Salivary Gland Tumors: Latest Updates (New Entities)

Asif Loya, MDConsultant Pathologist

Medical DirectorShaukat Khanum Memorial Cancer Hospital and Research Centre

Lahore, Pakistan

WHO Classification of Head & Neck Tumors 2016

WHO Classification of Head & Neck Tumors 2016

• Oropharynx as a distinctive sub-site– HPV related Squamous Cell Carcinoma, distinct

entity

• New entities in Sino-Nasal Tract– NUT Carcinoma

– HPV related carcinoma with adenoid cystic like features

• Salivary Gland Tumors, new tumors recognized.

Focus

1. Mammary Analog Secretory Carcinoma (Secretory Carcinoma)

2. Cribriform adenocarcinoma (Polymorphous Adenocarcinoma?)

3. Sclerosing polycystic adenosis/adenoma (SPA)

4. Mucinous Myoepithelioma/Secretory Myoepithelioma

5. Clear cell carcinoma(CCC)

Mammary Analog Secretory Carcinoma(Secretory Carcinoma (SC))

• Adults, Mean age 47 years (range: 14 to 78 years)

• Slightly more common in males

• Parotid gland most commonly involved followed by oral cavity and submandibular gland

• Features

• Firm mass, white-tan to gray cut surface

• Usually circumscribed but un-encapsulated

• Broad front invasion

Lobulated arrangement divided by fibrous septa with microcytic, tubular and solid arrangement.

Histologic Features

Abundant secretions in microcytic and tubular cystic spaces (A), highlighted by PAS (B)

A B

SC with arrangement in sheets showing moderate degree of atypia

• SC with prominent fibrosclerotic stroma with isolated tumor cells in small islands or trabeculae seen mostly in the central part of the tumor.

• SC with predominant single large cyst, apocrine-like epithelial lining. In this case D/D Mucoepidermoidcarcinoma.

Skálová A, Gnepp DR, Lewis Jr JS, Hunt JL, Bishop JA, Hellquist H, Rinaldo A, Vander Poorten V, Ferlito A. Newly Described Entities in Salivary Gland Pathology. The American Journal of Surgical Pathology. 2017 Aug 1;41(8):e33-47.

• The tumor cells with low-grade vesicular nuclei, finely granular chromatin and a distinctive centrally located prominent, but small, nucleolus.

Skálová A, Gnepp DR, Lewis Jr JS, Hunt JL, Bishop JA, Hellquist H, Rinaldo A, Vander Poorten V, Ferlito A. Newly Described Entities in Salivary Gland Pathology. The American Journal of Surgical Pathology. 2017 Aug 1;41(8):e33-47.

• SC with high-grade transformation, proliferation of a distinct population of anaplastic cells having areas of comedo-like necrosis

Chiosea SI, Griffith C, Assaad A, et al. Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands. Histopathology. 2012;61:387–394.

A B

C

Mammoglobin (A), GATA-3 (B), S100 (C) immunohistochemical stains showing positivity in SC

Differential diagnoses (Major)• Acinic cell carcinoma(ACC)

