WHO classification salivary tumours: What's new?

Transcription

1 WHO classification salivary tumours: What's new? Alena Skalova, MD, PhD Professor of Pathology Charles University, Faculty of Medicine in Plzen, Czech Republic An update on Histopathology of Salivary Gland Tumors, La Spezia, Italy, Oct 18-20, 2017

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4 WHO classification of salivary tumours 1972

5 Revised WHO classification 1991

6 WHO classification 2005

7 WHO ConsensusMeeting 2016

8 WHO Classification ofsalivary Gland Tumors2017

9 WHO Classification ofsalivary Gland Tumors2017

10 Mammary analogue secretory carcinoma (MASC) Intraductal carcinoma Cribriform adenocarcinoma of tongue (CATS/CASG) Sclerosing polycystic adenoma (SPA)

11 (MammaryAnalogue) Secretory Carcinoma(MASC)

12 (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

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14 Secretory carcinoma (mammary analogue) ETV6-NTRK3 ETV6-RET (ETV6-X) Skalova et al. AmJ SurgPathol2010; 34:

15 Secretory Carcinoma (mammary analogue) MASC Low grade vesicular nuclei, centrally located nucleolus, pink vacuolated cytoplasm

16 FISH foretv6gene breakis 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 theetv6gene region.

17 Less common and unexpected features in MASC

18 Masked MASC of parotid gland Petersson et al. A New Hitherto Unreported Histopathologic Manifestation of Mammary Analogue Secretory Carcinoma: Masked MASC Associated With Low-grade Mucinous Adenocarcinoma and Low-grade In Situ Carcinoma Components. Appl Immunohistochem Mol Morphol, in press

19 Lesscommonand unexpected featuresin MASC salivary gland tumor of the parotid gland in a 54- year-old woman which contained a minor mammary analogue secretory carcinoma (MASC) component (20%) intermixed with a different mucinous adenocarcinoma component (80%) morphologically nondescript low-grade intraductal carcinoma (in situ) component Both of the components revealed ETV6 rearrangement, RT-PCR failed to reveal an ETV6- NTRK3 fusion

20 MASC with mucinous adenocarcinoma component S100 protein positive in MASC component

21 Mucinous MASC with with macrocysticappearance mucinous MASC of parotid gland in 17-y old male with a macrocystic appearance should not be mistaken for low-grade MEC the cells of MASC can have single cytoplasmic vacuole thus mimicking mucous cells Macrocystic structures lined by single layer of apocrine cells with only rare, multivacuolated cells more characteristic of MASC S100/MMG stain and ETV6 gene rearrangement, RT- PCR failed to reveal an ETV6-NTRK3 fusion

22 Mucinous MASC MASC with prevailing macrocystic growth pattern

23 Mucinous MASC MASC with macrocystic appearance and apocrine features

24 Sclerotic MASC MASC with ETV6-X fusion

25 Sclerotic MASC MASC with ETV6-X fusion: prominent fibrosclerotic stroma

26 Mammary Analogue Secretory Carcinoma of Salivary Glands with High-grade Transformation HG-MASC with atypical ETV6/NTRK3 fusion

27 Mammary Analogue Secretory Carcinoma of Salivary Glands with High-grade Transformation Skalova et al. Am J Surg Pathol 2014;38:23-33

28 Molecular Features of MASC most SCs harbor the recurrent balanced t(12;15) (p13;q25) chromosomal rearrangement resulting in the fusion of the ETV6 and NTRK3 genes the ETV6 gene split visualized by FISH the classical ETV6-NTRK3 fusion transcript (exon 5- exon 15 junction) is in some cases not detected by standard reverse-transcriptase polymerase chain reaction (RT-PCR) atypical fusion transcripts (4-14 or 5-14 junctions) ETV6-RET fusion

29 25 cases FISH ETV6 positive, RT-PCR negative Nested RT-PCR positive in 4 16/25 rearrangement of NTRK3 4 cases of MASC ETV6-X gene fusion

