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 salivary glands

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.
    • Serous demilunes = mucinous gland with "cap" consisting of a serous glandular component.
  1. 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[5]

Entity 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 carcinoma occ. encapsulated,
mixed pop. of glandular,
myoepithelial and mesenchymal cells
 
PA. (WP)
Warthin tumour papillary,
bilayer
cuboid (basal), columnar (apical) clearly seen eosinophilic, abundant unremarkable sebaceous lymphadenoma AKA papillary cystadenoma lymphomatosum
 
PCL. (WP/Nephron)
Basal cell adenoma var., islands surrounded
by hyaline bands, lesion encapsulated
basaloid subtle scant,
hyperchromatic
granular basal cell adenocarcinoma - -
Canalicular adenoma chains of cells cuboid or columnar subtle scant,
hyperchromatic
granular basal cell adenoma exclusively oral cavity, 80% in upper lip; IHC: p63- (webpathology.com), (webpathology.com)
Sialoblastoma var., islands surrounded
by loose fibrous stroma
basaloid subtle scant, hyperch. granular basal cell adenocarcinoma - -

Malignant tumours

Tabular form - adapted from Thompson[6]

Entity Architecture Morphology Cell borders Cytoplasm Nucleus DDx Other Image
Mucoepidermoid carcinoma cystic & solid epithelioid distinct fuffy, clear,
abundant
nuclei sm. SCC (?) IHC: p63+
 
MEC. (WC)
Adenoid cystic carcinoma (AdCC) pseudocysts,
cribriform, solid,
hyaline stroma
epithelioid subtle scant,
hyperchromatic
small
+/-"carrot-shaped"
pleomorphic adenoma, PLGA Stains: PAS+ (pseudocyst material), CD117+, cyclin D1+
 
AdCC. (WC/Nephron)
Acinic cell carcinoma (AcCC) sheets, acinar (islands) epithelioid clear granular abundant stippled, +/-occ. nucleoli adenocarcinoma not otherwise specified, oncocytoma of salivary gland Stains: PAS +ve, PAS-D +ve; IHC: S-100 -ve, p63 -ve
 
AcCC. (WC/Nephron)
Salivary duct carcinoma glandular, cribriform columnar subtle/clear hyperchromatic columnar metastatic breast carcinoma similar to ductal
breast carcinoma; male>female
 
SDC. (WC/Nephron)
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+/-
 
PLGA. (WC/Nephron)
Epithelial-myoepithelial carcinoma nests (myoepithelial) with tubules (epithelial) epithelioid not distinct eosinophilic cytoplasm; epithelial: scant; myoepithelial: moderate focal clearing AdCC, pleomorphic adenoma rare
 
EMCa. (WC/Nephron)
Basal cell adenocarcinoma var., islands surrounded
by hyaline bands, lesion not encapsulated
basaloid subtle scant,
hyperchromatic
granular basal cell adenoma rare, usu. parotid gland, may arise from a basal cell adenoma
 
BCA. (WC/Nephron)

DDx

Palate

Benign parotid tumours

Oncocytic tumours

Clear cell tumours

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:[7]

Microscopic

Features:

  • +/-Fibrosis.
  • Non-neoplastic mononuclear inflammatory infiltrate (lymphocytes, plasma cells).

Note:

  • If the infiltrate is predominantly lymphocytes Sjögren's is a possibility, and reporting a Focus score should be considered.

DDx:

Image

Salivary gland mucocele

General

  • Benign.
  • Infected mucocele = mucopyocele.

Microscopic

Features:[9]

  • Granulation tissue-like and pseudocyst-like.
    • Granulation tissue-like:
      • Fibroblasts.
      • Small caliber blood vessels.
      • Histocytes.
      • Neutrophils.
    • Pseudocyst:
      • No epithelial lining.
      • Poorly circumscribed.
  • Pale pink extracellular material (mucous) - key feature.
  • +/-Granulomas.[10]

DDx:

Images

www:

Pleomorphic adenoma

  • Abbreviated PA.

General

Features:

  • Very common - approx. 60% of parotid gland tumours.[11]
  • 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.

Image:

Microscopic

Features:[11]

  • Proliferation of myoepithelium and epithelium (ductal cells) in mesenchymal stroma.
    • Cells in ducts = epithelial.
    • Cells not in ducts = myoepithelial.[12]
  • 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.[12]
  • 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.

DDx:

Images

www:

IHC

  • S-100 +ve, SMA +ve, GFAP +ve.

Myoepithelioma

General

  • Usually benign.
    • May be malignant.

Location:[13]

  • Parotid gland ~50%.
  • Palate ~25%
  • Submandibular gland ~12%.

Notes:

  • First described in 1972.[14]

Microsopic

Features:[15]

  • Myoepithelial cells - may be:
    • Spindled.
    • Plasmacytoid.
    • Epithelioid.
    • Clear (rare).
  • Lack tubules, i.e. epithelial component.
    • May be up to 10% (or 5%[16]).

DDx:

Images

IHC

Features:[15]

  • S100 +ve.
  • GFAP +ve.
  • CK14 +ve.