• Intraductal carcinoma

• Low grade mucoepidermoid cacinoma

Less common

• Polymorphous low-grade adenocarcinoma (PLGA),

• Low-grade adenocarcinoma or cystadenocarcinoma NOS, and

• Cystadenoma NOS

Three important points to differentiate ACC VSSecretory Carcinoma

I. SC shows no basophilic granularity in cytopalsm (Hallmark of ACC)

II. SC strongly expresses S100 and Mammoglobin and are negative for DOG1(ACC shows opposite profile)

III. Specific molecular alteration

Differences between SC & ACC

ACC SCSite Major salivary glands,

95% in parotidMajor and minor salivary glands common

Sex distribution Female predominance Slight male predominance

Growthpattern

Solid, follicular, andmicrocystic common,Macrocystic andpapillary cystic rare

Tubular and microcystic/solid predominant,follicular and papillarycystic common

Cytoplasm Zymogen granules present

pink granular tovacuolated cytoplasm,

zymogen granules absent

Nuclei Monomorphic Low-grade vesicular nuclei

with centrallylocated nucleoli

Immunoprofile S100, p63 and mammaglobin

negative, DOG1 membranous and

Apical staining

S100, mammaglobin& GATA-3 positive,

DOG1, p63 negative

Molecularalteration

t(12;15) ETV6-NTRK3

Chenevert J, Duvvuri U, Chiosea S, et al. DOG1: a novel marker of salivary acinar and intercalated duct differentiation. Mod Pathol. 2012;25:919–929. Shah AA, Wenig BM, LeGallo RD, et al. Morphology in conjunction with immunohistochemistry is sufficient for the diagnosis of mammary analogue secretory carcinoma. Head Neck Pathol. 2015;9:85–95. Ska ́ lova ́ A. Mammary analogue secretory carcinoma of salivary gland origin: an update and expanded morphologic and immuno- histochemical spectrum of recently described entity. Head Neck Pathol. 2013;7:S30–S36.

2. Intraductal carcinoma

• Overlapping features, SC

I. Proliferation of bland eosinophilic ductal cells

II. Frequent intraluminal secretions

III. S100 and Mammoglobin positive

• Differentiating featuresI. Epithelial structures of intraductal carcinoma are

surrounded by p63 positive myoepithelial cells Loening T, Leivo I, Simpson RHW, et al. Intraductal carcinoma. In: El-Naggar A, Chan JKC, Grandis JR, Takata T, Slootweg PJ, eds. World Health Organization (WHO) Classification of Head and Neck Tumours. Lyon, France: IARC Press; 2017:170–171.

3. Low grade Mucoepidermoid carcinoma

• Overlapping features

• Prominent cystic component

• Bland cells; eosinophilic, clear, or vacuolated.

• Focal mucicarmine staining in SC

• Differentiating Features

• Mucoepidermoid carcinoma, positive p63 staining in epidermoid foci

• Negative S100 and Mammoglobin

• Muco Epi, translocation, t(11;19), CRTC1-MAML2 fusion

Seethala R. Salivary gland tumors. Current concepts and controversies. Surg Pathol. 2017;10:155–176. Skalova A, Michal M, Simpson RHW. Newly described salivary gland tumors. Mod Pathol. 2017;30:S27–S43.

Molecular Findings

• Recurrent balanced chromosomal

translocation t(12;15) (p13;q25), with

fusion gene between the ETV6 gene on

chromosome 12 and the NTRK3 gene on

chromosome 15.

– Not observed in any other salivary gland tumor

Ska ́ lova ́ A. Mammary analogue secretory carcinoma of salivary gland origin: an update and expanded morphologic and immuno- histochemical spectrum of recently described entity. Head Neck Pathol. 2013;7:S30–S36.

ETV6- NTRK3

Non Salivary Gland Tumors:

1. Secretory carcinoma of the breast

2. Infantile fibrosarcoma

3. congenital mesoblastic nephroma

4. ALK-negative inflammatory myofibroblastic tumors

5. Radiation induced papillary thyroid carcinoma

Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2:367–376.Knezevich SR, McFadden DE, Tao W, et al. A novel ETV6- NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998; 18:184–187. Rubin BP, Chen CJ, Morgan TW, et al. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol. 1998;153:1451–1458.

Treatment and Prognosis of SC

• Simple excision to radical dissection, neck dissections, adjuvant radiotherapy, and/or adjuvant systemic chemotherapy

• Low grade SC; complete surgical resection (treatment of choice)

• Local recurrence and distant mets in high grade transformation have been reported

• Possible use of TKI’s

SECRETORY CARCINOMA@ SKMCH&RC

• Follow up of 13 cases (mean range, 2 years)

• 7 were previously called ACC

• All positive for ETV6/NTRK3

• 5 patients received adjuvant radiotherapy

• No patient developed local recurrence or metastasis

Cribriform Adenocarcinoma

• Also called cribriform adenocarcinoma of

tongue/minor salivary gland (CASG).

• Resembles Polymorphous low grade

adenocarcinoma (PLGA)

• WHO Classification of Head and Neck Tumours 2016 uses a synonymic designation “polymorphous adenocarcinoma” (PAC) for both tumor entities, referring to CASG as the “cribriform variant of PAC”

• CASG differs from PLGA

– Following Table shows distinguishing features

Ska ́ lova ́ A, Sima R, Kaspirkova-Nemcova J, et al. Cribriform adenocarcinoma of the tongue and other minor salivary glands: characterization of new entity. Am J Surg Pathol. 2011;35:1168–1176. Luna MA, Wenig BM. Polymorphous low-grade adenocarcinoma. In: Barnes EL, Eveson JW, Reichart P, et al, eds. World Health Organization Classification of Tumours Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005:223–224.

