ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. (INSERT NAME HERE) declares he/she has no conflict(s) of interest to disclose. OR Dr. (INSERT NAME HERE) declares affiliation with (INSERT AFFILIATION HERE) How Molecular Pathology Has Changed My Practice in Renal Neoplasia

Pedram Argani, MD The Johns Hopkins Medical Institutions Baltimore, MD, USA [email protected]

USCAP 2016 Renal Cell Carcinoma (RCC)-1997

• Clear cell • Papillary • Chromophobe • Collecting Duct – Medullary Renal Cell Carcinoma (RCC)-WHO 2016 • Clear cell RCC – Multilocular cystic renal neoplasm of low malignant potential • Papillary RCC • Hereditary leiomyomatosis RCC (HLRCC)-associated RCC • Chromophobe RCC • Collecting duct carcinoma • Renal medullary carcinoma • Mucinous tubular and spindle cell carcinoma • MiT family translocation RCC • Succinate dehydrogenase (SDH) deficient RCC • Tubulocystic RCC • Acquired cystic disease (ACD) associated RCC • Clear cell papillary RCC

Two Common Problems in Renal Tumor Classification • RCC with Papillary Architecture and Clear Cells • Hard to Classify Eosinophilic Renal Neoplasms Case 1: 24 year old female with 3cm renal mass

Renal Cell Carcinomas Which Often Have Papillary Architecture and Clear Cells • Clear cell RCC • Papillary RCC • Clear Cell Papillary RCC • Xp11 translocation RCC CLEAR CELL RCC CLEAR CELL RCC CLEAR CELL RCC: CA-IX PAPILLARY RCC PAPILLARY RCC: CK7 CLEAR CELL RCC PAPILLARY RCC Clear Cell Papillary RCC

• 1-4% of RCC • Originally reported in ESRD but most sporadic • All typical cases have had benign outcome • Histology – Architecture: papillary, tubular – Cytology: clear sub nuclear cytoplasmlinear suprabasal low grade nuclei

CLEAR CELL PAPILLARY RCC CLEAR CELL PAPILLARY RCC CK7 CA-IX CLEAR CELL PAPILLARY RCC MiT family Translocation RCC

• Xp11 translocation RCC • t(6;11) RCC Xp11 translocation Renal Cell Carcinoma (RCC) • Definition – RCC with translocations involving Xp11 – fusions involving TFE3 • Diagnosis confirmed by – Nuclear labeling for TFE3 by IHC – TFE3 gene rearrangement by FISH • Often young patients – Median= 22 years – Comprise majority of pediatric RCC – Comprise 1-2% of adult RCC • Outcome similar to clear cell RCC – Stage and Age predict outcome

Xp11 RCC CONFIRMED BY TFE3 BREAK-APART FISH Green WM et al. Am J Surg Pathol 2013;37:1150–1163 Cathepsin-K Immunoreactivity distinguishes Translocation RCC from other RCC

Martignoni G et al. Mod Pathol 2009;22: 1016-1022 RCC with Papillary Architecture and Clear Cells

CA-IX CK7 Cathepsin K Clear Cell RCC +++ - - Papillary RCC - +++ - Clear Cell Papillary RCC ++ +++ - Xp11 translocation RCC - - +/- Back to Our Case CK7- CA-IX- CATHEPSIN K- Diagnosis: Xp11 Translocation RCC with SFPQ-TFE3 Gene Fusion

TFE3 BREAK-APART FISH SFPQ BREAK-APART FISH

Johns Hopkins Cytogenetics Cristina Antonescu, MD

Red, centromeric; green, telomeric Xp11 translocation RCC Fusion Age Translocation ASPL-TFE3 1-75 t(X;17)(p11.2;q25) PRCC-TFE3 2-69 t(X;1)(p11.2;q21) SFPQ-TFE3* 5-68 t(X;1)(p11.2;p34) NonO-TFE3* 29-51 inv(X)(p11.2;q12) CLTC-TFE3 14 t(X;17)(p11.2;q23) PARP14-TFE3 32 t(X;3)(p11.2;q23) DVL2-TFE3 73 t(X;17)(p11;p13)