Others:[17]

  • SMA +ve.
  • Calponin +ve.

Basal cell adenoma

General

  • ~2% of salivary gland tumours.
  • May be multifocal.
  • Usually parotid gland, occasionally submandibular gland.
  • Female:male = ~2:1.
  • May be seen in association with dermal cylindromas in the context of a genetic mutation.[18]
  • Malignant transformation - rarely.

Microscopic

Features:

  1. Basal component.
    • Basophilic cells - key feature.
    • Usu. in nests.
    • Large basophilic nucleus.
    • Minimal-to-moderate eosinophilic cytoplasm.
  2. Stromal cells.
    • Plump spindle cells without significant nuclear atypia - distinguishing feature.
      • Stromal cell nuclei width ~= diameter RBC.
    • Dense hyaline stroma.
  3. Tubular component.
    • Within basal component, may be minimal.
  4. Lesion is encapsulated - key feature.

Notes:

  • No chondromyxoid stroma.
  • Neoplastic cells embedded 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.

DDx:

Images:

IHC

  • Luminal stains +ve: CK7 +ve, CAM5.2 +ve.
  • p63 +ve -- basal component.
  • S100 +ve -- spindle cells in the stroma.

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.

Images:

IHC

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

Warthin tumour

Sebaceous adenoma

Sebaceous lymphadenoma

General

  • Rare salivary gland tumour.[20]
  • Benign.

Microscopic

Features:[20]

  • Sebaceous glands within lymphoid tissue - key feature.

DDx:[21]

Images

www:

Oncocytoma of the salivary gland

  • AKA salivary gland oncocytoma.

General

  • No risk of malignant transformation.
  • ~1% of all salivary gland tumours.
  • Typical age: 60s-80s.
  • Associated with radiation exposure.
  • Major salivary glands - usually parotid gland.[22]

Gross

  • Golden brown appearance.

Image

Microscopic

Features:

  • Like oncocytomas elsewhere.
    • Eosinophilic cytoplasm (on H&E stain).
      • Due to increased number of mitochrondria.
    • Fine capillaries.
  • Architecture: solid sheets, trabeculae or duct-like structure.[22]

Notes:

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

DDx:

Images

www:

IHC

  • p63 +ve[23] 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.[24]
  • Female:male ~= 3:2.
  • Site: parotid > submandibular.

Gross

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

Microscopic

Features:

  • Architecture:[25]
    • Cystic (low grade).
    • Solid (high grade).
  • Mucous cells with abundant fluffy cytoplasm and large mucin vacuoles - key feature.
    • Nucleus distorted by mucin vacuole.
    • Mucous cell may be scarce - more difficult to diagnose.
  • Epidermoid cells:
    • Non-keratinized, polygonal squamoid cell with clear or oncocytic cytoplasm.
      • Clear cells contain glycogen (PAS +ve, PAS-D -ve).

Notes:

  • The classic description - composed of 3 cell types: epidermoid, intermediate, and mucin producing.[26]
    • "Intermediate cells" are described in textbooks. Weinreb thinks they are a pretty much a myth.[12]
  • Mucin vacuoles may be rare; in a superficial glance -- it may mimic squamous cell carcinoma.
  • The thought of high-grade MEC should prompt consideration of squamous cell carcinoma.

Images

www:

Subtypes

  • Conventional.
  • Oncocytic.
    • Definition: composed of 50% oncocytes.
    • Good outcome.[27]
  • 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.

Notes:

  • It seems pointless to memorize this but it is occasionally asked on exams.
    • How to remember: think of the Nottingham grading system (architecture, mitoses, nuclear grade) + necrosis + LVI.

Stains

Mucous cells:

  • Alcian blue +ve.
  • Mucicarcmine +ve.

Molecular

  • t(11;19)(q21;p13) -- MECT1-MAML2 fusion.[30][31]
    • 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 carcinoma

Not to be confused with pancreatic acinar cell carcinoma.
  • Abbreviated AcCC.
  • AKA acinic cell adenocarcinoma.

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 finely vacuolated cytoplasm with basophilic granules - key feature.
      • Granules may be focal.
    • 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.
  • +/-Glassy extracellular bluish/purple blobs.

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.[12]

Memory device:

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

DDx:

Images

www:

Grading

General:

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

Factors Weinreb uses:[12]

Subtypes

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

Stains

  • PAS +ve.
  • PAS-D +ve.

IHC

  • 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 these are not helpful.[12]

EM

Adenoid cystic carcinoma

See: Adenoid cystic carcinoma of the breast for the breast tumour.

General

  • Common malignant neoplasm of salivary gland.
  • AKA cylindroma.[34]
  • Composed of ductal cells and myoepithelial cells; myoepithelial cells > ductal cells.

Microscopic

Features:

  • Cribriform architecture or pseudoglandular spaces (classic pattern) - important feature.
    • Other patterns: solid, cords, (bilayered) tubules.
    • Cystic spaces filled with basophilic material (that is PAS +ve) - key feature.
  • Scant cytoplasm in most cells (myoepithelial cells) - clear/eosinophilic.
    • Moderate eosinophilic cytoplasm in the (rare) ductal cells.
  • Nucleus - small.
    • May be angulated (carrot-shaped) - myoepithelial cells; round/ovoid in ductal cells.
  • Hyaline stroma.

