Salivary gland carcinomas-update
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1 Salivary gland carcinomas-update 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
2 Salivary gland carcinomas Rare tumors with heterogenous morphology Newly described entities and reclassification of other salivary gland ca Genetic alterations, some of them specific o CRTC1/MAML2, ETV6/NTRK3, PLAG1,etc Immunohistochemistry omib1 and prognosis(acicc, MEC, AdCCa) Chalengingbothforpathologistsand clinicians
3 Incidence, etiology and risk factors about 0.5% of all malignancies and less that 5% of all head and neckcancers Risk factors are largely unknown o Ionising radiation o Endogenous hormones(ar in SDC) o Hereditary origin in basal cell carcinoma and acinic cell carcinoma
4 Grading different concepts of grading the heterogenous group of SG tumors have been proposed but there is no consensus to date grading of SG cancers is an important predictor of survival Carcinoma types for which grading systems exist and are relevant are incorporated into histologic type. amenable to grading include o adenoid cystic carcinoma, o mucoepidermoidcarcinoma, and adenocarcinoma, not otherwise specified. o polymorphous adenocarcinoma
5 Low-risk category LG mucoepidermoid carcinoma Acinic cell carcinoma Basal cell adenocarcinoma PLGA MASC Cystadenocarcinoma Clear cell carcinoma Epithelial-myoepithelial carcinoma
6 Intermediate-risk category Grade 2 mucoepidermoid carcinoma Tubular and cribriform adenoid cystic carcinoma Myoepithelial carcinoma Mucinous adenocarcinoma
7 High-risk category High grade mucoepidermoid carcinoma Solid (basaloid) adenoid cystic carcinoma SDC Carcinoma ex pleomorphic adenoma Carcinosarcoma HG clear cell myoepithelial carcinoma
8 High-grade transformation Acinic cell carcinoma MASC Adenoid cystic carcinoma Basal cell adenocarcinoma Epithelial-myoepithelial carcinoma PLGA, etc.
9 High-grade transformation High grade transformation (originally called dedifferentiation ) is defined as the histologic progression of a low grade malignant neoplasm to a high grade one, within which the original line of differentiation is lost always associated with tumor progression Aggressive behavior and poor outcome
10
11 HG transformation of MASC
12 HG transformation of MASC MIB1
13 Staging SG carcinomas are staged according to the recommendation of the Am Joint Committee on Cancer (AJCC) or the UICC (International Union against Cancer) distincttnm classification exists for major salivary glands minor salivarygland tumorsare staged as oral squamous cell carcinoma
14 Prognosis Histologic type Age (highageisworse) Stage and grade Gender (male worse) Site(submandibular gland worse) facial nerve involvement MIB1 proliferation activity CRTC1/MAML2 translocation(better)
15 "Molecular classification" of salivary gland carcinomas Mammary analogue secretory carcinoma (MASC) adenoid cystic carcinoma mucoepidermoid carcinoma hyalinizing clear cell carcinoma CATS versus PLGA Myoepithelial carcinoma Intraductal carcinoma
16 Tumor type Key molecular alterations in (Mammary analogue) secretory carcinoma Mucoepidermoid carcinoma Hyalinizing clear cell carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Cribriform adenocarcinoma of minor salivary glands Salivary duct carcinoma/ IC salivary gland carcinomas 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 <5
17 Mucoepidermoid carcinoma
18 Mucoepidermoid carcinoma
19 Mucoepidermoid carcinoma common salivary gland tumor occurs in broad age range and can appear both in major and minor glands translocationt(11;19) fuses MECT1 (mucoepidermoid carcinoma translocated-1) at 19p13 with MAML2(mastermind-like gene family) at 11q21 also known as CRTC1/MAML2 Tonon et al Nat Genet 33: Behboudi et al Genes Chromosomes Cancer 45:
20 Low grade mucoepidermoid carcinoma- prognosis Proportion of cystic and solid growth patterns MIB1 index Invasion CRTC1/CRTC3 MAML2 translocation
21 Mucoepidermoid carcinoma Highly variable clinical prognosis GradingofMEC o WHO 2005, AFIP, Brandwein-Gensler system, modified Healey grading system, etc. CRTC1/MAML2t(11;19) fusionpositive patients have better outcomes o Less local recurrences, metastases and tumor-related deaths
22 Adenoid cystic carcinoma
23 Adenoid cystic carcinoma bothminor and major SG relentlessclinicalcoursewithlaterecurrencesand distant metastases causes significant morbidity Perineural infiltration intracranial invasion
