes serve as diagnostic tools and in salivary cancer classification show promise as prognostic markers and targets of therapy

4 Key molecular alterations in salivary gland carcinomas Tumor type (Mammary analogue) Secretory carcinoma Mucoepidermoid carcinoma (Hyalinizing) Clear cell carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Cribriform adenocarcinoma of minor salivary glands (CASG) Salivary duct carcinoma/ IC Chromosomal alteration t(12;15)(p13;q25) t(12;x) t(11;19)(q21;p13) t(11;15)(q21;q26) Gene fusion/ rearrangement ETV6-NTRK3 ETV6-RET CRTC1-MAML2 CRTC3-MAML2 Prevalence (%) t(12;22)(q21;q12) EWSR1-ATF t(6;9)(q22-23;p23-24) t(8;9) 14q12 t(1;14)(p36.11;q12) t(x;14)(p11.4;q12) 17q21.1 3q26.32 inv(10)(q11.21q11.22) MYB-NFIB MYBL1-NFIB Hotspot activating PRKD1 somatic point mutation (E710D) ARID1A-PRKD1 DDX3X-PRKD1 PRKD2 and PRKD3 rearrangements HER2 amplification PIK3CA mutation NCOA4-RET, TRIM27-RET <5

5 Mucoepidermoid carcinoma

6 Adenoid cystic carcinoma MYB

7 Secretory carcinoma (MASC)

8 (Hyalinizing) Clear cell carcinoma

9 Polymorphous adenocarcinoma (PAC) WHO 2017 terminology, previously PLGA PAC classic variant (PLGA) hot spot point E710D mutations in PRKD1 gene PAC cribriform variant (CATS) translocations involving the PRKD1 3 genes

10 Salivary duct carcinoma HER2/neu HER2 gene amplification, mutations of TP53, PIK3CA, PTEN and HRAS NCOA4 RET fusion

11 Intercalated duct variant of IC with NCOA4 RET fusion S100 protein

12 Apocrine variant of IC with TRIM27 RET fusion Androgen receptor

13 Newly described salivary gland tumors

14 WHO classification 2017

15 Mammary Analogue Secretory Carcinoma (MASC)

16 Secretory carcinoma (mammary analogue, MASC) ETV6-NTRK3; ETV6-RET fusions Skalova et al. Am J Surg Pathol 2010; 34:

17 (Mammary analogue) Secretory carcinoma (MASC) akin to secretory carcinoma of the breast, MASC expresses CK7/S-100 protein, and mammaglobin harbours t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 fusion presence of t(12;15) was not demonstrated in any other salivary gland tumor o however, many fusion partners of ETV6 have been reported in a variety of epithelial and hematological malignancies other than salivary

18 Translocation t(12;15) (p13;q25) ETV6 NTRK3 fusion gene between the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15 o secretory breast carcinoma o Tognon et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human breast secretory carcinoma. Cancer Cell 2002:2: o congenital fibrosarcoma, variant of AML, chronic eosinophilic leukemia, congenital mesoblastic nephroma o ALK-negative inflammatory myofibroblastic tumor o Alassiri, et al. Am J Surg Pathol 2016;40: o Subset of radiation-associated thyroid cancer (Chernobyl) o Leeman-Neil, et al. Cancer 2014;120:

19 FISH for ETV6 gene break is positive FISH analysis of ETV6 gene (12p13) using break apart rearrangement probe Vysis ETV6 Break Apart FISH Probe Kit (Abbott Molecular) in FFPE tissue. Nuclei with one fusion (yellow), one orange, and one green (split) signal pattern indicative of a rearrangement of one copy of the ETV6 gene region.

20 Secretory carcinoma with ETV6 X translocation

21 Sequence analysis of ETV6 NTRK3 fusion transcripts in MASC

22 Secretory carcinoma with ETV6 RET translocation

23 Secretory carcinoma with HG transformation

24 Secretory carcinoma molecular testing SC has distinctive morphology and immunoprofile in most cases Diagnosis of classical SC features could be performed without molecular testing However, in cases that depart from the typical features of SC in some way Molecular testing in SC is of potential value in treatment of patients

25 Treatment of SC treatment of SC has varied, ranging from simple excision to radical resection, neck dissection, adjuvant radiotherapy, and/or adjuvant systemic chemotherapy For patients presenting with a locally advanced, recurrent or metastatic disease the treatment options are currently limited and mainly palliative Testing for ETV6-NTRK3 translocation-pan TrK inhibitor Entrectinib (Ignyta) targets NTRK, ROS1, and ALK fusions ETV6-RET testing Drilon et al. What hides behind MASC: Ann Oncol 2016;27:920 6