Memory device:

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

Notes:

DDx:

Images

www:

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.[35]

IHC

Features:[36]

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

Molecular

Features:[37]

  • t(6;9) MYB-NFIB.
    • Seen in ~50% of cases.
    • Worse prognosis if present, esp. if fusion assoc. with transcription.

Salivary duct carcinoma

General

  • Malignant counterpart of salivary duct adenoma.
  • Male:female ~= 4:1.
  • Dismal prognosis.[38]
  • Typically >50 years old.
  • Mostly in the parotid.

Microscopic

Features - resembles ductal breast carcinoma:[38]

  • 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.

Notes:

  • Similar to ductal breast carcinoma - key to remember.

DDx:

Images

www:

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 +/-.
  • ER-beta +ve.[39]
  • ER-alpha -ve (the common ER stain).

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.

Microscopic

Features:[40]

  • Architecture: often small nests, may be targetoid.
    • Classically has whorling with eye-of-storm & single file.
  • Cytologically monotonous (uniform) with variable architecture - key feature.
  • Indistinct cell borders.

DDx:

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:

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.

Microscopic

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

Extent of invasion:[42]

  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 ~1% of salivary gland tumours.[43]
  • Female:male = 1.5:1.[44]
  • Usu. older people - 50s or 60s.
  • Usu. parotid gland ~ 60% of cases.[44]
  • Prognosis: usually good; 5-year and 10-year survival over 90% and 80% respectively.[44]

Notes:

Microscopic

Features:

  • Biphasic tumour:[44]
    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.

Notes:

  • Usually few mitoses.

DDx:

Images

www:

IHC

  • CAM5.2 +ve -- epithelial component.
  • p63 +ve -- myoepithelial component.

Basal cell adenocarcinoma

  • Abbreviated BCAC.

General

Gross

  • Usually in the parotid gland ~90% of cases.[47]

Microscopic

Features:

  1. Lesion is not encapsulated - key feature.
  2. Basal-like cells:
    • Basophilic cells - key feature.
    • Usually in nests.
    • Large basophilic nucleus.
    • Minimal-to-moderate eosinophilic cytoplasm.
  3. Stromal cells.
    • Plump spindle cells without significant nuclear atypia.
      • Stromal cell nuclei width ~= diameter RBC.
    • Dense hyaline stroma.
  4. Tubular component.
    • Within basal component, may be minimal.

DDx:

Images

www:

IHC

Features:[48]

  • CK7 +ve (strong).
  • S100 +ve/-ve.

Sebaceous carcinoma

It is similar to the tumour found in the skin.

Hyalinizing clear cell carcinoma

  • Abbreviated HCCC.

General

  • Rare.
  • Good prognosis.[49]
  • Typically palate or tongue.[50]

Microscopic

Features:[51]

  • Groups of cells with abundant clear cytoplasm.
  • Hyalinized stroma.

Notes:

  • Clear cytoplasm due to glycogen.[52]
  • Low mitotic rate.

DDx:

Images

www:

Stains/IHC

  • PAS +ve.
  • AE1/AE3 +ve.
  • EMA +ve.[52]

Others:

Molecular

Recurrent translocation:[53]

See also

References

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  7. URL: http://emedicine.medscape.com/article/882358-overviewhttp://emedicine.medscape.com/article/882358-overview. Accessed on: 10 January 2011.
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  10. Seifert, G.; Donath, K.; von Gumberz, C. (Jun 1981). "[Mucoceles of the minor salivary glands. Extravasation mucoceles (mucus granulomas) and retention mucoceles (mucus retention cysts) (author's transl)].". HNO 29 (6): 179-91. PMID 7251405.
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  12. 12.0 12.1 12.2 12.3 12.4 12.5 IW. 10 January 2011. Cite error: Invalid <ref> tag; name "IW_10jan2011" defined multiple times with different content Cite error: Invalid <ref> tag; name "IW_10jan2011" defined multiple times with different content Cite error: Invalid <ref> tag; name "IW_10jan2011" defined multiple times with different content
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  14. Saksela, E.; Tarkkanen, J.; Wartiovaara, J. (Sep 1972). "Parotid clear-cell adenoma of possible myoepithelial origin.". Cancer 30 (3): 742-8. PMID 5075358.
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  17. Tadrous, Paul.J. Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum (1st ed.). Wiley. pp. 18. ISBN 978-0470519035.
  18. Choi, HR.; Batsakis, JG.; Callender, DL.; Prieto, VG.; Luna, MA.; El-Naggar, AK. (Jun 2002). "Molecular analysis of chromosome 16q regions in dermal analogue tumors of salivary glands: a genetic link to dermal cylindroma?". Am J Surg Pathol 26 (6): 778-83. PMID 12023583.
  19. URL: http://moon.ouhsc.edu/kfung/jty1/Com/Com304-3-Diss.htm. Accessed on: 25 October 2011.
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