*typically show subnuclear vacuoles mimicking clear cell papillary RCC *typically Cathepsin K negative Am J Surg Pathol 2016, in press Hard to Classify Eosinophilic Renal Neoplasms

Case 2: 54 year old female with 5cm renal mass

Features Acceptable in Oncocytoma • Capsular invasion • Vascular invasion (rare) • Degenerative atypia Features that Exclude Oncocytoma • Well-Formed Papillae • Clear cells (non-focal) • Diffuse Cytokeratin 7 immunoreactivity • Wrinkly nuclei with well-preserved chromatin Renal Cell Carcinomas with Eosinophilic Cytoplasm • High Grade Clear Cell RCC • “Type 2” Papillary RCC • Eosinophilic Variant of Chromophobe RCC • Acquired Cystic Disease-Associated RCC (ACD-RCC) • Renal Medullary Carcinoma • VCL-ALK RCC • Collecting Duct Carcinoma • SHDB RCC • HLRCC-associated RCC • MiT family translocation RCC

CLEAR CELL RCC CLEAR CELL RCC “type“Type II Papillary II Papillary RCC” RCC” “Type II Papillary RCC” • TCGA Study (NEJM 2015 Nov4 Epub) – At least 3 different entities genetically – 5% are actually MiT family Translocation RCC!

• WHO 2016: “ may not in fact constitute a single well defined entity… but remains a useful morphologic descriptor ”

Acquired Cystic Disease- Associated RCC (ACD-RCC) • Most common RCC in End Stage Renal Disease (36%), particularly in ACD (46%) • 50% multifocal, 20% bilateral

Tickoo S et al. Am J Surg Pathol 2006;30: 141-153 ACD-RCC: Key Features

• Cribriform/Sievelike Architecture – Intercellular and Intracellular Lumina • Eosinophilic Cytoplasm, Prominent Nucleolus • Intratumoral Oxalate Crystals ACD-RCC ACD-RCC Succinate Dehydrogenase Deficient RCC (SDH RCC) • Germline succinate dehydrogenase B mutations • PGL4 Syndrome – Pheochromocytoma – Paraganglioma – Type II GIST • Pediatric, Carney syndrome – Renal Neoplasms (14% lifetime risk) Barletta JA, Hornick JL. Adv Anat Pathol. 2012;19:193-203 SDHB RCC • Less than 0.6% of RCC • Typically young adults, 26% bilateral • Indolent course in most cases – Rare cases with aggressive histologic features metastasize – Can metastasize late (16, 30 years after resection) Gill AJ Am J Surg Pathol 2014;38: 1588-1602 Williamson SR Mod Pathol 2015;28: 80-94

SDHB RCC

• Compact nests of eosinophilic cells • Vacuolated cytoplasm • Pale eosinophilic cytoplasmic inclusions – Giant mitochondria • Loss of SDHB protein by IHC SDHB RCC VACUOLES SDHB RCC INCLUSIONS SDHB IHC Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC)- associated RCC

Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) Syndrome • Autosomal Dominant • Germline mutations in Fumarate Hydratase gene (1q42) • Multiple Cutaneous and Uterine Leiomyomas – 50% of women have hysterectomy before age 30 • RCC – 1/3 of patients – Solitary – Aggressive HLRCC-associated RCC HLRCC-associated RCC HLRCC-associated RCC: IHC Markers • Aberrant succination of  S-(2-succinyl) cysteine (2 SC) IHC – Bardella C et al. J Pathol 2011;225: 4-11 – Chen YB et al. Am J Surg Pathol 2014;38: 627-637 • Loss of Fumarate Hydratase by IHC – Trypkov K et al. Am J Surg Pathol 2016, in press

