Salivary glands

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The salivary glands help digest food. ENT surgeons take 'em out and want you to diagnose 'em. Cytopathology of the salivary glands is covered in the Head and neck cytopathology article.

Normal

Types of salivary glands

Types of glands:[1]

  1. Serrous - eosinophilic cytoplasmic granules, acinar arrangement - vaguely resembles the acinar morphology of the pancreas.
  2. Mucinous - light eosinophilic staining.

Identifying the glands

The three main glands:

  1. Parotid:
    • Serous glands - lower viscosity, acini (lobules).[2]
    • Most tumours in this gland are benign.
  2. Submandibular:
    • Serous and mucinous glands.
      • Serous ~90% of gland.
      • Mucinous ~10% of gland.
  3. Sublingual:
    • Mucinous glands.

Other:

  • Adipose tissue is found between the glands.
    • It increases with age.

Images:

Memory devices:

  • The parotid gland vaguely resembles the pancreas.
  • Submandibular = glands are mixed.

Overview

Benign tumours

Tabular form - adapted from Thompson[3]

Architecture Morphology Cell borders Cytoplasm Nucleus DDx Other Image
Pleomorphic adenoma var. mixed pop.; must include: (1) myoepithelium, (2) epithelium (ductal cells), (3) chondromyxoid stroma var. var. (1) plasmacytoid adenoid cystic c. occ. encapsulated,
mixed pop. of glandular,
myoepithelial and mesenchymal cells 		[1]
Warthin tumour papillary,
bilayer 		cuboid (basal), columnar (apical) clearly seen eosinophilic, abundant unremarkable sebaceous lymphadenoma AKA papillary cystadenoma lymphomatosum [2], [3]
Basal cell adenoma var., islands surrounded
by hyaline bands 		basaloid subtle scant,
hyperchromatic 		granular basal cell adenoca - -
Canalicular adenoma chains of cells cuboid or columnar subtle scant,
hyperchromatic 		granular basal cell adenoma exclusively oral cavity, 80% in upper lip; IHC: p63- -
Sialoblastoma var., islands surrounded
by loose fibrous stroma 		basaloid subtle scant, hyperch. granular basal cell adenoca - -

Malignant tumours

Tabular form - adapted from Thompson[4]

Architecture Morphology Cell borders Cytoplasm Nucleus DDx Other
Mucoepidermoid carcinoma cystic & solid epithelioid distinct fuffy, clear,
abundant 		nuclei sm. SCC (?) IHC: p63+
Adenoid cystic carcinoma (AdCC) pseudocysts,
cribriform, solid,
hyaline stroma 		epithelioid subtle scant,
hyperchromatic 		small
+/-"carrot-shaped" 		PLGA Stains: PAS+ (pseudocyst material), CD117+, cyclin D1+
Acinic cell adenocarcinoma (AcCC) sheets, acinar (islands) epithelioid clear granular abundant stippled, +/-occ. nucleoli ? Stains: PAS +ve, PAS-D +ve; IHC: S-100 -ve, p63 -ve
Salivary duct carcinoma glandular, cribriform columnar subtle/clear hyperchromatic columnar metastatic breast carcinoma similar to ductal
breast carcinoma; male>female
Polymorphous low-grade adenocarcinoma variable, often small
nests, may be targetoid 		epithelioid indistinct eosinophilic ovoid & small with
small nucleoli 		AdCC minor salivary gland tumour,
often in palate,
cytologically monotonous; IHC: S100+, CK+, vim.+, GFAP+/-, BCL2+/-

DDx

Palate:

  • Polymorphous low-grade adenocarcinoma.
  • Adenoid cystic carcinoma.
  • Pleomorphic adenoma.

Parotid (benign):

  • Pleomorphic adenoma.
  • Warthin tumour.

IHC overview

General:

  • Usually has limited value.

Specifics:

  • Luminal markers: CK7, CK19, CAM5.2 (LMWK).
  • Basal markers: p63, HMWK, CK14.
  • Myoepithelial markers: calponin, actin.
  • Uncommitted: S-100.

Notes:

  • p63 and S-100 are sometimes call myoepithelial.

Benign

General DDx:

  • Inflammation.
  • Neoplasm.
  • Ductal obstrution.

Chronic Sialadenitis

General

Etiology:[5]

Microscopic

Features:

  • Fibrosis.
  • Non-neoplastic mononuclear inflammatory infiltrate.

Image:

Mucocele

General

  • Benign.

Microscopic

Features:

  • Ball of mucous.

Pleomorphic adenoma

  • Abbreviated PA.