24 Adenoid cystic carcinoma Recurrent t(6;9) translocation in AdCC ofbothheadand neck(salivary, lacrimal, ceruminal glands) and breast Translocation fuses MYB oncogene withtranscriptionfactorgene NFIB o Leads to chimeric MYB-NFIB fusion transcript o MYBactivationthroughgene fusionisa major oncogenic event in AdCCa of many sites
25 Adenoid cystic carcinoma Differential diagnosis o MYB-NFIB fusion- in % cases o All anatomic locations prognosis o MYB-NFIBfusion-positive casesshow tendency toward higher local relapse rate MYB-NFIB fusion is a candidate therapeutic target
26
27 Mammary analogue secretory carcinoma (MASC)
28 Mammary analogue secretory carcinoma (MASC)
29 Mammary analogue secretory carcinoma (MASC) akin to secretory carcinoma of the breast, MASC expresses S-100 protein and mammaglobinand harboursa t(12;15)(p13;q25) translocation that results in an ETV6/NTRK3 fusion product presence of t(12;15) has not been demonstrated in any other salivary gland tumour so far
30
31 Mammary analogue secretory carcinoma of salivary glands
32
33
34 Mammary analogue secretory carcinoma of salivary glands ETV6 NTRK3
35 Hyalinizing clear cell carcinoma of minor salivary glands
36 Hyalinizing clear cell carcinoma of minor salivary glands
37 Hyalinizing clear cell carcinoma of minor salivary glands considered a diagnosis of exclusion Despite its very distinctive appearance it was labeled as not otherwise specified by WHO 2005 Dif. Dg. oclear epithelial-myoepithelialca, mucoepidermoid carcinoma, myoepithelial ca o metastatic renal cell ca o clear cell odontogenic ca Simpson et al: Histopathology 1990: 17: Milchgrub et al. Am J Surg Pathol 1994:18:74-92
38 EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland Cristina Antonescu, et al, and Ilan Weinreb. Genes Chromosomes Cancer 2011: 50:
39 EWSR1-ATF1 translocation EWSR1-ATF1 fusion gene in soft tissue tumors(also with other fusion partners, such as CREB1, etc.) EWSR1-ATF1fusionhas beencharacterizedby Antonescu et al. as a consistent finding in HCCCa Recently seen in clear cell odontogenic carcinoma(ccoca) HCCC canbedistinguishedfromitsmimics, such as epithelial-myoepithelialcarcinomaand mucoepidermoid carcinoma Molecular and biological link between HCCCa and CCOCa
40 EWSR1 positive clear cell myoepithelial carcinoma
41
42 EWSR1 positive clear cell myoepithelial carcinoma FISH analysis using EWSR1 dual color, break apart probe. Visualization under Triple Band Pass filter. Yellow signals indicate intact EWSR1 gene region, separated green and red signals represent rearrangered EWSR1 gene region. Several nuclei positive for EWSR1 break are shown.
43 Clear cell myoepithelial carcinoma EWSR1 positive arranged in nodules composed of compact nests of large polyhedral cells with abundant clear cytoplasm Necrosis, areas of squamous metaplasia, and hyalinization IHC-tumors expressed p63 (96%), cytokeratin CK14 (96%), and S-100 protein (88%) MIB1 index varied from % with most cases in 20-40% range
44
45 MIB1 40% Clear cell variant HG myoepithelial carcinoma
46 Clinical follow-up of CCMC available in 21 cases (84%), and ranged from 3 months to 15 years (mean 5.2 years) 10patients -alive NED in follow up period from 3 months to 15 years (mean 5 years) 3 patients -alive with recurrent/metastatic disease 8 died of disseminated cancer 9 months to 16 years after diagnosis (mean 6 years) LN mets-5 patients within 5 months to 4 years after diagnosis (mean 22 months) distant mets-7 patients o orbit (2 cases), one case each neck soft tissues, liver, lungs, mediastinum, and thoracic vertebra
47 Conclusions: CCMC We describe for the first time EWSR1gene rearrangement in a subset of MC arising in minor and major salivary glands The EWSR1rearranged CCMC represents distinctive aggressive variant composed predominantly of clear cells with frequent necrosis Most EWSR1-rearranged CCMC of salivary glands are characterized by poor clinical outcomes
48 Conventional classification of salivary gland carcinomas
49 Conventional classification of salivary gland carcinomas Acinic cell carcinoma PAC/PLGA Epithelial-myoepithelial carcinoma Oncocytic carcinoma Salivary duct carcinoma Carcinoma ex pleomorphic adenoma(pa) Metastasizing PA Hybrid and metastic tumors
50 Acinic cell carcinoma
51 Acinic Cell Carcinoma
