Bladder & urothelial tract
Glandular neoplasms
Clear cell (adeno)carcinoma
Editorial Board Member: Michelle R. Downes, M.D.
Deputy Editor-in-Chief: Maria Tretiakova, M.D., Ph.D.
Last author update: 25 September 2024
Last staff update: 25 September 2024
Copyright: 2003-2024, PathologyOutlines.com, Inc.
PubMed Search: Clear cell adenocarcinoma
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Valencia A, Gordetsky JB, Craig JC. Clear cell (adeno)carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bladderclearcell.html. Accessed December 22nd, 2024.
Definition / general
- Adenocarcinoma of the genitourinary tract that has a morphology and immunophenotype that resembles Müllerian type clear cell carcinoma of gynecologic tract
Essential features
- Nuclear pleomorphism and mitotic activity, with or without necrosis
- Tubulocystic and papillary architecture, hobnailing of nuclei
- Infiltrative growth
- Positive staining for PAX8
- References: Int Urol Nephrol 2021;53:815, Am J Surg Pathol 2021;45:270
Terminology
- Müllerian type clear cell tumor / carcinoma
- Mesonephric or mesonephroid carcinoma / adenocarcinoma (not recommended)
Epidemiology
- Strong female predominance (F:M = 4.6:1) (Am J Surg Pathol 2021;45:270)
- Median age of 58 years (Am J Surg Pathol 2021;45:270)
Sites
- Bladder
- Urethra
- Very rare reports of upper urothelial tract involvement
- References: Int Urol Nephrol 2021;53:815, Am J Surg Pathol 2021;45:270, Virchows Arch 2023;483:751
Pathophysiology
- Poorly understood origin (Am J Surg Pathol 2021;45:270)
- One theory proposes origin from nephrogenic adenomas; however, unlike nephrogenic adenomas, clear cell adenocarcinoma (CCA) does not have a known association with urothelial tract inflammation / injury
- Another theory suggests an association with the gynecologic tract / endometriosis, given the female predominance and morphologic similarities to clear cell carcinoma of the ovary / uterus
Etiology
- Unknown
Clinical features
- Patients most commonly present with gross hematuria or lower urinary tract symptoms
- Rarely may present with recurrent urinary tract infections or obstruction
- References: Int Urol Nephrol 2021;53:815, Am J Surg Pathol 2021;45:270, Virchows Arch 2023;483:751
Diagnosis
- Mass on imaging
- Gross hematuria
- Urine cytology may show atypical cells
- Evaluation by cystoscopy and transurethral resection / biopsy
- References: Int Urol Nephrol 2021;53:815, Am J Surg Pathol 2021;45:270, Virchows Arch 2023;483:751
Radiology description
- Bladder or urethral mass on imaging
- Subset of patients may show obstructive signs (hydronephrosis, hydroureter) (Int Urol Nephrol 2021;53:815)
Prognostic factors
- Higher age at presentation and presence of distant spread most strongly correlated with negative outcomes (Am J Surg Pathol 2021;45:270)
Case reports
- 57 year old woman with lower urinary tract symptoms and urethral diverticulum (Urol Case Rep 2021;38:101659)
- 58 year old woman with dysuria and urinary frequency (Asian J Surg 2024;47:2006)
- 70 year old man on active surveillance and with lower urinary tract symptoms (Urol Case Rep 2023;47:102338)
- 79 year old woman with gross hematuria (Cureus 2023;15:e39575)
Treatment
- Radical cystectomy / urethrectomy, with or without chemotherapy or radiation (Am J Surg Pathol 2021;45:270)
Gross description
- Grossly gray-white, infiltrative mass (Am J Clin Exp Urol 2023;11:344)
- Polypoid or papillary (Am J Clin Exp Urol 2023;11:344)
Microscopic (histologic) description
- Heterogeneous architecture within the same tumor: solid, tubular, tubulocystic or papillary patterns
- Luminal hobnailing of nuclei
- Abundant cytoplasm, clear to eosinophilic
- High grade nuclear features with occasional mitotic figures
- Invasive pattern of growth (muscularis propria or perivesical fat invasion)
- Necrosis and lymphovascular invasion may be present
- References: Virchows Arch 2023;483:751, Arch Pathol Lab Med 2009;133:987
Microscopic (histologic) images
Contributed by Aida Valencia, M.D., Jennifer B. Gordetsky, M.D. and @SueEPig on Twitter
Cystic and solid pattern
Cytologic atypia
Papillary and tubular pattern
Papillae
Hyalinization of papillary cores
Tubulocystic growth pattern
Mitosis
Nephrogenic adenoma
Clear cell (adeno)carcinoma
Clear cell (adeno)carcinoma
Serous carcinoma
PAX8
WT1
HNF-1B
Napsin A
Virtual slides
Images hosted on other servers:
Bladder, malignant CCA
Positive stains
- Keratins: AE1 / AE3 (100%), CK7 (97%), CK20 (89%) (Int Urol Nephrol 2021;53:815, Arch Pathol Lab Med 2009;133:987)
- PAX8 (100%) (Diagn Pathol 2022;17:87)
- Napsin (88%) (Diagn Pathol 2022;17:87)