• Comparison of PLGA and CASG

PLGA CASG

Site

Minor salivary glands,Palate, buccal mucosa

Minor salivary glands, baseof tongue

Growth

Single file, trabeculae, concentric whorls, target-like appearance. Associated tubular, trabecular, papillary, solid, and cribriform

Tubular or Solid with cribriform and glomeruloidStructures. Divided by septa

Nuclearfeatures

Vesicular and ovoid nuclei

Optically clear, papillary thyroid cancer like

Clinicalfeatures

Rare regional mets Common regional (cervical LN) metastasis. No distant mets

Molecularalterations

Hotspot, PRKD1 point mutation

PRKD1-3 translocations,

Tissueinvasion

Perineural invasion Lymphatic invasion

Clinical

• CASG is a rare tumor, 50 reported in the

literature

• Equal male : female ratio

• Mean age 53 years

Features

• Friable and cystic

• Unencapsulated,

• White to tan to gray in color, and hard in

consistency

• No areas of necrosis or hemorrhage.

Histologic features

CASG is unencapsulated covered by squamous epithelium, generally consist of solid mass and divided by fibrous septa.

The growth is infiltrative, and these tumorshave a higher propensity for lymphatic invasion.

CASG with solid, cribriform and microcysticappearance

Skálová A, Gnepp DR, Lewis Jr JS, Hunt JL, Bishop JA, Hellquist H, Rinaldo A, Vander Poorten V, Ferlito A. Newly Described Entities in Salivary Gland Pathology. The American Journal of Surgical Pathology. 2017 Aug 1;41(8):e33-47.

Characteristic microscopic feature is appearance of the nuclei.These often overlap one another, optically clear and vesicularwith a ground glass appearance, strongly resembling papillarythyroid carcinoma.Skálová A, Gnepp DR, Lewis Jr JS, Hunt JL, Bishop JA, Hellquist H, Rinaldo A, Vander Poorten V, Ferlito A. Newly Described Entities in Salivary Gland Pathology. The American Journal of Surgical Pathology. 2017 Aug 1;41(8):e33-47.

S100 stain showing positivity in CASG

• Adenoid cystic carcinoma (AdCC) is also included in differential diagnosis.

CASG AdCC

Morphology Monophasic ductal tumor Biphasic tumor

Nuclei Optically clear and vesicular with a ground glass appearance

Angulated hyperchromatic nuclei

P63 Positive (staining is diffuse or random and variable)

Positive (biluminalpattern)

S100 Strong Positive Weak to Negative

C-kit, MYB Negative Positive (t6;9) (MYB/NFIB)Skalova A, Michal M, Simpson RHW. Newly described salivary gland tumors. Mod Pathol. 2017;30:S27–S43.Seethala R. Salivary gland tumors. Current concepts and controversies. Surg Pathol. 2017;10:155–176.

Prognosis

• Most CASGs are indolent; local recurrence

rates of 10% to 30%

• Regional metastases in most patients

• There are no reported distant metastases

Sclerosing Polycystic Adenosis/Adenoma (SPA)

• Non-neoplastic sclerosing and inflammatory process

resembling fibrocystic change and sclerosing adenosis of

breast

• SPA can harbor intraductal epithelial dysplastic (mild

dysplasia to severe dysplasia/carcinoma in situ) change

• The local recurrence rate is up to 30%.

Fulciniti F, Losito NS, Ionna F, et al. Sclerosing polycystic adenosisof the parotid gland: report of one case diagnosed by fine-needle cytology with in situ malignant transformation. Diagn Cytopathol. 2010;38:368–373.Petersson F. Sclerosing polycystic adenosis of salivary glands: a review with some emphasis on intraductal epithelial proliferations. Head Neck Pathol. 2013;7(suppl 1):S97–106.Petersson F, Tan PH, Hwang JSG. Sclerosing polycystic adenosis of parotid gland: report of a bifocal, paucicystic variant with ductal carcinoma in situ and pronounced stromal distortion mimicking stromal invasion. Head and Neck Pathology. 2011;5:188–192.

