Endometrioid adenocarcinoma with squamous differentiation pathology outlines

Uterus

Clear cell carcinoma

Editorial Board Member: Jennifer A. Bennett, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Last author update: 21 April 2020

Last staff update: 18 August 2020

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PubMed search: Clear cell carcinoma[TI] uterus

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Cite this page: Huvila J, Gilks CB. Clear cell carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusclearcell.html. Accessed October 15th, 2022.

Definition / general

• Tumor of postmenopausal patients that histologically resembles ovarian clear cell carcinoma with clear, oxyphil or hobnail cells

Essential features

• Diagnosed based on characteristic morphology
• Solid architecture more common than papillary
• HNF-1B, napsin A and AMACR positive
• Can be any of the 4 molecular subtypes of endometrial carcinoma but most common is no specific molecular profile (p53, mismatch repair and POLE wild type, estrogen receptor negative)

Terminology

• Also called clear cell adenocarcinoma

ICD coding

• ICD-O: 8310/3 - clear cell adenocarcinoma, NOS
• ICD-10: C54.1 - malignant neoplasm of endometrium

Pathophysiology

• Heterogeneity of molecular pathogenesis (Histopathology 2015;66:664)
• All 4 molecular subtypes can be seen (p53 abnormal, mismatch repair deficient, POLE mutant and no specific molecular profile) (Histopathology 2015;66:664)
• p53 abnormal (serous-like) are aggressive, similar to other p53 abnormal endometrial carcinomas (Histopathology 2015;66:664)
• Mismatch repair deficient often shows mixed morphology, with clear cell and endometrioid components (J Natl Cancer Inst 2016;108:djv427)
• Only no specific molecular profile (p53, POLE and mismatch repair wild type) fit the classic clinical profile of clear cell carcinoma

Clinical features

• Postmenopausal bleeding
• High grade carcinoma confined to the uterus in the majority of cases (Int J Gynecol Cancer 2017;27:1714)
• Associated with an increased risk for thromboembolic events (Int J Gynecol Cancer 2017;27:1714, Am J Cancer Res 2013;3:70)

Diagnosis

• Diagnosis is based on characteristic findings on an endometrial biopsy or curettage, which is typically performed for postmenopausal bleeding
• Abdominal and pelvic imaging can be performed for the purpose of clinical staging

Prognostic factors

• Age and stage are important prognostic factors (Am J Cancer Res 2013;3:70)
• p53 abnormal has worse prognosis (Int J Gynecol Pathol 2019;38:S40)
• Mismatch repair deficient and POLE mutant have more favorable prognosis (J Pathol 2017;243:230)

Case reports

• 66 year old woman with clear cell carcinoma present in endometrial polyps (J Menopausal Med 2016;22:122)
• 73 year old woman with tumor arising from adenomyosis (Int J Gynecol Pathol 2009;28:262)

Treatment

• Total hysterectomy and bilateral salpingo-oophorectomy
• Radiation therapy may be considered

Clinical images

Images hosted on other servers:

Endometrial mass

Microscopic (histologic) description

• Diagnosis should be based on the presence of prototypical morphologic (both architectural and cytological) features (Int J Gynecol Pathol 2019;38:S40)
• Cytological features (Am J Cancer Res 2013;3:70, Int J Gynecol Pathol 2019;38:S40)
  • Polygonal cells with moderate to abundant clear or eosinophilic cytoplasm
  • Hobnail cells and flat cells
  • Occasional enlarged irregular nucleoli
  • Variable cytological atypia
  • Relatively low mitotic index
  • High mitotic index or pleomorphic nuclei does not rule out clear cell carcinoma in an otherwise typical tumor
  • Occasionally targetoid bodies, eosinophilic globules or psammoma bodies
• Architectural features (Am J Cancer Res 2013;3:70, Int J Gynecol Pathol 2019;38:S40)
  • Solid, glandular or papillary architecture or a combination of these
  • Stromal hyalinization (uncommon)
  • No diffuse nuclear stratification in the papillary areas or diffuse columnar cell changes

Microscopic (histologic) images

Contributed by Jutta Huvila, M.D.

Solid architecture

Glandular architecture

Glandular pattern

Papillary and glandular architecture

Papillary architecture

Hyalinized stroma

Clear cell cytology

Clear and hobnail cells

Oxyphilic cells

Clear and hobnail cells

Targetoid bodies

Psammoma bodies

ER

Napsin A

MSH6

Molecular / cytogenetics description

• ~50% are related to p53 abnormal, mismatch repair deficient or POLE mutant
• Remaining cases show occasional KRAS or PIK3CA mutations, without PTEN or TP53 abnormalities (Hum Pathol 2019;92:10)

Sample pathology report

• Endometrium, biopsy:
  • Clear cell carcinoma of the endometrium (MMR intact, p53 wild type) (see comment)
  • Comment: There is intact expression of mismatch repair proteins (PMS2 and MSH6) and wild type expression of p53, i.e. staining of variable intensity in < 80% of tumor cell nuclei.

Differential diagnosis

• Clear cell carcinoma of ovarian origin:
  • Endometrial involvement is presumptive evidence of endometrial primary site
• Endometrial serous carcinoma (Am J Surg Pathol 2013;37:874):
  • If p53 abnormal, then serous carcinoma unless completely typical clear cell carcinoma morphology
• Endometrioid endometrial carcinoma with clear cell or secretory change:
  • Low grade nuclear features, associated atypical hyperplasia, estrogen receptor positive (strong, diffuse)
• Arias-Stella reaction:
  • Younger age, associated pregnancy / progesterone treatment
  • Normal glandular architecture
  • Low Ki67 labeling index
• Clear cell carcinoma of cervical origin:
  • Distinction is based on tumor site; no morphological distinguishing features
• Metastatic renal cell carcinoma, clear cell type:
  • History of renal cell carcinoma
  • Usually CK7, estrogen receptor and progesterone receptor negative (Arch Pathol Lab Med 2015;139:39)
  • Usually positive for CD10 and HNF-1B (Arch Pathol Lab Med 2015;139:39)

Board review style question #1

Which of the following is true about clear cell carcinoma of the endometrium (shown in the image)?

1. It is associated with a favorable prognosis
2. It is associated with high levels of estrogen exposure (endogenous or exogenous)
3. There is molecular heterogeneity
4. There is no association with Lynch syndrome

Board review style answer #1

C. There is molecular heterogeneity. Clear cell carcinomas of the endometrium can be associated with mutations in POLE (in which case they have a very favorable prognosis), mismatch repair deficiency (which may be a result of Lynch syndrome), mutations in TP53 (poor prognosis) or none of the above.

Comment Here

Reference: Clear cell carcinoma

Board review style question #2

The immunoprofile of most endometrial clear cell carcinomas includes

1. Immunonegativity for AMACR
2. Immunopositivity for progesterone receptor
3. Immunoreactivity for Napsin A
4. Mutant pattern staining for p53

Board review style answer #2

C. Immunoreactivity for napsin A. The immunophenotype of a majority of endometrial clear cell carcinomas is positivity for napsin A and AMACR, negativity for progesterone receptor and wild type staining pattern for p53.

Comment Here

Reference: Clear cell carcinoma

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