30 Secretory carcinoma (MASC) with ETV6-X translocation MASC with ETV6-X fusion, predominatly macrocystic and papillary structures

31 Secretory carcinoma (MASC) with ETV6-X translocation SC with prominent hyalinization and trabeculae of neoplastic cellsembedded in a completely hyalinized central part

32 Molecular profiling of mammary analogue secretory carcinoma revealed a subset of tumors harboring a novel ETV6-RET translocation: report of 10 cases The presence of ETV6-RET fusion in MASC was proved by at least three independent tests, i.e. NGS, FISH, RT-PCR Histomorphology is variable MASC patients with ETV6-RET fusions may benefit from RET-targeted therapy o Skalova et al. AmJ SurgPatholAug2017, in press

33 Secretory carcinoma (MASC) with novel ETV6-RET translocation SC with typical morphology and immunoprofile harboring a novel ETV6-RET translocation (4 cases)

34 Secretory carcinoma (MASC) with novel ETV6-RET translocation predominantly multicystic growth pattern with multiple mural nodules (3 cases)

35 Secretory carcinoma (MASC) with novel ETV6-RET translocation prominent fibrosclerotic stroma with isolated tumor cells in small islands or trabeculae (3 cases)

36 Primary extrasalivary MASC

37 PrimaryMASC ofthyroidgland ETV6-NTRK3 fusion was found in about 14% of radiation-induced well-differentiated papillary thyroid carcinomas Leeman-Neil, et al. Cancer 2014;120: In up to 2% of sporadic well-differentiated papillary thyroid carcinomas Primary MASC of the thyroid masquerading as papillary thyroid cancer Reynolds, et al. Head Neck Pathol 2016;10: Primary thyroid MASC Stevens, et al. Modern Pathol 2015;28: Dettloff, et al Head Neck Pathol 2017;11(2):

38 PrimaryMASC ofthe thyroid gland two cases of papillary carcinoma of the thyroid, which showed transitions to the MASC papillary carcinoma component of the thyroid was TTF1 and thyroglobulin positive, MASC component was negative on these thyroid markers and was mammaglobin, S-100, p63, PAX8, GCDFP-15 positive Both of the components of this composite tumors revealed ETV6 rearrangement Dogan,et al.mammary analogue secretory carcinoma of the thyroid gland: A primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion. Modern Pathol 2016;29:

39 Primary composite MASC of thyroid gland Papillary thyroid carcinoma component of MASC

40 Primary composite MASC of thyroid gland conventional MASC component

41 Treatmentof MASC treatment of MASC 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 foretv6-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

42 TargetedtreatmentofMASC Use of and response to tyrosine kinase inhibitors in SC is limited, so far recent study suggested that the inhibition of ETV6-NTRK3 activation could be used for the treatment of patients with this fusion DrilonA, Li G, DoganS, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinibafter ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol. 2016;27:

43 Conclusions; Secretorycarcinoma MASC has distinctive morphology and immunoprofile in most cases Diagnosis of classical MASC features could be performed without molecular testing However, in cases that depart from the typical features of MASC in some way Molecular testing in MASC is of potential value in treatment of patients

44 Draft WHO classification 2017

45 CribriformAdenocarcinoma of Tongue (CAT) and (other) SalivaryGlands (CASG) Michal et al. Cribriform adenocarcinoma of the tongue. Histopathology 1999;35:

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47 Possiblevariant of PLGA is CAT/CASG, but it isnot yet clear whether this represents a genuine entity or just an unusual growth pattern in PLGA. WHO Classification of Tumours: Pathology and Genetics Head and Neck Tumours, IARC Press, 2005