• Extensive in situ component gives the impression of

intralesional invasive adenocarcinoma; frankly clinically

malignant invasive carcinoma ex-SPA was recently

reported.

• No metastases or disease-related deaths are

documented

• Suggestion: SPA as a neoplastic Lesion with appropriate

name “sclerosing polycystic adenoma” (SPA).

Petersson F, Tan PH, Hwang JSG. Sclerosing polycystic adenosis of parotid gland: report of a bifocal, paucicystic variant with ductal carcinoma in situ and pronounced stromal distortion mimicking stromal invasion. Head and Neck Pathology. 2011;5:188–192. Marques RC, Fe ́ lix A. Invasive carcinoma arising from sclerosing polycystic adenosis of the salivary gland. Virchows Arch. 2014;464: 621–625.

Clinical

• Parotid gland (>70%), but also occur in

submandibular gland, oral cavity and rarely

nasal cavity

• Present as slow growing painless mass

• Mean patient age is about 40 years

• Female to male ratio is 1.3:1

Features

• Firm or rubbery

• Well circumscribed, surrounded by normal salivary

gland tissue.

• The tumors range in size from 0.3 to 7 cm in

greatest dimensions.

• Pale and glistening with multiple tiny visible cystic

spaces ranging from 1 to 3mm in diameter

Histological Features

Well-circumscribed, partially encapsulated mass with variable amounts of sclerotic stroma

Multiple dilated ducts are often lined by a flattened bilayered epithelium.

The ductal cells range from being vacuolated, foamy, apocrine, and mucous in appearance, and focal squamous metaplasia may also be present.

The hallmark of the tumor is the presence of large acinar cells with numerous coarse eosinophilic cytoplasmic granules.

In most cases, nuclear polymorphism has been noted, ranging in severity from mild to severe, and sometimes amounting to low-grade ductal carcinoma in situ

Skálová A, Gnepp DR, Lewis Jr JS, Hunt JL, Bishop JA, Hellquist H, Rinaldo A, Vander Poorten V, Ferlito A. Newly Described Entities in Salivary Gland Pathology. The American Journal of Surgical Pathology. 2017 Aug 1;41(8):e33-47.

Ducts filled with hyperplastic epithelium are surrounded by an intact myoepithelial layer, positive for Calponin and p63.

Calponin p63

Genetic Profile

• X chromosome inactivation detected in

certain cases by Human androgen receptor

(HUMARA) assay suggest monoclonal nature

Skalova A, Gnepp DR, Simpson RHW, et al. Clonal nature of sclerosing polycystic adenosis of salivary glands demonstrated by using the polymorphism of the human androgen receptor locus (HUMARA) as a marker. Am J Surg Pathol. 2006;30:939–944.

Differential Diagnoses

1. Pleomorphic Adenoma

• The characteristic lobular growth pattern and

large Paneth cell-like acinar cells of SPA are not

seen in Pleomorphic Adenoma.

• SPA lacks a prominent myoepithelial cell

component and the abundant chondromyxoid

stroma typical of Pleomorphic Adenoma.

2. Chronic sclerosing sialadenitis

• Chronic sclerosing sialadenitis lacks a nodular

pattern and typical structural heterogeneity of

SPA, although both lesions share prominent

fibrosis.

• Large acinar cells with coarse PAS-positive

zymogen-like cytoplasmic granules are not seen

in chronic sclerosing sialadenitis.

3. Acinic Cell Carcinoma

4. Intraductal Carcinoma

Management and Prognosis

• Management of SPA is surgical with complete but

conservative local surgical resection followed by

prolonged surveillance.

• SPA recurs in 11% of cases that are multifocal or

incompletely excised.

• There is one reported case of SPA that showed

malignant transformation after three recurrences.

Mucinous Myoepithelioma/Secretory Myoepithelioma

• A new myoepithelioma variant

• Myoepithelial cells; spindle shaped,

plasmacytoid, epithelioid or with clear

cytoplasmic features.

• Occasional tumors; oncocytic or basaloid

features

• 17 reported cases of Mucinous

myoepithelioma (MM).

• Majority of MM are found in minor salivary

glands.