General

Features:

  • Very common - approx. 60% of parotid gland tumours.[6]
  • May transform into a malignant tumour.
    • Other benign salivary gland tumours do not do this.
  • Only benign childhood salivary gland tumour of significance.

Weinreb's dictums

  1. Most common salivary tumour in all age groups.
  2. Seen in all sites (unlike other benign tumours).
  3. Recurrence and malignancy risk (unlike other benign salivary gland tumours).
  4. Any part of a tumour that looks like PA makes it a PA.

Gross

  • May be cartilaginous appearing.

Microscopic

Features:[6]

  • Proliferation of myoepithelium and epithelium (ductal cells) in mesenchymal stroma.
    • Cells in ducts = epithelial.
    • Cells not in ducts = myoepithelial.[7]
  • Mesenchymal stroma - important feature.
    • May be any of following: myxoid, mucochondroid, hyalinized, osseous, fatty.
      • Chondroid = specific for PA; can diagnose PA without an epithelial (ductal) component if chondroid is present.
      • Myxoid = not specific for PA.

Notes:

  • Mesenchymal stroma not required for diagnosis -- if >5% ducts.[8]
    • No chondroid stroma and <5% ductal cells = myoepithelioma.
  • Complete excision is often elusive; stating "completely excised" on a surgical pathology report is unwise.
  • Look for, i.e. rule-out, poorly differentiated carcinoma: carcinoma ex pleomorphic adenoma.

Memory device: MEC = myoepithelium, epithelium, chondromyxoid stroma.

IHC

  • S-100 +ve, SMA +ve, GFAP +ve.

Basal cell adenoma

General

  • ~2% of salivary gland tumours.
  • May be multifocal.
  • Usu. parotid gland, occasionally submandibular gland.
  • Female:male = ~2:1.
  • May be seen in association with dermal cylindromas in the context of a genetic mutation.
  • Malignant transformation - rarely.

Microscopic

Features:

  • Basophilic cells.
  • Usu. nests; may be bilayered tubules or trabeculae.

Notes:

  • No chondromyxoid stroma.
    • Chondromyxoid stroma present -> pleomorphic adenoma.
  • Neoplastic cells embeded in stroma ("stromal invasion") = basal cell adenocarcinoma.
    • Basal cell adenocarcinoma may be cytologically indistinguishable from basal cell adenoma, i.e. "bad" architecture makes it a basal cell adenocarcinoma.

IHC

  • Luminal stains +ve: CK7 +ve, CAM5.2 +ve.

Canalicular adenoma

General

  • Exclusively oral cavity.
    • 80% of lesions on upper lip.

Microscopic

Features:

  • Channels - "beading of cell".
  • Mucoid/hemorrhagic stroma.

DDx:

  • Basal cell adenoma.

IHC

  • p63 -ve.
    • Basal cell adenoma p63 +ve.

Papillary cystadeoma lymphomatosum

  • AKA Warthin tumour.

General

Epidemiology:

  • May be multicentric ~ 15% of the time.
  • May be bilateral ~10% of the time.
  • Classically: male > female -- changing with more women smokers.
  • Smokers.
  • Old - usu. 60s, very rarely < 40 years old.

Notes:

  • No malignant transformation.
  • Not in submandibular gland.
  • Not in sublingual gland.
  • Not in children.

Gross

  • Motor-oil like fluid.
  • Cystic component larger in larger lesions.
    • Small lesions may be solid.

Microscopy

Features:

  • Papillae (nipple-shaped structures) with a two rows of pink (eosinophilic) epithelial cells (with cuboidal basal cells and columnar luminal cells) -- key feature.
  • Fibrous capsule - pink & homogenous on H&E stain.
  • Cystic space filled with debris in situ (not necrosis).
  • Lymphoid stroma.

Notes:

  • +/-Squamous differentiation.
  • +/-Goblet cell differentiation.

DDx:

  • Lymphoepithelial cyst.
    • Cyst within a lymph node.

Images:

Sebaceous adenoma

Microscopic

Features:

  • Benign counterpart of sebaceous carcinoma.

Oncocytoma

General

  • No risk of malignant transformation.
  • ~1% of all salivary gland tumours.
  • Typical age: 60s-80s.
  • Associated with radiation exposure.
  • Major salivary glands - usu. parotid gland.

Gross

  • Golden brown appearance.

Microscopic

Features:

  • Like oncocytomas elsewhere.
    • Eosinophilic cytoplasm (on H&E stain).
      • Due to increased number of mitochrondria.
    • Fine capillaries.

Notes:

  • May have clear cell change.
  • Multiple small incidental lesions = oncocytosis - not oncocytoma.