- GATA3 (while usually thought to be negative, may stain up to 55%) (Diagn Pathol 2022;17:87)
- CA125, CEA (Int Urol Nephrol 2021;53:815, Arch Pathol Lab Med 2009;133:987)
- p16 (Int Urol Nephrol 2021;53:815)
- p53 (Arch Pathol Lab Med 2009;133:987)
Negative stains
- p63 (9%) (Diagn Pathol 2022;17:87)
- CDX2 (Int Urol Nephrol 2021;53:815)
- ER / PR (Int Urol Nephrol 2021;53:815)
- NKX3.1 (Int Urol Nephrol 2021;53:815)
- WT1 (Diagn Pathol 2022;17:87)
- Vimentin (Arch Pathol Lab Med 2009;133:987)
- RCC (Arch Pathol Lab Med 2009;133:987)
- CD10 (Arch Pathol Lab Med 2009;133:987)
- CAIX (Arch Pathol Lab Med 2009;133:987)
Molecular / cytogenetics description
- Not routinely performed for diagnostic purposes
- ARID1A mutations (Cancer Res Treat 2024;56:280)
- PIK3CA and KRAS mutations, suggesting a possible role of the PI3K / AKT / mTOR pathway (Virchows Arch 2019;475:727)
- Other potential driver mutations include AMER1, CHD4, KMT2D, KRAS, PBRM1, PIK3R1 (Cancer Res Treat 2024;56:280)
Molecular / cytogenetics images
Sample pathology report
- Bladder and prostate, radical cystoprostatectomy:
- Clear cell adenocarcinoma (see synoptic report)
- Tumor invades perivesical soft tissue
- Lymphovascular invasion is present
- Margins are negative for tumor
- No malignancy identified in 10 lymph nodes (0/10)
- PT3b N0
Differential diagnosis
- Nephrogenic adenoma:
- Immunohistochemistry (IHC) is often not helpful (Cureus 2023;15:e41285)
- Low mitotic rate / Ki67 proliferation rate (< 2%) (Am J Surg Pathol 2021;45:270)
- Lacks overtly malignant features (muscle invasion, necrosis) (Am J Surg Pathol 2021;45:270)
- Lack of p53 mutated phenotype (overexpression or null) (Arch Pathol Lab Med 2009;133:987)
- Urothelial carcinoma:
- May have overlapping histology such as tubulopapillary growth or clearing of cytoplasm
- Overlapping IHC (CK7, GATA3, PAX8) (Mod Pathol 2020;33:1165)
- p63 positive (Diagn Pathol 2022;17:87)
- Metastatic Müllerian adenocarcinoma from gynecologic tract (Arch Pathol Lab Med 2024;148:705):
- Can look and stain identically to primary clear cell adenocarcinoma of the bladder
- Diagnosis of metastasis often requires clinical history
- Prostatic adenocarcinoma:
- NKX3.1 positive
- Both CCA and prostatic adenocarcinoma may express AMACR / racemace (Int Urol Nephrol 2021;53:815)
- Metastatic clear cell renal cell carcinoma:
- Lacks architectural heterogeneity of clear cell adenocarcinoma (Virchows Arch 2023;483:751)
- CAIX, RCC, CD10, vimentin positive (CCA is negative) (Virchows Arch 2023;483:751, Arch Pathol Lab Med 2009;133:987)
Additional references
Board review style question #1
A patient undergoes a radical cystectomy for a 5 cm papillary mass. The above tumor is seen on H&E examination. This tumor should show which immunophenotype?
- PAX8+, BAP1 loss, calretinin+, WT1+
- PAX8+, CAIX+, CD10+, CK7-
- PAX8+, CK7+, vimentin-, p53 overexpression
- PAX8+, TTF1+, CK7+
Board review style answer #1
C. PAX8+, CK7+, vimentin-, p53 overexpression. The images show a clear cell adenocarcinoma, which should have positive staining for PAX8, CK7 and a p53 mutated phenotype. Vimentin should be negative. Answer D is incorrect because this immunophenotype is more in keeping with metastatic lung or thyroid cancer. Answer B is incorrect because this immunophenotype is more in keeping with clear cell renal cell carcinoma. Answer A is incorrect because this immunophenotype is more in keeping with mesothelioma.
Comment Here
Reference: Clear cell (adeno)carcinoma
Comment Here
Reference: Clear cell (adeno)carcinoma
Board review style question #2
Which of the following features would be most helpful in distinguishing a clear cell adenocarcinoma from a metastatic renal cell carcinoma?
- Mutated p53 immunophenotype (overexpression or loss)
- PAX8+, CK7+, vimentin+, CD10+
- Presence of papillary and tubular growth
- VHL mutation on molecular studies
Board review style answer #2
D. VHL mutation on molecular studies. VHL mutations are not found in clear cell adenocarcinoma of the urinary tract. This would be more consistent with a clear cell renal cell carcinoma. Answer B is incorrect because this immunophenotype can be found in renal cell carcinoma. Answer A is incorrect because although a p53 mutated immunophenotype is seen in clear cell adenocarcinoma of the bladder, it can also be seen in renal cell neoplasms. Answer C is incorrect because both clear cell adenocarcinoma and renal cell carcinoma can have papillary and tubular growth.
Comment Here
Reference: Clear cell (adeno)carcinoma
Comment Here
Reference: Clear cell (adeno)carcinoma