48 Polymorphousadenocarcinoma (PAC)- WHO 2017 Syn. Low-grade polymorphous adenocarcinoma (PLGA); terminal duct carcinoma; lobular carcinoma CATS/CAMSG considered as cribriform variant of PAC FonsecaI; AssaadA; KatabiN; SeethalaR; Simpson RHW; Skálová A;Weinreb I; Wenig B

49 Polymorphous (low-grade) adenocarcinoma(plga/pac) Spindle shaped cells, streaming Perineural invasion Targetoid structures Regular nuclei

50 CribriformAdenocarcinoma of Tongue and SalivaryGlands (CATS/CASG)

51 CASG; solid and cribriform structures

52 CASG overlapping clear, grooved nuclei Papillary growth pattern, ground-glass nuclei

53 Key Featuresdistinguishing PLGA versus CASG PLGA 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 PLGAs are characterized by PRKD1 E710D mutations, whereas CASGs are characterized by PRKD1-3 translocations CASGs have a high capacity for nodal spread

54 Conclusions; CASG Histologic and molecular overlap between CASG and PLGA CASG is a distinct tumor entity, differs from PLGA 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

55 Draft WHO classification 2017.

56 Intraductal carcinoma Syn. cribriform cystadenocarcinoma; intraductal carcinoma, low-grade; low-grade SDC Solid, cystic, in situ Mostly parotid gland Excellent prognosis Loening T; Leivo I; Simpson RHW; Weinreb I CK14

57 Intraductalcarcinoma(IC) IC show a variety of growth patterns, both solid and cystic, ranging from cribriform to solid to micropapillary reminiscent of low-grade ductal carcinoma in situ or atypical ductal hyperplasia of the breast. Tumor cells are monomorphic and ovoid and evenly spaced with round nuclei and scant eosinophilic cytoplasm. Oncocytic and apocrine change and intermediate grade cytonuclear features are uncommon.

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61 p63

62 mammaglobin

63 S100 protein

64 S100 protein

65 S100 Calponin AR

66 S100 Apocrine variant of IDC AR

67 Intraductalcarcinoma; conclusions Pure intraductal lesions with either intercalated duct or mixed apocrine/intercalated duct morphology and S100 positivity should be called intraductal carcinoma they rarely invade and are associated with good outcome after excision Pure apocrine equivalents are generally invasive and are likely more related to true SDC and are better termed SDC in-situ or in-situ and microinvasive SDC these should be treated as if they could behave like fully invasive SDC

68 Draft WHO classification 2017.

69 SclerosingPolycysticAdenosis/ Adenoma (SPA) Smith BC, Ellis GL, Slater LJ, Foss RD, Sclerosingpolycystic adenosisof major salivary glands. A clinicopathologic analysis of nine cases. Am J Surg Pathol 1996:20:

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

71 Sclerosing polycystic adenoma Circumscribed lesion, embedded in parotid gland

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

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

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75 Dysplastic epithelium/ DCIS like

76 Sclerosing polycystic adenoma CK14

77 Biological natureand 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:

78 Differentialdiagnosis and management of patientswithspa 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

79 Conclusions; SPA is a distinctive entity, rare neoplastic condition with characteristic histologic features, Atypical hyperplasia, dysplasia, DCIS Evidence of clonality (HUMARA assay) Frequent recurrences, including multiple Report of invasive carcinoma ex SPA No metastases, no DOD so far Skalova, et al. Virchows Arch 2002;440: Skalova, et al. Am J Surg Pathol 2006;30:

80 2017 WHO Classificationof salivarytumors;conclusions Useful summary of present knowledge Includes new entities, such as MASC/Secretory carcinoma Good to include Other epithelial lesions Improves the section on undifferentiated and neuroendocrine carcinomas Improves the section on low-grade SDC by including intraductal carcinoma Polymorphous adenocarcinoma is confusing I would have preferred to keep PLGA and include CATS as a separate entity.

81 Thank you for attention An update on Histopathology ofsalivary Gland Tumors, La Spezia, Italy, Oct 18-20, 2017