Salivary glands

Primary salivary gland neoplasms

Malignant

Hyalinizing clear cell carcinoma



Last author update: 27 October 2022
Last staff update: 27 October 2022

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PubMed Search: Hyalinizing clear cell carcinoma

See Also: Mandible / maxilla: Clear cell carcinoma of salivary gland

Kim A. Ely, M.D.
Page views in 2021: 5,339
Page views in 2022 to date: 5,433
Cite this page: Ely KA. Hyalinizing clear cell carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/salivaryglandsclearcellcarcinoma.html. Accessed December 1st, 2022.
Definition / general
  • Unique malignancy commonly arising in minor salivary glands, usually intraoral
  • Molecularly defined by expression of EWSR1::ATF1 fusion oncogene or related fusion variants
  • Low grade salivary gland tumor composed of bland monomorphic tumor cells with clear to eosinophilic cytoplasm, arranged in nests, trabeculae and cords in a hyalinized stoma
Essential features
  • Rare salivary gland neoplasm
  • Most commonly involves intraoral minor salivary glands (> 80%)
  • 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma, is virtually pathognomonic
  • Molecularly defined by presence of EWSR1 fusion (ATF1 most common partner)
  • Low grade with few nodal and distant metastases
Terminology
  • Clear cell carcinoma (2017 WHO)
  • Clear cell adenocarcinoma (2008 AFIP )
  • Clear cell carcinoma, not otherwise specified (2005 WHO)
ICD coding
  • ICD-9: 142.9 - malignant neoplasm of salivary gland, unspecified
  • ICD-10: C08.9 - malignant neoplasm of major salivary gland, unspecified
Epidemiology
Sites
Etiology
Clinical features
  • Submucosal swelling that may ulcerate
  • Many are found on routine dental exam
  • Majority endorse a short history prior to medical attention (Head Neck Pathol 2013;7:S20)
Diagnosis
  • Definitive diagnosis may be difficult on histology alone due to its wide range of appearance and both morphologic and immunohistologic overlap with other entities in the differential; thus, FISH analysis for ESWR rearrangements is often necessary
Radiology description
Radiology images

Contributed by Tony Ng, M.D., Ph.D.
CT scan

CT scan



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Echo, CT, MRI

Prognostic factors
Case reports
Treatment
Clinical images

Contributed by Pallavi Parashar, D.D.S.

Submucosal mass



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Buccal mass

Gross description
Gross images

Contributed by Erin Chapman, M.D
https://www.pathologyoutlines.com/imgau/salivaryglandsclearcellcarcinomaGrossChapman1.jpg

Well demarcated mass

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Pooja Navale, M.D. (Case #483), Tony Ng, M.D., Ph.D. and Erin Chapman, M.D
Circumscribed lesion Circumscribed lesion