52 Acinic Cell Carcinoma Accounts for 18% of malignant SG tu Parotis (80%), minor SG, subm gland Women affected more commonly Age: evenly distributed 3-7th decades 2nd most common malignant SG tumor in children 3rd most common bilateral tumor (3 %), after Warthin s tumor (5-10%) and PA Multifocal, familiar occurrence
53
54 Acinic Cell Carcinoma Well differentiated AciCCa with lymphoid stroma
55 Acinic Cell Carcinoma: Disease course Notoriously protracted clinical course Expected rates: Recurrence: Metastasis : 13% Mortality : 30% 30-50%, often multiple Death of progressive loco-regional or metastatic disease Metastasis: lymphatic and/or hematogenous (lung, bone)
56 Polymorphous (low-grade) adenocarcinoma (PLGA)
57 Polymorphous low grade adenocarcinoma PLGA Minor glands only Perineural infiltration Tumour cells show bland cytonuclear abnormality Indian filing appearance resembling lobular carcinoma of the breast
58 Salivary duct carcinoma
59 Salivary duct carcinoma about 10% of malignant salivary gland tumors Male to female ratio 4:1 Most patients older than 50 years Parotid gland most commonly involved Pain and facial nerve paralysis Perineural invasion 60% Intravascular tumor emboli 31% Most patients present with stage III and IV Lymph nodes positive in 50% (range 40-72%)
60 AR Luminal type SDC
61 HER2 type SDC HER2
62 Rare salivary gland carcinomas Myoepithelial carcinoma carcinosarcoma Cystadenocarcinoma Mucinous adenocarcinoma Basal cell adenocarcinoma Cribriform adenocarcinoma of tongue and other minor salivary glands(cats)
63 Myoepithelial carcinoma
64 Most cases arise in parotid gland but they also occur in submandibular and minor glands, usually the palate they rarely may arise in the base of tongue, maxillary sinus and larynx may arise de novo, but at least half of them develop in pre-existing pleomorphic adenomas (PA) or benign myoepitheliomas mean age of patients at presentation is about 55 years (range years)
65 Macroscopy unencapsulatedbut may be well-defined with nodular surfaces cut surface is grey-white and can be glassy sometumorsreveal areas of hemorrhage, necrosis and pseudocystic degeneration
66
67 p63 protein ASMA
68 Prognosis of myoepithelial carcinoma one third of patients die of disease another third have multiple recurrence remaining third are disease free Myoepithelialcarcinomasexrecurrent PAs may persuea prolonged clinical course markedcellular pleomorphism, high mitotic rate and high proliferative activity (MIB1 index) correlate with poor prognosis
69 Differential diagnosis salivary duct carcinoma spectrum of clear cell tumors mucoepidermoid carcinoma soft tissue sarcomas variety of clear cell neoplasms primary and metastatic, including epithelial-myoepithelial carcinoma, clear cell carcinoma NOS, hyalinizing clear cell carcinoma and metastatic renal cell carcinoma immunohistochemistryis helpful in excluding these neoplasms
70 Carcinosarcoma
71 Carcinosarcoma Very rarebiphasicsalivaryglandtumor composedofsarcomatousand carcinomatous component Variable histomorphology Arise ex pleomorphic adenoma or de novo Aggressive, high grade malignancy
72
73 CK
74 AR HER-2/neu
75 MIB1 proliferative activity
76 Cystadenocarcinoma
77 Cystadenocarcinoma rare malignant tumor of salivary glands characterized by invasive growth and multiple cystic structures lined with epithelium accounting for 0.5 to 2.0% of malignant salivary gland tumors Although the age range is broad (5 to 87 years), more than 70 % of patients are over 50 years of age grossly, the tumours are cystic or multicystic, well circumscribed unencapsulatedlesions that usually range in size from 0.4 to 10 cm in greatest dimension cystadenocarcinomarepresents malignant counterpart of cystadenoma
78
79
80
81 Site and treatment In AFIP series about 60 percent occur in major salivary glands, most of these were located in parotid gland minorglands are affected in descending order in frequency in palate, buccal mucosa, lips, floor of mouth and tongue majority are low-grade or intermediate-grade neoplasms treatmentshould be relevant to grade and stage of the tumor
82 Mucinous adenocarcinoma
83 Mucinous adenocarcinoma a malignant epithelial tumor composed of epithelial clusters within large pools of extracellular mucin mucincomponent occupies the majority of the tumor Signet-ring cell carcinoma -characterized by presence of isolated tumor cells with intracytoplasmic mucus vacuoles
84