IHC

  • p63 +ve focally in nucleus.

Malignant

One approach:

  • Differentiate -- luminal vs. myoepithelial vs. basal (mucoepideroid).

Mucoepidermoid carcinoma

  • Abbreviated MEC.

General

  • Most common malignant neoplasm of salivary gland in all age groups.
  • Female:male ~= 3:2.
  • Site: parotid > submandibular.

Gross

  • Cystic or solid, usu. a mix of both.

Microscopic

Features:

  • Architecture:[9]
    • Cystic (low grade).
    • Solid (high grade).
  • Mucous cells with abundant fluffy cytoplasm and large mucin vacuoles - key feature.
    • Nucleus distorted by mucin vacuole.
  • Epidermoid cells:
    • Non-keratinized, polygonal squamoid cell with clear or oncocytic cytoplasm.
      • Clear cells contain glycogen (PAS +ve, PAS-D -ve).

Notes:

  • Mucin vacuoles may be rare; in a superficial glance -- it may mimic squamous cell carcinoma.
  • "Intermediate cells" are described in textbooks. Weinreb thinks they are a pretty much a myth.[10]
  • The thought of high-grade MEC should prompt consideration of squamous cell carcinoma.

Images:

Subtypes

  • Conventional.
  • Oncocytic.
    • Definition: composed of 50% oncocytes.
    • Good outcome.[11]
  • Clear cell.
  • Unicystic (cystadenocarcinoma).
    • Based on the gross. (???)
  • Sclerosing MEC +/- eosinophilia.
    • Rare.

Grading

General:

  • Two competing system exist:

Notes:

  • Both systems have their pros and cons.
  • Weinreb uses the AFIP system with a slight modification.
AFIP
  1. Low cystic content <20%) - 2 points.
  2. Perineural invasion - 2 points.
  3. Necrosis - 3 points.
  4. Mitoses > 4 per 10 HPFs (HPF not defined in paper - see HPFitis) - 3 points.
  5. Anaplasia - 4 points.

Scoring:

  • Low grade = 0-4 points.
  • Intermediate grade = 5-6 points.
  • High grade = 7+ points.
Weinreb modification

Weinreb looks for the following:

  • Tumour invades in small nests/islands - 2 points.
    • If applicable, the two points are added to the AFIP score.
    • The tumour is graded using the AFIP (scoring) cut points -- see above.

Stains

Mucous cells:

  • Alcian blue +ve.
  • Mucicarcmine +ve.

Molecular

  • t(11;19)(q21;p13) -- MECT1-MAML2 fusion.[14][15]
    • Present in ~65% of MECs.
    • Presence assoc. with low-grade MEC (vs. high-grade MEC) & favourable prognosis.
    • Not seen in tumours that are in the DDx of MEC.

Acinic cell adenocarcinoma

  • Abbreviated AcCC.

General

  • Malignant neoplasm of salivary gland arising from acinic cells.
  • The relative prevalence of the neoplasm in the various salivary gland reflects the abundance of acinic cells: parotid gland (~80%) > minor salivary glands (~17%) > submandibular glands (~3%).
  • Affects wide age range -- including children.
  • Site affect prognosis (most aggressive to least aggressive): submandibular > parotid > minor salivary.

Gross

  • Tan or reddish.

Microscopic

Features:

  • Sheets of acinic cells with:
    • Abundant cytoplasm.
    • Small nuclei stippled chromatin.
  • Scattered intercalcated duct type cells with:
    • Eosinophilic cytoplasm with moderate amount of cytoplasm.
    • Bland nuclei with slightly larger than seen in acinic cells.
  • +/-Peri-tumoural lymphocytes.

Notes:

  • Adipose tissue -- present in the salivary glands -- is absent in AcCC.
  • May focally resemble thyroid tissue.
  • Smaller (characteristic) microvacuoles (unreported in the literature) may be present that have a bubbly appearance and glassy basophilic inclusions.[16]

Memory device:

  • AcCC - lots of "C"s - chromatin stipled, cytoplasm generous.

Images:

Grading

General:

  • Not prognostic.
  • Done to avoid phone calls from clinician.

Factors Weinreb uses:[17]

  • Necrosis.
  • Nuclear atypia.
  • Perineural invasion.
  • Mitoses.
  • Infiltrative margin.
  • Tumour sclerosis.

Subtypes

  • Oncocytic variant - rare.
  • Clear cell variant - rare.
  • Papillary cystic variant.

Stains/IHC

  • PAS +ve.
  • PAS-D +ve.
  • S-100 -ve.
  • p63 -ve.
    • p63 +ve in mucoepidermoid carcinoma.