• Equal male to female ratio

• One reported case shows lymph node

metastasis

• Tumors range in size from 1 to 5 cm.Zamecnik M, Gogora M. Signet-ring cells simulating carcinomas in minor salivary gland of the lip. Pathol Res Pract. 1999;195:723–724. 82. Foschini MP, Baldovini C, Pennesi MG, et al. Signet ring cell tumor of the minor salivary gland exhibiting benign behavior. Hum Pathol. 012;43:303–306.Franquemont DW, Mills SE. Plasmacytoid monomorphic adenoma of salivary glands. Absence of myogenous differentiation and comparison to spindle cell myoepithelioma. Am J Surg Pathol. 1993; 17:146–153.

Histological features

Benign mucinous myoepithelioma. The tumor is encapsulated and composed of numerous closely packed solid nests.Skálová A, Gnepp DR, Lewis Jr JS, Hunt JL, Bishop JA, Hellquist H, Rinaldo A, Vander Poorten V, Ferlito A. Newly Described Entities in Salivary Gland Pathology. The American Journal of Surgical Pathology. 2017 Aug 1;41(8):e33-47.

Tumor with numerous plasmacytoid tumor cells containing abundant mucinous material.

A

A. Mucicarmine stain showing abundant intracellular mucin. B, p63 stain demonstrating nuclear staining. C, S100 IHC stain.

C

B

Criteria for malignancy

• Same histologic criteria for this tumor to evaluate for malignancy as with any other myoepithelioma, such as

Circumscription,

Encapsulation,

Destructive peripheral growth,

Increased mitotic and proliferative rates,

Neural/vascular invasion,

Tumor necrosis, and

Degree of nuclear pleomorphism,

Differential Diagnosis

1. Signet-ring adenocarcinoma, likely metastatic

Immunohistochemistry (Calponin, S100, GFAP)

to confirm the myoepithelial nature with

metastatic work-up

2.Mucoepidermoid carcinoma,

Mucoepidermoid carcinoma has foci of

squamous differentiation and will not stain with

myoepithelial-specific markers.

3. Colloid carcinoma,

• Abundant pools of extracellular mucin material.

4. Salivary duct carcinoma with signet-ring type

cells

• More typical salivary duct carcinoma pattern

and lack staining with myoepithelial specific

markers.

Clear Cell Carcinoma (CCC)

• Low grade salivary gland neoplasm

• Also called “Hyalinizing clear cell carcinoma”

• More common in women

• Typically presents in 5th decade, rare in children

• Found most frequently in intraoral salivary gland

sites (palate and base of tongue).

• Show consistent EWSRI-ATF1 gene fusion.

EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland, Cristina R. Antonescu et al, Genes, Chromosomes and Cancer 2011.

Gross features

• Poorly circumscribed solid mass

• 3cm or less in greatest dimension

• Prominent hyalinisation may be grossly seen

• Infiltration of adjacent tissue may be seen

Microscopic features

Submucosal tumor with solid nests and intervening sclerotic areas

CCC with sclerotic areas and clear cells

Sheets of clear cells with monomorphic appearance

C

CK IHC stain showing positivity in tumor cells

Differential diagnosis

1. Mucoepdermoid carcinoma with clear cell variant

• In clear cell carcinoma, cells are diastase- sensitive,

PAS – positive, Mucicarmine negative while in clear

cell variant of mucoepidermoid carcinoma, clear

cells are diastase- resistant, PAS – positive,

Mucicarmine positive.

2. Metastatic clear cell renal cell carcinoma

These tumors are differentiated from CCC as clear

cells in these tumor cells show CD10, PAX8,

Carbonic anhydrase staining. These

immunohistochemical stains are negative in CCC.

• Other differential diagnosis included

Clear cell oncocytoma

Clear cell myoepithelioma

Acinic cell carcinoma, clear cell variant

Clear cell odontogenic carcinoma

Prognosis and predictive factors

• Clear cell carcinomas are low grade tumors

with good prognosis after complete surgical

excision

• Local recurrence and nodal metastasis may

occur.

• Distant metastasis is very rare.

Solar AA, et al, Hyalinizing Clear Cell Carcinoma Case Series and Comprehensive Review, Cancer, 2009

Thank You

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