26 Conclusions; SC SC has distinctive morphology and IHC in most cases Diagnosis of classical SC features could be performed without molecular testing However, in cases that depart from the typical features of SC in some way (higher-grade features or unusual immunostaining pattern) and in consultation cases perform ETV6 rearrangement studies by FISH to confirm the diagnosis

27 New variants

28 (Hyalinizing) clear cell carcinoma of minor salivary glands EWSR1-ATF1 fusion

29 (Hyalinizing) clear cell carcinoma of minor salivary glands HCCC is a rare salivary gland malignancy with squamous differentiation and prominent clear cell morphology WHO clear cell carcinoma recurrent t(12;22)(q13;q12) chromosomal translocation, leading to fusion of the EWSR1 and ATF1 genes o EWSR1 gene intact in myoepithelioma, PLGA, MEC, or epithelial-myoepithelial carcinoma o EWSR1 gene rearrangement detected in clear cell odontogenic ca and subset of myoepithelial ca with clear cell morphology Simpson et al: Histopathology 1990: 17: Milchgrub et al. Am J Surg Pathol 1994:18:74-92

30 (Hyalinizing) Clear Cell Carcinoma neoplastic nests and lobules are surrounded by, or admixed with a hyalinized basement membrane-like material

31 Significance of testing of EWSR1 ATF1 HCCC does not always show hyalinization or prominent clear cell differentiation Mucinous differentiation is not an exclusion criterion for HCCC HCCC has squamous differentiation and can mimic SCC It is distinct from EMCa, MEC, SMET and other clear cell and low-grade tumors of the head and neck (salivary, mucosal and skin) except CCOC.

32 Hyalinizing clear cell carcinoma with EWSR1 CREM fusion

33 New variants, reclassified old salivary entities, and/or re named tumors

34 Conceptual Changes and Controversies PLGA versus CASG

35 Polymorphous adenocarcinoma (PAC) Syn. Low-grade polymorphous adenocarcinoma (PLGA); terminal duct carcinoma; lobular carcinoma CATS/CAMSG considered as cribriform variant of PAC Fonseca I; Assaad A; Katabi N; Seethala R; Simpson RHW; Skálová A; Weinreb I; Wenig B

36 Cribriform Adenocarcinoma of Tongue and (other) Salivary Glands (CASG) Michal et al. Cribriform adenocarcinoma of the tongue. Histopathology 1999;35:

37 CASG intact squamous epithelium devoid of ulceration or dysplasia, solid and cribriform patterns with glomeruloid appearances

38 CASG cribriform and microcribriform pattern with variable amount of fibrous stroma

39 CASG; glomeruloid structures

40 CASG; solid and cribriform structures

41 CASG; overlapping clear, grooved nuclei

42 TTF1, Thyreoglobulin neg Papillary growth pattern, ground-glass nuclei CK7, S-100, actin+

43 Lymphovascular invasion D2 40

44 CASG versus PLGA/PAC PAC wide range of architectural appearances such as streaming columns of single file or narrow trabeculae of cells forming concentric whorls extensive nuclear ground-glass change in CASG with overlapping clear Orphan Annie eye like nuclei

45 Polymorphous adenocarcinoma (PAC) classic variant hot spot point E710D mutations in PRKD1 gene, no alterations seen in PRKD2-3 genes

46 Polymorphous adenocarcinoma (PAC) cribriform variant (CASG) translocations involving the PRKD1-3 genes (fusion genes included ARID1A and DDX3X)

47 Polymorphous adenocarcinoma (PAC) (WHO 2017 terminology, previously PLGA) Hotspot activating E710D point mutations in PRKD1 were reported in nearly three-quarters of PACclassic variant (PLGA) cases Mutations in PRKD2 and PRKD3 were not found in PAC-classic variant (PLGA) translocations involving the PRKD1-3 genes PACcribriform variant (CASG) Although CASG and PLGA have molecular alterations of the PRKD gene family, there are notable differences