Renal Cell Carcinomas Associated with Sickle Cell Trait • Renal Medullary Carcinoma – Often rhabdoid morphology – Loss of INI1 expression – Poor prognosis • VCL-ALK RCC – Vacuolated Cytoplasm – INI1 intact – Prognosis unclear Renal Medullary Carcinoma VCL-ALK RCC Back to Our Case Additional Sections

FUMARATE HYDRATASE Diagnosis: HLRCC-Associated RCC

Hard to Classify Eosinophilic Renal Neoplasms • r/o Oncocytoma • Consider high grade clear cell RCC • Beware of type II PRCC • Clues – Young age: MiT family Translocation RCC – ESRD: ACD-RCC – Sickle Cell Trait: RMC, VCL-ALK RCC – Vacuoles, Inclusions: SDHB RCC – Prominent Nucleoli: HLRCC-associated RCC Arthur Purdy Stout Society March 13, 2016 How has molecular pathology changed my diagnostic surgical pathology practice? Renal Neoplasia Pedram Argani MD The Johns Hopkins Medical Institutions [email protected]

I. Renal Cell Carcinomas (RCCs) with Clear Cells and Papillary Features

Clear Cell RCC

Clear cell RCC represents the most common RCC subtype, comprising approximately 60% of all renal tumors. The typical architecture is solid or acinar, with clear cells separated by hypervascular thin fibrous septa. The neoplastic cells of low nucleolar grade clear cell RCC (ISUP grade 1-2) typically have water-clear, virtually agranular cytoplasm. However, high nucleolar grade clear cell RCC typically has densely granular eosinophilic cytoplasm. Rarely, true cases of low grade clear cell RCC have well-developed papillae. In other low grade tumors, small papillae lined by clear cells protrude into cystic spaces. More commonly, high grade clear cell RCC with necrosis demonstrate pseudopapillae resulting from fragmentation of the acinar architecture. Additional sections of such tumors often show diagnostic lower grade acinar areas with clear cytoplasm.

Clear cell RCC typically demonstrates strong immunoreactivity for cytokeratin Cam5.2, vimentin, CD10, EMA, RCC marker as well as PAX8 and/or PAX2. Additionally, diffuse membranous staining for CA-IX is present, reflecting inactivation of the von Hippel-Landau (VHL) gene and constitutive activation of the hypoxia-inducible-factor (HIF) pathway. Notably, clear cell RCCs are typically negative for both cytokeratin 7 (CK7) and α-methylacyl-CoA racemase (AMACR), though both may be focally positive, especially in higher grade tumors. CK7 may also label cystic areas. Cathepsin K is consistently negative.

In summary, the most helpful morphologic clue for a clear cell RCC is hypervascular septa intimately associated with the neoplastic cells with transparent clear cytoplasm. Features further supporting the diagnosis are diffuse, strong, complete membranous CA-IX labeling and absence of CK7 labeling by IHC, as well as 3p loss by genetics.

Papillary RCC

Papillary RCC comprises 11-20% of renal tumors. In contrast to other RCC subtypes, papillary RCC is the more often multifocal (up to 45% of cases) and these typically are of independent origin. The prognosis is more favorable for papillary RCC than for clear cell RCC.

Histologically, the papillary RCC typically contains discrete papillary fronds comprised of fibrovascular cores lined by neoplastic cells. However, tubulopapillary and solid papillary growth patterns are also common. Foamy histiocytes are characteristically present within the fibrovascular cores. Hemosiderin-laden macrophages can be prominent. The neoplastic cells can vary from having basally oriented nuclei that are typically low-grade and scant amphophilic cytoplasm (so called type 1 papillary RCC) to showing nuclear pseudostratification typically associated with more prominent nucleoli and more abundant eosinophilic cytoplasm (so called type 2 papillary RCC). Clear cell change and fine cytoplasmic granulations are typically seen in association with hemosiderin deposition and/or necrosis, and may reflect phagocytic activity of the RCC cells. Clear cell change can become quite extensive in some tumors resulting in morphologic confusion with clear cell RCC. The cytoplasm is typically more foamy and granular than that of clear cell RCC.

