Hereditary renal tumors: General Hereditary Renal Tumors · 2015-06-08 · 5/23/2015 1 Hereditary Renal Tumors Karuna Garg, MD University of California San Francisco Hereditary renal

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Hereditary Renal TumorsKaruna Garg, MD

University of California San Francisco

Hereditary renal tumors: General• 5-8% of all renal tumors are hereditary• Clinical history• Younger age of onset• Bilaterality and multifocality

• Pathologic features?

Hereditary renal tumors: Syndromes• Von Hippel-Lindau (VHL)• Hereditary papillary renal cell carcinoma

syndrome (HPRC)• Birt Hogg-Dube syndrome (BHD)• Tuberous sclerosis• Succinate dehydrogenase B syndrome (SDHB)• Hereditary leiomyomatosis and renal cell

carcinoma syndrome (HLRCC)




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von Hippel-Lindau (VHL)• Autosomal dominant• Germline mutations of VHL gene at 3p25-26- Hemangioblastoma of CNS or retina- Pheochromocytoma- Pancreatic tumors- Renal tumors- Epididymal and broad ligament cystadenomas

VHL associated renal lesions• Mean age of presentation with kidney tumors

37 years (16-67 years) • Bilateral and multiple

1. Renal cysts2. Microscopic nodules of clear cells3. Clear cell renal cell carcinoma

Solomon D, Hum Pathol 1988

Gross: Multiple cystic and solid lesions

VHL associated renal lesions

VHL associated renal lesionsRenal cysts:• Multiple, small, unilocular or multilocular• Lined by clear cells (single layer or stratified)

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VHL associated renal cysts VHL associated renal cysts

VHL associated renal lesionsClear cell RCC:-Mean age 44 years-70% of patients develop RCC by age 60

Clear cell RCC

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VHL associated renal lesions• Microscopic nodules (tumorlets) of clear cells

in background kidney

VHL associated microscopic clear cell nodules

von Hippel-Lindau: Diagnosis• Mutation analysis

von Hippel-LindauKey morphologic features:• Multiple and bilateral clear cell RCCs• Cysts lined by clear cells • Microscopic nodules of clear cells

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Hereditary papillary renal cell carcinoma (HPRC)

• Autosomal dominant• Activating mutations in MET oncogene• Late presentation (50-70 years)• No extrarenal manifestations


• Bilateral multiple (hundreds to thousands) papillary renal cell carcinomas (type 1) and papillary adenomas

• Resemble sporadic type 1 papillary RCC

Papillary RCC

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Papillary RCC Hereditary papillary renal cell carcinoma (HPRC): Diagnosis

• Mutation analysis


Key morphologic features:• Bilateral and multiple type 1 papillary RCCs• Background kidney with numerous papillary

adenomas (but can be sporadic)




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Birt-Hogg-Dube Syndrome• Autosomal dominant• Mutations in BHD gene that encodes folliculin

on 17p11.21. Skin papules (fibrofolliculomas)2. Lung cysts (spontaneous pneumothorax)3. Renal tumors

Fig. 1 BHD cutaneous manifestations. BHD hallmark is cutaneous fibrofolliculoma ( A and B , arrows). Fibrofolliculoma is benign tumor of hair follicle that can appear on face and upper trunk. Histologically f...

CHRISTIAN P. PAVLOVICH , ROBERT L. GRUBB III , KATHLEEN HURLEY , GLADYS M. GLENN , JORGE TORO , LAURA S. SCHMIDT ,...

EVALUATION AND MANAGEMENT OF RENAL TUMORS IN THE BI RT-HOGG-DUBÉ SYNDROME

The Journal of Urology, Volume 173, Issue 5, 2005, 1482 - 1486

http://dx.doi.org/10.1097/01.ju.0000154629.45832.30

Fig. 2 Pulmonary manifestations of BHD. Patients with BHD are at risk for lung cysts ( A and B , asterisks) and spontaneous pneumothorax ( B , arrowheads).

CHRISTIAN P. PAVLOVICH , ROBERT L. GRUBB III , KATHLEEN HURLEY , GLADYS M. GLENN , JORGE TORO , LAURA S. SCHMIDT ,...

