Cervix
Adenocarcinoma
Clear cell carcinoma
Last author update: 1 February 2018
Last staff update: 15 February 2023 (update in progress)
Copyright: 2018-2023, PathologyOutlines.com, Inc.
PubMed Search: Clear cell carcinoma cervix
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Clinical features | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Hameed NM, Mneimneh WS, Parra-Herran C. Clear cell carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cervixclearcell.html. Accessed September 30th, 2023.
Definition / general
- Composed mainly of clear or hobnail cells whose architectural patterns are solid, tubulocystic or papillary
- Accounts for about 4% of adenocarcinoma of the cervix
- Bimodal age distribution (J Midlife Health 2015;6:85)
- First peak occurs in women aged 17 - 37 years
- Second peak occurs in women aged 44 - 88 years
Essential features
- Multiple architectural patterns with hyalinized stroma and hobnail cells
- Cytoplasm may be clear or eosinophilic
- High nuclear grade, at least focally, contrasting with relatively low mitotic count and mildly increased Ki67
- Hyaline globules (intracytoplasmic)
- HNF1β and napsin A positive; ER, PR and p16 negative, normal p53 expression in most cases (Int J Gynecol Pathol 2018;37:388, Am J Surg Pathol 2011;35:633)
ICD coding
- C53.0: malignant neoplasm of endocervix
Epidemiology
- Accounts for 4% of adenocarcinoma of cervix
- Historically associated with intrauterine diethylstilbestrol (DES) exposure, use declined after US FDA warning in 1971 (NCI - DES and Cancer [Accessed 30 January 2017])
- Cervical endometriosis might contribute to the occurrence of clear cell carcinoma of the cervix in women without DES exposure (Br J Radiol 2009;82:e20, Int J Gynecol Pathol 2018;37:88)
- Not related to high risk HPV infection (Int J Gynecol Cancer 2013;23:1084)
- Median age of DES related clear cell carcinoma is 18.9 years, while median age of non-DES associated clear cell carcinoma is 53 years
Clinical features
- Vaginal bleeding is the most frequent initial symptom (Int J Gynecol Cancer 2014;24:S90)
- Postcoital bleeding
- Abnormal vaginal discharge
- Physical examination shows endocervical lesion, barrel shaped cervix or normal appearing cervix
- Rarely the only finding is a pelvic mass (Onco Targets Ther 2014;7:111)
Prognostic factors
- Traditional prognostic factors include the following (Gynecol Oncol 2008;109:335)
- FIGO stage, in particular related to:
- Lymph node status
- Parametrial involvement
- > 1/3 cervical stromal involvement
- Positive surgical margins
- Tumor diameter > 4 cm
- Lymph vascular space involvement
- FIGO stage, in particular related to:
- Although clear cell ovarian carcinomas have an unfavorable prognosis, clear cell cervical cancer in itself does not seem to have a worse prognosis than squamous cell carcinoma of the cervix (Onco Targets Ther 2014;7:111)
- Median time to recurrence is 12 months overall (Gynecol Oncol 2008;109:335); 8 months for stage I and II (Gynecol Oncol 2000;76:147)
- Common sites of relapse include pelvis, para-aortic lymph nodes and distant sites but does not seem to have high propensity to peritoneal dissemination (Int J Gynecol Cancer 2014;24:S90)
- 3 year overall survival: stage I and II: 91% vs advanced stage 22% (Gynecol Oncol 2008;109:335);
- 5 year PFS: 85% stage I - IIA and 42% stage IIB - IV; 5 year OS: 90% stage I - IIA and 63% IIB - IV (Gynecol Oncol 2008;109:335)
Case reports
- 26 year old woman with cesarean radical hysterectomy in a triplet pregnancy complicated by clear cell carcinoma of the cervix (Int J Gynecol Cancer 2012;22:1198)
- 47 year old woman with synchronous invasive squamous cell carcinoma and clear cell carcinoma of the uterine cervix: (Gynecol Oncol 2005;97:976)
- 52 year old woman with clear cell carcinoma of the cervix exhibiting choriocarcinomatous differentiation and mismatch repair protein abnormality (Int J Gynecol Pathol 2017;36:323)
- 56 year old woman with clear cell carcinoma of the uterine cervix and cervical endometriosis (Int J Gynecol Pathol 2018;37:88)
Treatment
- Initial treatment: radical hysterectomy or trachelectomy with pelvic
- Recommended for early stage (IA - IB1) disease with no evidence of metastasis
- Trachelectomy has evolved as a valuable fertility preserving option (Int J Gynecol Cancer 2011;21:137)
- The role of adjuvant treatment is limited
- No evidence based approach exists to direct therapy for more advanced stages at presentation or for recurrence (Int J Gynecol Cancer 2014;24:S90), but surgery, chemotherapy and radiation are options
Gross description
- In non-DES exposure cases, the tumor arises in ectocervix or endocervix; in DES exposure cases the tumor most commonly arises in the ectocervix
- Tumor median size is 3.3 cm (Int J Gynecol Cancer 2017;27:1009)
- Variable presentation: everting nodular red lesions, small punctate ulcers, exophytic mass or normal appearing cervix (Onco Targets Ther 2014;7:111)
Microscopic (histologic) description
- Three major patterns:
- Tubulocystic pattern (most common pattern): tubules lined by a single layer of bland cells or prominent hyperchromatic nuclei project into the apical cytoplasm forming hobnail appearance
- Papillary pattern (least common pattern): papillae with central hyaline fibrous tissue cores lined by hobnail cells with hyperchromatic nuclei
- Solid pattern: nests of cells with clear to pale eosinophilic cytoplasm, notable nuclear atypia, focal gland formation and variable sized cytoplasmic vacuoles, simulating signet ring cell differentiation, appears to be more common in clear cell carcinoma of the cervix (Int J Gynecol Pathol 2018;37:388)
- Intracytoplasmic hyaline globules especially in solid pattern
- Morphologic spectrum is comparable to that of endometrial and ovarian counterparts with few differences (Int J Gynecol Pathol 2018;37:388):
- Low mitotic index (0 - 5/10 HPF) often encountered in cervical (85%) compared to endometrial and ovarian cases (72% and 50% respectively)
- Necrosis or psammoma bodies usually absent in endocervical cases (present in 38% and 6% in ovarian CCC and 59% and 5% endometrial CCC respectively, without statistical significance)
Microscopic (histologic) images
Contributed by Nadia Hameed, M.D.