There are a bunch of other stains that are touted to be useful (amylase, anti-chymotrypsin, lactoferrin); Weinreb thinks they are not helpful.[18]

Adenoid cystic carcinoma

General

  • Common malignant neoplasm of salivary gland.
  • AKA cylindroma.[19]
    • Should not be confused with dermal cylindroma (a benign skin tumour).
  • Composed of ductal cells and myoepithelial cells; myoepithelial cells > ductal cells.

Microscopic

Features:

  • Cribriform architecture (classic).
    • Others: solid, cords, (bilayered) tubules.
    • Cystic spaces filled with eosinophilic material (that is PAS +ve).[20]
  • Scant cytoplasm - eosinophilic to clear.
  • Nucleus - "bland" (small).
    • May be angulated (carrot-shaped).
  • Hyaline stroma.

Images: Adenoid cystic carcinoma - Mod. Pathol.

Memory device:

  • AdCC - mostly DNA (scant cytoplasm), distinct nucleus (carrot-shaped).

Notes:

Grading

Based on solid component:

  • Low grade = tubules and cribriform structures only; no solid component.
  • Intermediate grade = solid component <30%.
  • High grade = solid component >=30%

Stains

Special stains:

  • PAS +ve material - cystic spaces.[20]

IHC:[21]

  • CD117 +ve.
  • Cyclin D1 +ve.
  • Myoepithelial markers (e.g. calponin, actin) +ve.
    • Typically -ve in PLGA.

Salivary duct carcinoma

General

  • Malignant counterpart of salivary duct adenoma.
  • Male:female ~= 4:1.
  • Typically >50 years old.
  • Mostly in the parotid.

Microscopic

Features:

  • Architecture: sheets, nests, cords, cribriform, micropapillary.
  • Neoplastic cells line-up around cystic spaces "Roman bridges".
  • Nuclear atypia (variation in size, shape, staining).
  • Apocrine snouts - pseudopod-like/lollipop-like undulations of the cell membrane.
  • Decapitation secretions - apocrine snouts (membrane bound blobs of cytoplasm) that have separated from its mother cell.

Image:

Notes:

  • Similar to ductal breast carcinoma - key to remember.

Subtypes

  • Conventional.
  • Mucinous - worse prognosis; opposite of what would one expect from the outcomes in breast cancer.
  • Micropapillary - assoc. with a poor prognosis.
  • Sarcomatoid/spindle cell.

IHC

  • LMWK, EMA, CK7, CK19 +ve.
  • p63 -ve.
  • Androgen receptor +ve.
  • BRST2 (GCDFP-15) +ve.
  • HER2 +ve ~21%; use of trastuzumab (Herceptin) not systematically studied.

Curiosity:

  • PSA +/-.
  • PSAP +/-.

Polymorphous low-grade adenocarcinoma

  • Abbreviated PLGA.

General

  • Almost exclusively in the oral cavity.
    • Classically found in the palate -- 60% of PLGAs in palate.
  • Tumour of the minor salivary glands.
  • Always a low-grade tumour - by definition.
  • Female:male ~= 2:1.
  • Older people ~50-70 years old.

Microscopy

Features:

  • Cytologically monotonous (uniform) with variable architecture - key feature.
    • Architecture: often small nests, may be targetoid.
  • Nucleus: ovoid & small with small nucleoli.
  • Indistinct cell borders.
  • Eosinophilic cytoplasm.

DDx:

  • Adenoid cystic carcinoma.
  • Pleomorphic adenoma.

Images:

IHC

  • S100 +ve, CK +ve, vimentin +ve.
  • GFAP +ve/-ve.
  • BCL2 +ve/-ve.
  • Generally negative for myoepithelial markers (calponin, actin) - useful if negative.

Carcinoma ex pleomorphic adenoma

  • Abbreviated Ca ex PA.

General

Definition:

  • Malignant transformation of a pleomorphic adenoma.

Diagnosis (either 1 or 2):

  1. History of a pleomorphic adenoma at the same site.
  2. Features of a pleomorphic adenoma and a carcinoma.

Epidemiology:

  • Rare.

Microscopy

Features:

  • Cells with cytologic features of malignancy.
  • Architecture (any of the following):
    • Glands.
    • Nests.
    • Single cells (may be subtle).

Architectural patterns:

  • Ductal carcinoma NOS (arising from ductal cells) - most common pattern for Ca ex PA.
  • Myoepithelial cacinoma NOS (arising from myoepithelial cells).
  • "Named carcinoma":
    • Salivary duct carcinoma - second most common pattern for Ca ex PA.
    • Mucoepidermoid carcinoma.
    • Adenoid cystic carcinoma.