EVALUATION AND MANAGEMENT OF RENAL TUMORS IN THE BI RT-HOGG-DUBÉ SYNDROME

The Journal of Urology, Volume 173, Issue 5, 2005, 1482 - 1486

http://dx.doi.org/10.1097/01.ju.0000154629.45832.30

Renal tumors in BHD• Multiple, often bilateral• Mean age at diagnosis ~50 years1. Chromophobe RCC2. Oncocytoma3. Hybrid oncocytic/chromophobe tumors

(HOCT) 4. Clear cell renal cell carcinoma

Pavlovich CP, et al. Am J Surg Pathol 2002

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Renal tumors in BHD• Hybrid oncocytic/chromophobe tumors of

BHD- Mixture of areas resembling oncocytoma and

chromophobe renal cell carcinoma- Scattered chromophobe cells in a background

of classic oncocytoma- Large eosinophilic cells with intracytoplasmic

clearing© 2013 by Lippincott Williams & Wilkins. Published by Lippincott Williams & Wilkins, Inc. 2

Renal tumors in BHDThe International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.Srigley, John; Delahunt, Brett; Eble, John; Egevad, Lars; MD, PhD; Epstein, Jonathan; Grignon, David; Hes, Ondrej; MD, PhD; Moch, Holger; Montironi, Rodolfo; Tickoo, Satish; Zhou, Ming; MD, PhD; Argani, Pedram

American Journal of Surgical Pathology. 37(10):1469-1489, October 2013.DOI: 10.1097/PAS.0b013e318299f2d1

FIGURE 12 . HOCT associated with BHD syndrome. Note admixture of chromophobe and oncocytic-type cells. Many large eosinophilic cells have prominent intracytoplasmic vacuoles.

Hybrid oncocytic tumor Renal tumors in BHD

• Renal oncocytosis:- Numerous oncocytic masses of variable sizes- Often one dominant mass (hybrid features)- Can have a diffuse infiltrative pattern- Oncocytic change in non-neoplastic tubules- Cysts lined by oncocytic cells

Tickoo SK, et al. Am J Surg Pathol 1999

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Renal oncocytosisRenal oncocytosis

Birt-Hogg-Dube Syndrome: Diagnosis• Mutation analysis

Birt-Hogg-Dube SyndromeKey morphologic features:• Hybrid oncocytic tumors• Multiple/bilateral chromophobe RCC or hybrid

tumors• Background kidney with oncocytosis (not

specific)

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Tuberous Sclerosis• Autosomal dominant• Mutations in TSC1 or TSC2 gene• No family history (new mutations and variable

penetrance)• Mental retardation and seizures• Tumor like lesions of multiple organs including

brain (subependymal giant cell tumor), skin (angiofibromas) and heart (rhabdomyomas)

• Perivascular epithelioid cell tumors (PEComas)

Tuberous Sclerosis associated renal lesions

• Renal involvement in 50% of patients• Younger age• Kidney lesions:1. Multiple renal cysts2. Angiomyolipoma3. Renal cell carcinoma

Renal cysts in tuberous sclerosis• 30-40% of patients• Small cysts lined by granular eosinophilic cells

with large nuclei (can be papillary/tufted)

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Renal cysts in tuberous sclerosisAngiomyolipoma in tuberous sclerosis• Common (80%)• Multifocal and bilateral• AML in other organs (including lymph nodes)- More likely to have an epithelioid component?- Angiomyolipoma with epithelial cysts (AMLEC)?- Microscopic AML foci in background kidney

Aydin H, et al. Am J Surg Pathol 2009

Combination of epithelioid AML, presence of associated epithelial cysts and microscopic AML foci is highly suggestive of tuberous sclerosis

Angiomyolipoma Angiomyolipoma

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Epithelioid angiomyolipomaMicroscopic AML foci

Lymph node involvement

Angiomyolipoma with epithelial cysts (AMLEC)

Three components:1. Cystic spaces lined by cuboidal to columnar epithelium2. Condensed stroma immediately adjacent to the cyst lining3. Muscle predominant AML

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Angiomyolipoma with epithelial cysts (AMLEC)

Fine SW, et al. Am J Surg Pathol 2006

Tuberous Sclerosis associated renal cell carcinoma

• Clear cell carcinoma most common• Chromophobe RCC• RCC with prominent smooth muscle stroma• Unclassified cystic and solid tumors with large

cells and eosinophilic granular cytoplasm

Guo J et al. Am J Surg Pathol 2014


“RCC with smooth muscle proliferation”


Renal cell carcinomas in tuberous sclerosisChromophobe RCC Cystic eosinophilic RCC