Tubulocystic pattern
Papillary pattern
Solid pattern
Rare intracytoplasmic eosinophilic globules
Cytology description
- Pap test:
- Cells arranged in sheets, clusters or papillae
- Cells have delicate, vacuolated, glycogen rich cytoplasm or finely granulated cytoplasm, naked nuclei and a tigroid background
- Nuclei are large, pale and round with prominent nucleoli
Cytology images
Contributed by Nadia Hameed, M.D.
SurePath Pap test
Positive stains
- Pancytokeratin (AE1 / AE3, CAM5.2)
- CK7, CK8, CK18, CK19
- HNF1β (Int J Gynecol Pathol 2018;37:388)
- Napsin A (Int J Gynecol Pathol 2018;37:388)
- Ki67
- Epithelial membrane antigen (EMA)
- Rarely (14%) diffuse nuclear p53 expression by IHC (associated with TP53 mutation) (Int J Gynecol Pathol 2018;37:388)
Negative stains
- CK20
- High molecular weight CK 34βE12
- ER, PR (only rarely focally expressed) (Int J Gynecol Pathol 2018;37:388)
- Vimentin, SMA, desmin
- Chromogranin, synaptophysin, CD56, NSE
- CEA, unlike most other types of cervical adenocarcinoma (Am J Surg Pathol 2011)
Electron microscopy description
- Continuous lamina densa, numerous mitochondria and rough endoplasmic reticulum, abundant glycogen and blunt microvilli
- Vesicular aggregates in nucleoplasm, perinuclear cytoplasm or between membranes of nuclear envelope (Acta Cytol 1976;20:262)
Electron microscopy images
Images hosted on other servers:
Clear cell carcinoma
Molecular / cytogenetics description
- No evidence of mutations in the KRAS or HRAS proto-oncogenes, the Wilms tumor (WT1) tumor suppressor gene or the estrogen receptor gene (Cancer 1996;77:507)
- In cases with sporadic overexpression, the p53 tumor suppressor gene was detected by immunohistochemistry but in the absence of detectable p53 gene mutation (Cancer 1996;77:507)
- Genetic instability as manifested by somatic mutation of microsatellite repeats has been reported in all DES associated tumors and in 50% of DES-unrelated tumors, suggesting that induction of genomic instability may be an important mechanism of DES induced carcinogenesis (Cancer 1996;77:507)
Differential diagnosis
- Benign entities:
- Arias-Stella reaction: history of intrauterine or ectopic pregnancy, progestin treatment or gestational trophoblastic disease, hypersecretory glands, decidual change in stromal cells, focally enlarged and hyperchromatic nuclei, no mitosis, no infiltration
- Microglandular hyperplasia: polypoid with small markedly crowded glands lined by a single layer of bland cuboidal cells and usually associated with squamous metaplasia; may present with sheets of clear cells
- small bland nuclei and low mitotic activity should distinguish it from clear cell carcinoma
- Malignant entities:
- Alveolar soft parts sarcoma: alveolar pattern, keratin negative, TFE3 positive, SMA and desmin positive
- Mesonephric adenocarcinoma: develops deep in the lateral wall of the cervix (corresponding to the location of mesonephric duct remnants), invades the wall of the cervix, lacks clear cells and hobnails cells, does not display the admixture of tubulocystic, papillary and solid patterns; positive for CK7, EMA, CD10, calretinin and GATA3
- Metastatic clear cell renal cell carcinoma: history is very important; positive for PAX8, CAIX and vimentin (Pathol Oncol Res 2015;21:893)
- Non clear cell carcinomas of endometrial origin: may be difficult to differentiate on biopsy specimens
- Endometrioid carcinoma: PAX8, ER, PR and vimentin positive
- Serous carcinoma: PAX8 positive, p53 diffusely positive or null type, p16 positive, ER focally positive
- Squamous cell carcinoma: some squamous cell carcinomas are composed of clear cells with abundant glycogen but glands and tubules are usually not present, CK5 / 6, p40, p63 positive
- Urothelial carcinoma: Positive for CK7, CK20 and GATA3
Additional references
Board review style question #1
All of the following statements regarding clear cell adenocarcinoma of the cervix are true EXCEPT
- All cases are linked to perinatal exposure of diethylstilbestrol (DES)
- Diagnosis is very rare in patients younger than 12 years
- Histologically, there are tubules and cysts lined by clear cells; solid and papillary areas may also be identified
- Immunohistochemical profile of this neoplasm includes positivity for cytokeratin 7, AE1 / AE3, CAM 5.2 and HNF1β
Board review style answer #1
A. All cases are linked to perinatal exposure of diethylstilbestrol (DES). There are sporadic cases of clear cell adenocarcinoma of the cervix that are not associated with DES exposure.
Comment Here
Reference: Clear cell carcinoma (adenocarcinoma)
Comment Here
Reference: Clear cell carcinoma (adenocarcinoma)
