Thyroid & parathyroid

Other uncommon thyroid carcinomas

Secretory carcinoma

Last author update: 1 November 2016
Last staff update: 6 April 2023

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PubMed search: mammary analog secretory carcinoma thyroid

See also: Secretory carcinoma of salivary glands, Secretory carcinoma of breast

Andrey Bychkov, M.D., Ph.D.
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Cite this page: Bychkov A. Secretory carcinoma. website. Accessed February 22nd, 2024.
Definition / general
  • Rare salivary gland type tumor arising in thyroid
  • First described by Stevens et al. in 2015 (Mod Pathol 2015;28:1084)
Essential features
  • Recently described rare cancer, originally reported in salivary glands, which is associated with ETV6-NTRK3 translocation
  • Highly reminiscent of papillary thyroid carcinoma with oncocytic features, can be suspected by the presence of microcystic / cribriform pattern
  • Important to differentiate from thyroid cancer because of likely aggressive course and ineffectiveness of radioactive iodine / RAI therapy
  • Diagnosis: Mammaglobin+, Thyroglobulin-, TTF1-; also confirmed by molecular testing
  • MASC: mammary analog / analogue secretory carcinoma
  • MASC was originally described in salivary glands, and shares the same histology, immunophenotype and molecular background as secretory carcinoma of breast (Am J Surg Pathol 2010;34:599)
  • Reported in major salivary glands (parotid > submandibular), occasionally in other head / neck locations (lip, palate and thyroid), also in skin
Pathophysiology / etiology
  • Origin is debated (Head Neck Pathol 2016 Jul 11 [Epub ahead of print], Mod Pathol 2016;29:985):
    • Primary thyroid tumor from ectopic salivary gland remnants, intra- or perithyroidal
    • Metastatic from occult primary (salivary glands, breast)
    • May have the same origin with papillary thyroid cancer, some MASCs coexist with PTC and share molecular aberrations
  • Initiating molecular event is a chromosomal translocation t(12;15)(p12;q25) resulting in the ETV6-NTRK3 gene fusion
  • Chimeric protein is a constitutively active protein tyrosine kinase with transformation activity
  • ETV6-NTRK3 fusion is found in several malignancies other than MASC, e.g., secretory carcinoma of the breast, congenital fibrosarcoma, cellular or mixed mesoblastic nephroma, myeloid leukemias and papillary thyroid carcinoma (2% sporadic, 14% radiation induced) (Head Neck Pathol 2016;10:405)
Diagrams / tables

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ETV6-NTRK3 fusion

Clinical features
  • Invasive / locally aggressive growth with nodal metastasis, 2 out of 7 reported cases were disseminated and fatal (in contrast to the indolent MASC of salivary gland)
  • Frequent recurrences
  • On histopathology, confirmed by IHC and molecular testing
  • Occult primary (breast, salivary glands) should be considered
  • Recurrence after total thyroidectomy produce no elevated serum thyroglobulin
Radiology description
  • Non RAI avid, both primary tumor and relapses / metastases
Prognostic factors
  • Probably more aggressive than follicular derived, well differentiated thyroid tumors
Case reports
  • Surgical excision, usually total thyroidectomy with lymph node dissection
  • Does not respond to RAI (Head Neck Pathol 2016;10;405)
  • ETV6-NTRK3 is a "druggable" fusion, Trk inhibitors are currently used for MASC patients in clinical trials (Mod Pathol 2016;29:985)
Gross description
Microscopic (histologic) description
  • Invasive growth with multiple nodules in fibrotic stroma
  • Complex architecture with microcystic / cribriform, solid, trabecular, tubular and papillary growth patterns
  • Polygonal eosinophilic cells with vacuolated cytoplasm:
    • Prominent single centrally placed nucleolus
    • Abundant nuclear grooves (in all architectural patterns), rare pseudoinclusions
    • Focal vesicular nuclei with chromatin clearing
    • Sometimes apocrine-like capitations
    • Cellular atypia is mild to focally moderate, rarely may have high grade features (increased mitoses and necrosis)
  • Intraluminar (sometimes intracytoplasmic) colloid-like mucin secretions, from slightly pink watery to purple dense
  • Stroma:
    • Extensive fibrosis
    • Few psammoma bodies
    • Lymphoplasmacytic infiltrate and chronic lymphocytic thyroiditis in adjacent thyroid tissue
  • Minor papillary thyroid carcinoma component can exist, either classic or follicular variant (Mod Pathol 2016;29:985)
Microscopic (histologic) images

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Cytology description
  • Hypercellular smear with sheets, caps, blunted papillary structures without fibrovascular cores ("tentacular nubbins") and loss of polarity (Diagn Cytopathol 2017;45:45)
  • Round to oval nuclei with prominent grooves, vesicular to powdery chromatin, single central nucleoli and rare nuclear pseudoinclusions
  • Abundant granular cytoplasm with vacuolation
  • No increased colloid
Positive stains
Negative stains
Electron microscopy description
  • Large number of secretory granules with extrusion into the intercellular spaces, well developed endoplasmic reticulum, lipid laden vacuoles and well formed microvilli (Int J Surg Pathol 2017;25:127)
Molecular / cytogenetics description
  • FISH (on paraffin sections) to detect chromosome translocation t(12;15)(p12;q25)
  • RT-PCR or NGS (RNA template) to detect ETV6-NTRK3 gene fusion
Molecular / cytogenetics images

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FISH (separate signals)

Differential diagnosis
  • Both histology and cytology closely mimics papillary thyroid cancer
  • Oncocytic PTC:
    • Histology rarely shows unusual patterns (cribriform / microcystic), no intracytoplasmic secretions and capitation
    • Absence of tentacular nubbins in smears
    • Immunophenotype is inconsistent with MASC, IHC panel with mammaglobin and Tg / TTF1 can be used on surgical samples and FNA (cell block)
  • Poorly differentiated thyroid carcinoma: high grade features like mitoses and necrosis, TTF1+ / Tg+ (evident or residual)
  • Metastasis from salivary MASC and secretory carcinoma of breast should be excluded clinically (history, imaging)
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