By IHC, papillary RCC (particularly lower grade type 1 tumors) typically shows strong membranous labeling for CK7. AMACR typically demonstrates diffuse cytoplasmic granular labeling. CD10, PAX2, PAX8 and RCC marker are also usually positive, similar to clear cell RCC. CA-IX is either completely negative, or may be focally positive near areas of necrosis, reflecting foci of physiologic hypoxia. Cathepsin K is consistently negative.

In summary, one may occasionally see clear cell change in papillary RCCs. Clues for accurate diagnosis include finely granular cytoplasm and fine pigmented cytoplasmic reticulations representing hemosiderin. The diagnosis is supported by strong diffuse CK7 and AMACR IHC labeling but only focal CA-IX labeling. Cytogenetic findings of trisomy 7 and 17 further support the classification of the tumor as papillary RCC.

Clear cell papillary RCC

Clear cell papillary RCC was initially described in patients with end-stage renal disease, but is now known to arise in healthy kidneys as well. These tumors are most commonly singular and small (less than 5 cm) but multifocality can be present, especially in the setting of end-stage renal disease. The tumor is indolent. Uncomplicated cases have behaved in a uniformly benign fashion.

Grossly, these tumors have a thick capsule and are often cystic. The architecture varies and includes true papillary structures, branching tubules and solid acini. The papillary structures and tubules are lined by cells with clear cytoplasm and low ISUP nucleolar grade. The nuclei are typically polarized away from the basement membrane, creating a characteristic subnuclear vacuole similar to that seen in secretory endometrium. The stroma of clear cell papillary RCC not infrequently demonstrates smooth muscle metaplasia. The extreme end of this spectrum is likely neoplasms reported as renal angiomyoadenomatous tumor (RAT). Smooth muscle metaplasia in the kidney (as in the lung) may be a non-specific common reaction to a variety of stimuli.

Clear cell papillary RCCs displays a distinctive IHC profile overlapping with clear cell RCC and papillary RCC. Like clear cell RCC, CA-IX is diffusely positive; however, CA-IX commonly shows an absence of labeling along the luminal surface, yielding a “cup-like” labeling pattern. In contrast to clear cell RCC, CD10 is typically negative. Like papillary RCC, CK7 is diffusely positive but, in contrast to papillary RCC, AMACR is negative. Cathepsin K is consistently negative. Patchy labeling for high molecular weight cytokeratin (34BE12) is common.

Cytogenetically, clear cell papillary RCC lacks typical abnormalities seen in either clear cell RCC or papillary RCC. Clear cell papillary RCC does not demonstrate 3p deletion or trisomy 7/17. VHL gene mutation and promoter methylation are also absent.

In summary, clues to the diagnosis of clear cell papillary RCC include distinctive subnuclear cytoplasmic clearing, low nucleolar grade, prominent smooth muscle stroma, and an association with end-stage background kidney. The morphology and typical immunhistochemical pattern of positivity for CK7 and CAIX but negative CD10 and AMACR supports the diagnosis. Absence of 3p loss or trisomy of 7 and 17 also supports the diagnosis.

Xp11 translocation RCC

Xp11 translocation RCCs are defined by chromosomal translocations involving TFE3 transcription factor gene located at the Xp11.2 locus. TFE3 belongs to the same family of transcription factors as MiTF, TFEB and TFEC. The translocation fuses TFE3 to one of multiple possible reported partner including ASPL, PRCC, NonO (p54nrb), SFPQ (PSF), CLTC, DVL2 and PARP14. All of the gene fusions result in overexpression of the TFE3 fusion protein, making it detectable by IHC.