48 Key features distinguishing PAC versus CASG PAC is a low-grade infiltrative malignancy with a mixture of tubular, cribriform, papillary, and solid growth, arranged in fascicles with targetoid neurotropism CASG is a tumor with distinctive cribriform/papillary glomeruloid patterns and highly vesicular papillary thyroid carcinoma like nuclei predominating in base of tongue PACs are characterized by PRKD1 E710D mutations, whereas CASGs are characterized by PRKD1-3 translocations CASGs have a high capacity for nodal spread

49 Conclusions; CASG Histologic and molecular overlap between CASG and PAC CASG is a distinct tumor entity, differs from PAC by location, cytology, histological architecture, and behavior frequent lymph node metastasis at the time of presentation Paradoxically, early metastatic disease is associated with an indolent behavior It makes CASG a unique neoplasm among all lowgrade salivary gland tumors

50 Intraductal carcinoma (IC) versus SDC

51 Intraductal carcinoma of salivary glands (IC) new WHO 2017designation for tumors previously called low grade cribriform cystadenocarcinoma relationship of IC to salivary duct carcinoma (SDC) has been controversial, but they now are considered to be distinct entities IC is rare low grade malignant salivary gland neoplasm with features similar to mammary atypical ductal hyperplasia or ductal carcinoma in-situ diffuse S100 protein and mammaglobin positivity intact myoepithelial cell layer decorated by p63 protein/calponin and cytokeratin 14

52 Intraductal carcinoma Bland morphology

53 Intraductal carcinoma P63 decorates intact myoepithelial cell layer

54 Intraductal carcinoma Diffuse staining for S100 protein

55 Molecular profiling of IC Weinreb et al: NCOA4-RET fusion in index case of IC by NGS, FISH RET break-apart was negative 6 additional cases of pure IC showed RET rearrangement by FISH (6/15 =47%), but no NGS Skálová et al: NGS analysis detected a NCOA4-RET fusion transcript joining exon 7 and 8 of NCOA4 gene and exon 12 of RET gene in 6 cases (6/17; 38%) novel TRIM27-RET fusion transcript between exons 3 and 12 in two cases of salivary gland tumors displaying histological and IHC features typical of apocrine IC

56 NCOA4 RET fusion transcript (exons 8 12 joining) by NGS

57 TRIM27 RET fusion transcript (exons 3 12 joining) by NGS

58 Apocrine variant of IC with TRIM27 RET fusion Androgen receptor

59 Challenging and/or emerging entities

60 Sclerosing Polycystic Adenosis/ Adenoma (SPA) Smith BC, Ellis GL, Slater LJ, Foss RD, Sclerosing polycystic adenosis of major salivary glands. A clinicopathologic analysis of nine cases. Am J Surg Pathol 1996:20:

61 Sclerosing polycystic adenosis (SPA) Synonymum: sclerosing polycystic adenoma o Benign neoplasm o Recurrences common o Clonal by HUMARA o Dysplasia, DCIS, carcinoma arising in

62 Sclerosing polycystic adenoma Circumscribed lesion, embedded in parotid gland

63 Sclerosing polycystic adenoma Well circumscribed, with multiple variably sized cystic ducts

64 Ducts lined by flattened to cuboidal epithelium with apocrine and foamy change

65

66 Dysplastic epithelium/ DCIS like

67 Sclerosing polycystic adenoma CK14

68 Biological nature and behavior of SPA All but one reported cases of SPA are benign recurrence occurs in about one-third of cases lesion may be multifocal, difficult treatment focal atypical hyperplasia and DCIS in most cases infiltrative foci mimicking intra-lesional invasive adenocarcinoma invasive carcinoma arising in SPA Manajlovic et al. Pathol Res Pract 2014; Marques et al. Virchows Arch 2014;464:

69 Differential diagnosis and management of patients with SPA Both benign and malignant conditions sclerosing sialadenitis, polycystic dysgenetic disease, PA, LG cystadenocarcinoma, AciCCa, mucoepidermoid carcinoma management is surgical with conservative subtotal parotidectomy prolonged surveillance High risk of recurrences very low risk of carcinomatous transformation

70 Conclusions Salivary gland tumors remain diverse with new entities, such as secretory carcinoma included in the 4th edition of the WHO classification The new category other epithelial lesions, adds tumor like lesions such as SPA and potential precursor lesion as IDH intraductal carcinoma Specific grade has been removed from the names of salivary gland entities such as PAC Despite heated discussion, CASG remains within the spectrum of PAC

71 Thank you for your attention 2018 IAP Congress; Jordan, October 2018