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Tuberous Sclerosis: Diagnosis• Mutation analysis

Tuberous SclerosisKey morphologic features:• Bilateral and/or multiple angiomyolipomas

(epithelioid and AMLEC)• Multiple cysts lined by large eosinophilic cells• Microscopic AML foci• Renal cell carcinoma and concurrent

angiomyolipoma




Succinate dehydrogenase B syndrome (SDHB)

• Rare• Mutations in SDH-B• Patients at increased risk for

pheochromocytoma, paraganglioma, GIST, pituitary adenoma and renal tumors

• Early onset• Bilateral

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SDH deficient RCC• Well circumscribed• Variably sized cysts with pale eosinophilic fluid• Stroma with myxoid change or hyalinization• Intracytoplasmic eosinophilic inclusions• Flocculent cytoplasm with vacuolization and

wispy eosinophilic material• Entrapped tubules and glomeruli• Can be higher grade, sarcomatoid transformation

Gill AJ, et al. Am J Surg Pathol 2014Gill et al, American Journal of Surgical Pathology 2011

SDHB deficient RCC

Gill et al, American Journal of Surgical Pathology 2014

SDHB deficient RCC SDH deficient RCC: Clinical• Low grade tumors (Fuhrman grade 2) have

good prognosis• Higher grade tumors (Fuhrman grade 3-4 or

presence of sarcomatoid transformation) more aggressive

• Can show late recurrence/metastasis

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Succinate dehydrogenase B syndrome (SDHB): Diagnosis

• Immunohistochemistry• Mutation analysis

SDH deficient RCCImmunohistochemistry:• Cytokeratins and EMA can be negative or only

focally positive• PAX8 positive (can be focal)• Loss of staining for SDH-B• C-kit negative

SDHB deficient RCC

Gill et al, American Journal of Surgical Pathology 2014

Key morphologic features:• Intracytoplasmic pale eosinophilic inclusions• Flocculent vacuolated cytoplasm with wispy

eosinophilic material

Succinate dehydrogenase B syndrome (SDHB)

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Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)

• Autosomal dominant• Germline mutations in fumarate hydratase

(FH) gene• Cutaneous and uterine leiomyomas (high

penetrance)• Renal cell carcinoma (low penetrance)

HLRCC associated RCC• Often unilateral and single • 3rd-4th decade (can present late)• Often no apparent personal or family history• Clinically aggressive

• Included as a distinct tumor subtype in the recent ISUP classification of renal tumors

HLRCC associated RCCArchitecture (not specific): Often mixed pattern• Papillary• Tubulo-papillary• Solid• Cysts• Collecting-duct like• Sieve like/cribriform

Chen YB, et al. Am J Surg Pathol 2014

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HLRCC associated RCCCharacteristic cytology: -Large nucleus with prominent eosinophilic nucleolus surrounded by perinucleolar halo-May not be uniformly present throughout tumor

Merino MJ, et al. Am J Surg Pathol 2007Chen YB, et al. Am J Surg Pathol 2014

HLRCC associated RCC

HLRCC associated RCC HLRCC associated RCC

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HLRCC associated RCC HLRCC associated RCC

HLRCC associated RCC HLRCC associated RCC• Poor prognosis• Presentation at high stages• 7 of 9 patients with distant metastases• 5 of 9 patients died within 15 months

• Early detection of syndrome??


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HLRCC associated uterine smooth muscle tumors

• Present in virtually all women with HLRCC• Often present in 2nd decade• Large and symptomatic• Early surgical intervention• Can be cellular and/or atypical

• Detection of HLRCC could provide opportunity for renal tumor surveillance

• Morphologic features?


• Large eosinophilic macronucleoli surrounded by perinucleolar halos

Sanz-Ortega et al, USCAP 2008

© 2011 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Morphologic Features of Uterine Leiomyomas Associated With Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome: A Case Report.Garg, Karuna; Tickoo, Satish; Soslow, Robert; Reuter, Victor

American Journal of Surgical Pathology. 35(8):1235-1237, August 2011.DOI: 10.1097/PAS.0b013e318223ca01


• Large eosinophilic nucleoli surrounded by perinucleolar halos

• Eosinophilic cytoplasmic globules• Hemangiopericytomatous blood vessels

Sanz-Ortega et al, Am J Surg Pathol 2013Reyes C, et al. Mod Pathol 2014

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HLRCC associated uterine leiomyoma HLRCC associated uterine leiomyoma