RCCs of any type are rare in children, and constitute 5% of pediatric renal neoplasms. However, Xp11 translocation RCC likely comprises the most common subtype seen in this age group. Approximately 1-4% of adult RCCs are Xp11 translocation RCC. However, because RCC is overall much more common in adults, adult Xp11 translocation RCC likely outnumber pediatric cases. Since these neoplasms have only recently been recognized, outcome data is still premature and good long term follow up data are lacking. Those patients presenting with metastatic disease almost always die of disease. Adult cases have fared worse than pediatric ones. In contrast, children presenting with lymph node involvement and lack of hematogenous spread have a favorable short term prognosis.

Microscopically, the most distinctive and common pattern is the presence of both clear cells and papillary architecture. The ASPL-TFE3 gene fusion, in particular, is associated with voluminous cytoplasm, vesicular nuclei, and numerous psammoma bodies within the stroma. Xp11 translocation RCC can have a wide range of morphologic appearances. Some cases even have a subpopulation of smaller bluer cells surrounding discrete hyaline material mimicking the related RCCs with the t(6:11)(p21;q12) translocation and resulting Alpha-TFEB gene fusion.

The IHC profile of Xp11 translocation RCC differs from both clear cell RCC and papillary RCC. Epithelial markers such as AE1/AE3, CK7 and EMA tend to be underexpressed. Vimentin can be negative. However, similar to both clear cell RCC and papillary RCC, PAX8 is positive. Occasional Xp11 translocation RCCs can express melanocytic markers such as Melan-A and HMB-45. They only focally express CA-IX. In the setting of RCC, cathepsin-K, a lysosomal protease, is a highly specific but only approximately 50% sensitive marker for Xp11 translocation RCCs. Other renal neoplasms including clear cell RCC and papillary RCC are negative for this marker.

The most sensitive and specific IHC marker is strong nuclear labeling for TFE3. This assay uses an antibody to the C-terminal portion of the TFE3 transcription factor, which is retained in the fusion product. Although TFE3 protein is ubiquitously expressed, it is normally expressed at levels undetectable by immunohistochemistry. The fusion product brings TFE3 in close proximity to a novel promoter, leading to overexpression of the fusion protein. Unfortunately, this assay can be technically challenging, as suboptimal fixation may result in high background with detection of native TFE3 protein. Adjacent tubules provide a helpful negative control. TFE3 break-apart FISH assays can be performed on paraffin embedded tissue are useful tools to provide molecular confirmation of the diagnosis.

In summary, papillary architecture with clear cells is quite typical of an Xp11 translocation RCC. Specific clues to suspect the diagnosis include young age of the patient, stromal psammomatous calcifications, and underexpession of cytokeratins by immunohistochemistry. Support for the diagnosis can be achieved with cathepsin K immunoreactivity and TFE3 labeling by IHC, or most optimally by demonstration of TFE3 gene rearrangement by FISH.

II. Recently Described Renal Cell Carcinomas (RCCs) with Eosinophilic Cells

HLRCC-Associated RCC

The hereditary leiomyomatosis renal cell carcinoma (HLRCC) syndrome is autosomal dominant and associated with germline mutations in the fumarate hydratase gene located at chromosome 1q42. The main features of this syndrome are smooth muscle and renal neoplasms. These patients frequently harbor multiple cutaneous and uterine leiomyomas. The uterine leiomyomas are particularly difficult to manage, and approximately 50% of women require hysterectomy before reaching the age of 30 years. Rare cases of leiomyosarcoma have been reported.

The RCCs associated with this syndrome affect approximately one-third of patients, and typically resemble sporadic “type 2” PRCC or high grade collecting duct carcinoma. Unlike most hereditary RCC, HLRCC-associated RCC are solitary and highly aggressive. The majority of patients have presented with advanced stage disease, and have died of these cancers. Morphologically, the most distinctive feature of these neoplasms is a distinct prominent eosinophilic nucleolus with a clear halo, similar to the cytology of a cytomegalovirus inclusion. Interestingly, the distinctive eosinophilic nucleolus is also found in the leiomyomas that these patients typically harbor. The renal neoplasms frequently have papillary architecture, but other architectures such as cribriform and solid may also be present. The diagnosis carries significant implication for both patient management and follow-up of family members. For example, patients with this syndrome (unlike patients with other hereditary RCC syndromes), are followed more closely for even small (<3cm) renal masses, and taken to surgery more quickly due to the highly aggressive nature of these RCC relative to other hereditary RCC. Loss of fumarate hydratase or abnormal S-(2-succinyl) cysteine (2SC) labeling by IHC can support the diagnosis, which should be confirmed by genetic testing.