Note:

  • Often adenocarcinoma-like.
  • Myoepithelial cells may be clear cells. (???)

Subclassification

  1. Non-invasive AKA intracapsular AKA in situ.
  2. Minimally invasive <1.5 mm beyond the capsule.
  3. Widely invasive >=1.5 mm beyond the capsule.

Epithelial-myoepithelial carcinoma

  • Abbreviated EMCa.

General

  • Rare.
  • Female:male = 2:1.
  • Usu. old 50-60s.
  • Usu. parotid gland.
  • Prognosis: usu. good.

Microscopic

Features:

  • Biphasic tumour:
    1. Epithelial layer.
    2. Myoepithelial layer - key feature.
  • Architecture: variable (solid, cystic, tubular, papillary).
  • +/-Spindle cells.
  • Basement membrane-like material; may mimic adenoid cystic carcinoma.

DDx:

  • Adenoid cystic carcinoma.
  • Pleomorphic adenoma.

Notes:

  • Usu. few mitoses.

Images:

Sebaceous carcinoma

  • Arises from sebaceous glands
  • Sebaceous glands are serous glands and clear on H&E.
  • Uncommon. (???)

See also

References

  1. ↑ http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Oral/oral.htm#LABSALIVA
  2. ↑ http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Epithelia/Epithel.htm
  3. ↑ Thompson, Lester D. R. (2006). Head and Neck Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 295-319. ISBN 978-0443069604.
  4. ↑ Thompson, Lester D. R. (2006). Head and Neck Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 325-357. ISBN 978-0443069604.
  5. ↑ URL: http://emedicine.medscape.com/article/882358-overviewhttp://emedicine.medscape.com/article/882358-overview. Accessed on: 10 January 2011.
  6. ↑ 6.0 6.1 Thompson, Lester D. R. (2006). Head and Neck Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 295. ISBN 978-0443069604.
  7. ↑ IW. 10 January 2011.
  8. ↑ IW. 10 January 2011.
  9. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/D2A001-PQ01-M.htm. Accessed on: 19 October 2010.
  10. ↑ IW. 10 January 2011.
  11. ↑ Weinreb I, Seethala RR, Perez-Ordoñez B, Chetty R, Hoschar AP, Hunt JL (March 2009). "Oncocytic mucoepidermoid carcinoma: clinicopathologic description in a series of 12 cases". Am. J. Surg. Pathol. 33 (3): 409–16. doi:10.1097/PAS.0b013e318184b36d. PMID 18971778.
  12. ↑ Goode RK, Auclair PL, Ellis GL (April 1998). "Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria". Cancer 82 (7): 1217–24. PMID 9529011.
  13. ↑ Brandwein MS, Ivanov K, Wallace DI, et al. (July 2001). "Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading". Am. J. Surg. Pathol. 25 (7): 835–45. PMID 11420454.
  14. ↑ Tonon G, Modi S, Wu L, et al. (February 2003). "t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway". Nat. Genet. 33 (2): 208–13. doi:10.1038/ng1083. PMID 12539049.
  15. ↑ Seethala RR, Dacic S, Cieply K, Kelly LM, Nikiforova MN (August 2010). "A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas". Am. J. Surg. Pathol. 34 (8): 1106–21. doi:10.1097/PAS.0b013e3181de3021. PMID 20588178.
  16. ↑ IW. 11 January 2011.
  17. ↑ IW. 11 January 2011.
  18. ↑ IW. 11 January 2011.
  19. ↑ Chest. May 1957. Vol. 31. No. 5. PP. 493-511. http://www.chestjournal.org/content/31/5/493.abstract
  20. ↑ 20.0 20.1 URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970070-5. Accessed on: 12 May 2011.
  21. ↑ Sequeiros-Santiago, G.; García-Carracedo, D.; Fresno, MF.; Suarez, C.; Rodrigo, JP.; Gonzalez, MV. (May 2009). "Oncogene amplification pattern in adenoid cystic carcinoma of the salivary glands.". Oncol Rep 21 (5): 1215-22. PMID 19360297.
  22. ↑ [http://www.pathologyimagesinc.com/sgt-cytopath/epith-myoepith-ca/cytopathology/fs-emc-cytopath-feat.html "Cytopathologic Features of Epithelial-myoepithelial Carcinoma"]. http://www.pathologyimagesinc.com/sgt-cytopath/epith-myoepith-ca/cytopathology/fs-emc-cytopath-feat.html. Retrieved January 18, 2011.
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