HLRCC associated uterine leiomyoma HLRCC associated uterine leiomyoma

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HLRCC associated uterine leiomyoma HLRCC associated uterine smooth muscle tumors

• 194 uterine smooth muscle tumors from patients ≤40 years

• Fumarate hydratase gene aberration detected in 5 cases (2.6%)

• 4 of 5 cases showed morphologic features suspicious for HLRCC

• Immunohistochemistry for 2SC and FH helpful

Joseph N, et al. Am J Surg Pathol (accepted for publication)

HLRCC associated cutaneous leiomyomas

- Multiple uterine and cutaneous leiomyomatosis (MCUL) or Reed syndrome

- Multiple, grouped lesions on trunk or limbs, painful

- Morphologic features not well described

HLRCC associated cutaneous leiomyomas

- 22 patients with multiple cutaneous leiomyomas and 25 patients with single cutaneous leiomyomas

- Lack cytologic features seen in renal tumors and uterine leiomyomas

- Majority of multiple leiomyomas showed FH gene aberrations

- Good correlation between IHC for 2SC and FH and mutation status

Buelow B, et al. USCAP 2015 abstract

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HLRCC: Diagnosis• FH mutation analysis• Immunohistochemistry1. 2SC (2 succino-cysteine)2. FH (fumarate hydratase)

HLRCC: Diagnosis2SC immunohistochemistry:- Genetic ablation of FH leads to high levels of

protein succination- 2SC serves as a metabolic biomarker for FH

deficiency- 2SC positive in FH deficient renal cysts and

known renal tumors with FH mutations- Negative in normal tissue (n=200) and non-

HLRCC tumors (n=1342)Bardella C, et al. J Pathol 2011

HLRCC: Diagnosis2SC immunohistochemistry- Strong diffuse staining indicative of FH gene

aberration- Sensitive and specific (renal tumors, uterine

and cutaneous leiomyomas)- Not commercially available


2SC staining in HLRCC associated renal cell carcinoma

9/9 HLRCC associated tumors were 2SC positiveNumerous other tumor types negative (cytoplasmic only staining in rare cases)

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2SC positive uterine leiomyoma

5 of 5 cases with FH gene mutations were 2SC positiveAll 2SC negative cases also negative for FH mutations


HLRCC: DiagnosisFH immunohistochemistry- Complete loss of staining indicative of FH gene

aberration- Specific- Not sensitive (missense mutations lead to

retained staining)- Retained staining does not exclude HLRCC

FH loss in uterine leiomyoma


2 of 5 cases with FH mutations negative for FH IHC3 of 5 cases with FH mutations showed variable positivity

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)

Key morphologic features:- Kidney tumors: Prominent eosinophilic

nucleoli surrounded by perinucleolar halo- Uterine smooth muscle tumors: Eosinophilic

cytoplasmic inclusions, prominent eosinophilic nucleoli surrounded by perinucleolar halo

- Cutaneous leiomyomas: Multiple, distinct morphologic features absent

- Consider IHC for 2SC and FH in suspicious cases

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Summary• Some renal tumors are hereditary• Patient age, clinical history and radiology can

be helpful (but often not)• The presence of some morphologic features

can raise the possibility of an underlying syndrome and should be reported (classify tumor as usual and raise the possibility of a syndrome in the comment section)

Acknowledgements• Dr. V Reuter, MKCC• Dr. S Tickoo, MSKCC

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May 1997;16(1):68-73.• Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. The

American journal of pathology. Aug 1999;155(2):517-526.• Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary

leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Human molecular genetics. Jun 1 2003;12(11):1241-1252.• Chen YB, Brannon AR, Toubaji A, 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. The American journal of surgical pathology. May 2014;38(5):627-637.• Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC)

syndrome. The American journal of surgical pathology. Oct 2007;31(10):1578-1585.• Garg K, Tickoo SK, Soslow RA, Reuter VE. Morphologic features of uterine leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome:

a case report. The American journal of surgical pathology. Aug 2011;35(8):1235-1237.• Sanz-Ortega J, Vocke C, Stratton P, Linehan WM, Merino MJ. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and

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Hereditary renal tumors: General Hereditary Renal Tumors · 2015-06-08 · 5/23/2015 1 Hereditary Renal Tumors Karuna Garg, MD University of California San Francisco Hereditary renal