Acquired Cystic Disease-Associated Renal Cell Carcinoma (ACD-RCC)

Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is the most common subtype of RCC occurring in end-stage kidneys, specifically those with acquired cystic disease. Most tumors are diagnosed incidentally on radiologic follow-up in patients with chronic renal disease. Multifocality and bilaterality are seen in greater than 50 and 20 percent of the cases, respectively. The tumor is characterized by cells with eosinophilic cytoplasm, cribriform/sieve- like architecture, and intratumoral oxalate crystals. Most tumor cells have abundant granular eosinophilic cytoplasm, with round to oval nuclei showing vesicular chromatin and prominent nucleoli. Foci with clear to vacuolated cytoplasm may also be present. Intra- and/or inter-cellular microscopic lumina ("holes"), impart a cribriform/sieve-like appearance.

ACD-associated RCC label diffusely for AMACR and are often negative for CK7, but a specific IHC profile is not required to make the diagnosis. Molecular genetic studies have not revealed a specific underlying alteration. ACD- RCC has a relatively favorable prognosis because most cases are diagnosed early in patients on long-term follow-up for chronic renal disease. However, rare typical cases, as well as rare tumors with sarcomatoid or rhabdoid features, can metastasize. ACD-RCC is likely more aggressive compared to other histological types arising in the setting of end-stage kidney disease.

SDH-Deficient RCC

RCCs are associated with germline succinate dehydrogenase B mutations which defines the pheochromocytoma/paraganglioma syndrome type IV (PGL4). This syndrome is characterized by predisposition to pheochromocytoma, paraganglioma, so called type II gastrointestinal stromal tumors (similar to those frequently seen in children and in association with Carney syndrome), and an estimated approximately 14% lifetime risk of renal neoplasia. RCC associated with germline succinate dehydrogenase B mutations (SDHB RCC) have generally affected young adults, and most cases have been associated with an indolent course on limited follow-up. The exceptions are rare cases which underwent high grade transformation or sarcomatoid change, some of which metastasized and resulted in patient death.

Morphologically, these neoplasms are typically unencapsulated and composed of compact nests of eosinophilic polygonal cells, with entrapped renal tubules at the periphery. The cells may have vacuolated cytoplasm, or distinctive pale eosinophilic cytoplasmic inclusions which correspond to giant mitochondria by electron microscopy. Loss of SDHB protein by immunohistochemistry is a sensitive and specific marker for these neoplasms.

Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) was recognized by Charles Davis et. al. in 1995, and occurs almost exclusively in children and young adults with sickle cell trait. It is highly invasive and almost uniformly lethal. These tumors often have rhabdoid cytology, and inflamed desmoplastic stroma. RMC shows loss of INI1 labeling by IHC, similar to pediatric rhabdoid tumors.

VCL-ALK RCC

Three cases of RCC harboring a t(2;10)(p23;q22) translocation resulting in a fusion of the gene for the cytoskeletal protein vinculin (VCL) with the anaplastic lymphoma kinase (ALK) gene have been reported. Of note, all cases occurred in young patients (mean 9 years) with sickle cell trait (raising the differential diagnosis of renal medullary carcinoma), and demonstrated distinctive morphology characterized by polygonal to spindle cells with abundant eosinophilic cytoplasm and frequent intracytoplasmic lumina. INI1 is intact. While the case numbers are small, the findings suggest that VCL-ALK RCC have distinctive clinical and pathologic features. References

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