Circumscribed lesion

Cord-like to trabecular architecture

Cord-like to trabecular architecture

Hyalinzied stroma

Hyalinzied stroma

Anastomosing nests

Anastomosing nests


Monotonous cells

Monotonous cells

Clear to eosinophilic cytoplasm

Clear to eosinophilic cytoplasm

Bland nuclei

Bland nuclei

Centrally placed nuclei

Centrally placed nuclei

Inconspicuous nucleoli

Inconspicuous nucleoli


Soft palate mass

Soft palate mass

Clear cell proliferation

Clear cell proliferation

Base of tongue mass

Base of tongue mass

Clear cell and columnar phenotype

Clear cell and columnar phenotype

Buccal mass

Buccal mass


Nests and cords of clear cells

Nests and cords of clear cells

Submucosal tissue

Submucosal tissue

Posterior maxilla submucosal tumor

Posterior maxilla submucosal tumor

Islands and cords of tumor cells

Islands and cords of tumor cells

p40

p40

PASD

PASD

Cytology description
  • Cohesive clusters of monotonous epithelial cells with abundant clear cytoplasm, uniform round to oval nuclei, granular chromatin, small nucleoli, nuclear grooves and intranuclear cytoplasmic inclusions
  • Naked nuclei
  • Prominent tigroid background (Liu stain) (Diagn Cytopathol 2016;44:338)
  • Lacks myoepithelial cells (Diagn Cytopathol 2000;23:333)
Positive stains
Negative stains
Electron microscopy description
Molecular / cytogenetics description
Sample pathology report
  • Oropharynx, right base of tongue, complete excision:
    • Hyalinizing clear cell carcinoma (see comment)
    • Comment: The carcinoma is composed of cells with abundant clear to variably eosinophilic cytoplasm, which are arranged in long cords, interconnecting trabeculae and nests. Nuclei are centrally placed with inconspicuous nucleoli. The background is remarkable for a myxoid appearing stroma that is sharply demarcated from a hyalinized basement membrane-like material. There is no evidence of necrosis or perineural invasion. Immunohistochemical stains were performed with the following results: cytokeratin and p40 positive; S100, SMA and calponin negative.
Differential diagnosis
Board review style question #1

A mass from the soft palate of a 54 year old woman is resected. A representative image of the tumor is shown above. Which of the following statements is true regarding this entity?

  1. By definition, it does not contain mucin, making it distinct from mucoepidermoid carcinoma
  2. Microscopically, these are characterized by 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid; this finding is virtually pathognomonic
  3. Most behave in an aggressive fashion
  4. These carcinomas should be graded according to the 3 tiered system described by Milchgrub
  5. While it can arise from the minor salivary glands, the majority occur in the parotid
Board review style answer #1
B. Microscopically, these are characterized by 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid; this finding is virtually pathognomonic. Most cases of hyalinizing clear cell carcinoma (HCCC) arise from the intraoral minor salivary glands, commonly those of the base of tongue and soft palate. A minority occur in the major salivary glands. Mucinous differentiation can be seen in up to 50% of cases, ranging from focal dot-like to diffuse. This can make the distinction from mucoepidermoid carcinoma challenging. There is no formal grading system for HCCC (Milchgrub first described HCCC, however). While most tumors are low grade, there are a few cases in the literature with high grade transformation. Finally, HCCC is characterized microscopically by cells with abundant clear to variably eosinophilic cytoplasm, which are arranged in long cords, interconnecting trabeculae and nests. The background is remarkable for 2 stroma types: dense hypocellular hyalinized tissue, juxtaposed to a desmoplastic stroma that may appear myxoid. The latter finding is virtually pathognomonic.

Comment Here

Reference: Hyalinizing clear cell carcinoma
Board review style question #2
Hyalinizing clear cell carcinoma of salivary gland is most commonly associated with which of the following gene fusions?

  1. CRTC1 (MECT1)::MAML2
  2. ETV6::NTRK3
  3. EWSR1::ATF1
  4. EWSR1::CREM
  5. EWSR1::PBX1
Board review style answer #2
C. EWSR1::ATF1. Greater than 80% of hyalinizing clear cell carcinomas (HCCCs) have EWSR1::ATF1 fusions. Albeit, anchored multiplex polymerase chain reaction has demonstrated a novel variant EWSR1::CREM fusion in a minority of cases. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. Soft tissue myoepithelial tumors (SMET) also harbor EWSR1 rearrangements. The partner genes in these neoplasms include PBX1, ZNF444 and POU5F1, suggesting that HCCC is not the salivary gland equivalent of soft tissue myoepithelial tumor. HCCC can be difficult to discriminate from mucoepidermoid carcinoma (MEC). Both can have mucinous differentiation. The former, however, possesses a characteristic myxoid appearing stroma that is sharply demarcated from a hyalinized basement membrane-like material. MEC predominantly affects the parotid and has a greater tendency for cysts lined by goblet cells rather than a cord-like or anastomosing trabeculae architecture. Lastly, MEC contains MAML2 fusions.

Comment Here

Reference: Hyalinizing clear cell carcinoma
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