85 Mucinous (colloid) adenocarcinoma of major and minor salivary glands is an extremely rare neoplasm Most tumors arise in minor salivary glands o o o o namely in the glands of palate buccal mucosa floor of the mouth, and base of the tongue few cases have been described in the parotid gland tumor is often nodular and ill defined cut surface is whitish-grey with multiple cystic spaces containing gelatinous secretory material Mucinous (colloid) adenocarcinoma of salivary glands is histologically identical with breast and colorectal analogues
86 Differential diagnosis mucinous cystadenoma mucinous cystadenocarcinoma mucoepidermoid carcinoma (MEC) mucin-rich salivary duct carcinoma metastic tumors mucin extravasation phenomenon
87 Basal cell adenocarcinoma
88 Basal cell adenocarcinoma rare malignant epithelial tumor of major and minor salivary glands composed of predominantly basaloid cells cytologicallyand morphologically similar to basal cell adenoma but has invasive growth and potential to develop metastases
89 Site and gross appearance Over90% ofbcac occurin parotidgland occursovera wideagerangewithaverageageof 60 most are well defined nonencapsulated lesions on cut section, they are mostly homogenous, some of them partly cystic
90 Microscopy 4 main growth patterns tubular, trabecular, solid, and membranous BCAC is composed of basaloidcells with large round to oval nuclei and little cytoplasm mosttumors have a limited mitotic activity and nuclear and celllular polymorphism diagnosis of BCAC is based on invasive growth into the adjacent tissues and identification of perineural or vascular invasion
91 Vážený pane docente, chtěla bych Vás požádat o přidání termínů na zkoušky z Farmakologie. Ve zkouškovém období byl vypsán sice dostatečný počet míst pro studenty 4. ročníku, boh
92
93 Treatment and prognosis low-grade malignancy cumulativedata from the literature reveal a local recurrence rate of about 37%, locoregional metastatic rate of 8% and very low risk of distant metastasis Optimal treatment includes wide surgical resection with free margins, additional radiotherapy or elective neck dissection are not warranted
94 Sialoblastoma
95 Sialoblastoma-definiton low-grade malignant neoplasm usually present at birth or shortly thereafter composed of epithelial basaloid and myoepithelial cells that recapitulate primitive salivary gland anlage Sialoblastoma was first reported in 1996 by Vawter and Tefft who used the term embryoma approximately 40 tumors, that fit into a definition of sialoblastoma, were reported under different names o o o congenital basal cell adenoma congenital hybrid basal cell adenoma/adenoid cystic carcinoma sialoblastoma
96 Sialoblastoma-grossly arises almost exclusively in perinatal period with rare cases presenting after 2 years of age tumors range up to 15 cm in greatest dimension and are well circumscribed and even partly encapsulated they may be locally invasive with extension to adjacent soft tissues and bone
97 Sialoblastoma-microscopy Itrecapitulatesembryonic development of major salivary glands variable histological patterns, composed of variably sized nests and solid sheets of basaloidcells with focal ductal differentiation and cystic and microcystic change cells arefairly uniform with minimal cytoplasm and round to oval nuclei with only slight polymorphism Mitoses are frequently found and may be numerous, atypical mitoses are not present Neural and occasionally vascular invasion may be found
98
99
100 Cribriform carcinoma of minor salivary glands
101 23 patients/15x cervical LN meta In 3 patietns original dg was metastasis of PTC
102 Ground-glass nuclei ( Orhan Annie eyes )-resemble papillary ca of thyroid
103 TTF1, Thyreoglobulin neg Papillary growth pattern, ground-glass nuclei CK7, S-100, actin+
104 Ground glass nuclei in LN metastasis
105 LVI D2-40
106 CATS versus PLGA extensive nuclear ground-glass change in CATS with overlapping clear Orphan Annie eye like nuclei a novel and recurrent ARID1A-PRKD1fusionin CATS was recently detected CATS had lymph node metastases in mostcases already at the time of the presentation of the primary tumor
107 Conclusions Morphology and immunoprofile unique oncogenic translocations o Diagnostic markers(hccc, MASC) oidentifyas yetnot discoveredtumor typesor reclassify(masc) osomemaybeprognostic(maml2in MEC) omay serve as targetsfortherapy(myb-nfib? ETV6/NTRK3?) omany otherswaitforidentification(ccmc, PLGA, CATS, etc.)
108 Thank you for attention An update on Histopathology ofsalivary Gland Tumors, La Spezia, Italy, Oct 18-20, 2017
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