Renal Cell Carcinoma Associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome
Definition
Renal cell carcinomas with inclusion-like nucleoli and perinucleolar clearing that occur in the setting of skin and uterus leiomyomatosis and demonstrate germline fumarate hydratase (FH) mutations
Common abbreviation
HLRCC-associated RCC
Diagnostic Criteria
- Large nuclei with prominent, eosinophilic, inclusion-like nucleoli with perinucleolar clearing
- May only be present focally
- Papillary architecture most common
- Foamy histiocytes uncommon
- May also demonstrate tubular, tubulopapillary tubulocystic, solid, and mixed architecture
- May show collecting duct-like morphology with tubules, solid nests or individual cells infiltrating through desmoplastic stroma
- May show sarcomatoid growth
- Large cells with abundant eosinophilic cytoplasm
- Focal areas may have amphophilic or clear cytoplasm
- Loss of fumarate hydratase (FH) expression
- Concurrent overexpression of S-(2-succino)cysteine (2SC)
Supplemental studies
- Loss of cytoplasmic fumarate hydratase (FH) expression
- Concurrent nuclear and cytoplasmic overexpression of S-(2-succino)cysteine (2SC)
- Loss of FH results in accumulation of aberrantly succinated proteins, which can be detected as increased cytoplasmic and nuclear 2SC
- Together, these two stains have high sensitivity and specificity for HLRCC-associated RCC
- Consider doing FH immunohistochemistry in cases with compatible morphology or clinical characteristics
- The term “FH-deficient RCC” has been suggested for tumors with suggestive morphology and FH- and 2SC+ immunophenotype, but where HLRCC history cannot be ascertained
- Typically negative for CK7, CK20, UEA-1 and High molecular weight cytokeratins
Grading/Staging
Use WHO/ISUP grading system for clear cell and papillary renal cell carcinomas
- Although this grading system has not been validated as an indicator of prognosis for other types of renal cell neoplasia (due primarily to small numbers of reported cases), the system can be used to describe the morphologic features of these tumors
- Grade should be assigned on the basis of the single high-power field showing the greatest degree of nuclear pleomorphism.
Grade 1 |
Nucleoli are absent or inconspicuous and basophilic at 400x magnification |
Grade 2 |
Nucleoli are conspicuous and eosinophilic at 400x and visible but not prominent at 100x |
Grade 3 |
Nucleoli are conspicuous and eosinophilic at 100x |
Grade 4 |
Extreme nuclear pleomorphism, multinucleate giant cells, and/or rhabdoid and/or sarcomatoid differentiation |
Clinical
- Uncommon
- Predominantly younger patients
- Mean 36 years
- May present with multiple cutaneous and uterine leiomyomas
- Present in 85% of cases
- Cutaneous lesion most common on arms and thorax
- Uterine leiomyomas have nuclear features similar to those seen in the renal tumors
- Caused by germline mutation in fumarate hydratase gene
- Referral for genetic counseling is recommended
- Unlike other hereditary tumors, these may be unilateral and single
- Poor prognosis
- Early widespread dissemination common
- Often at least pT3
- Often lymph node metastases
- Metastases reported even with small tumors
Differential diagnosis
Papillary renal cell carcinoma
Tubulocystic renal cell carcinoma
Collecting duct carcinoma
| Hereditary Leiomyomatosis RCC | Papillary Renal Cell Carcinoma |
|---|---|
FH Negative, 2SC Overexpressed |
FH intact, No 2SC over expression |
CK7 negative |
CK7 positive |
Prominent eosinophilic nucleoli |
May have prominent nucleoli |
Foamy macrophages uncommon |
Foamy macrophages common |
Average age 36 |
Average age 60 |
| Hereditary Leiomyomatosis RCC | Tubulocystic Carcinoma of the Kidney |
|---|---|
FH Negative, 2SC Overexpressed |
FH intact, No 2SC over expression |
Papillary architecture predominates |
Tubulocystic architecture predominates (small to intermediate-sized tubules with admixed larger cysts) |
Mean age 36 |
Mean age 58 |
Prominent eosinophilic nucleoli |
May have prominent nucleoli |
| Hereditary Leiomyomatosis RCC | Collecting Duct Carcinoma |
|---|---|
FH Negative, 2SC Overexpressed |
FH intact, No 2SC over expression |
CK7 and HMWCK negative |
CK7 and HMWCK positive |
Predominant papillary morphology |
Predominantly tubular morphology |
Predominantly located in renal cortex |
Must have medullary involvement |
Bibliography
- Moch H, Humphrey PA, Ulbright TM, Reuter VE eds. World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. 4th Ed. IARC Press: Lyon 2016.
- Udager AM, Mehra R. Morphologic, Molecular, and Taxonomic Evolution of Renal Cell Carcinoma: A Conceptual Perspective With Emphasis on Updates to the 2016 World Health Organization Classification. Arch Pathol Lab Med. 2016 Oct;140(10):1026-37.
- Smith SC, et al. Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci: A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma. Am J Surg Pathol. 2016 Nov;40(11):1457-1472.
- Chen YB et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 2014 May;38(5):627-37.
- Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007 Oct;31(10):1578-85.
Kurt Schaberg MD
John P Higgins MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342
Original posting 12/29/16
