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New and emerging renal tumour entities
PATHOLOGY OF KIDNEY TUMOURS
New and emerging renal tumour entities
distinct clinicopathological features and are therefore recognized as new RCC subtypes. Other entities, such as anaplastic lymphoma kinase associated RCC and thyroid like follicular carcinoma of the kidney, are considered emerging RCC entities and additional studies are needed to further elucidate their clinical, pathological and molecular characteristics. Correct diagnosis of these tumours is, however, critical for not only understanding of their pathogenesis but also patient management.
Naoto Kuroda Ondrej Hess Ming Zhou
Clear cell papillary renal cell carcinoma
Abstract
Although initially reported in end-stage kidneys, this tumour is now most commonly sporadic in otherwise normal kidneys.2e9 It accounts for 1e4.3% of all epithelial neoplasms. The patient’s age ranges from 18 to 88 (mean 70) years. There is no gender predilection. Patients are usually asymptomatic.9 Tumours are usually small.3e6 Grossly, the tumour shows variable cystic formation with focal solid consistency and the cut surface is white-tan, pale yellow, or red-brown. Histologically, the tumour is composed of clear cells forming a variety of growth patterns including papillary, tubular, acinar, solid and cystic. Branching tubules and papillae are common.6 Nuclear grade is low, typically ISUP nucleolar grade 1 or 2 in most cases. Nuclei often show linear arrangement away from the basement membrane (Figure 1A).5e7 Smooth muscle is often identified within the stroma. Immunohistochemically, neoplastic cells are positive for cytokeratin 7 and carbonic anhydrase IX with characteristic “cup-shaped pattern” (Figure 1B), but negative for AMACR, CD10 and RCC Ma.2e9 TFE3 is consistently negative.5,7 This tumour shows no genetic characteristics of clear cell RCC or papillary RCC.3,4 The array CGH analysis showed no chromosomal imbalances.5 Partial nephrectomy may be best therapeutic option for a solitary lesion. Active surveillance may be considered if a correct diagnosis is rendered on needle core biopsy.9 Prognostically there has been no reports of local recurrence or distant metastasis.6e8 Further studies are needed to ascertain its biological behaviour; however, this tumour is best regarded as having an indolent clinical behaviour.
In this review, we discuss new and emerging renal cell carcinoma (RCC) entities, including anaplastic lymphoma kinase (ALK) RCC, oncocytic variant of chromophobe RCC, atrophic kidney-like renal tumour, biphasic alveolosquamoid RCC, tubulocystic RCC, thyroidlike follicular carcinoma of the kidney, succinate dehydrogenase syndrome-associated renal tumour, deficient RCC, BirteHoggeDube hereditary leiomyomatosis/renal cell carcinoma associated RCC, tuberous sclerosis-associated RCC, PTEN hamartoma tumour syndrome, clear cell papillary RCC, acquired cystic disease-associated RCC, Xp11.2 RCC, t(6;11) RCC and renal hemangioblastoma. These tumours have clinical, pathological and genetic features distinct from other common RCCs and therefore are important to recognize. Some of them have been recognized as distinct histological subtypes in the 2016 World Health Organization Classification. However, further studies are needed to elucidate their clinicopathologic features and molecular mechanisms.
Keywords Acquired cystic disease-associated RCC; ALK; anaplastic lymphoma kinase; atrophic kidney-like renal tumour; BirteHoggeDube syndrome-associated renal tumour; clear cell papillary RCC; HLRCC associated RCC; succinate dehydrogenase-deficient RCC; thyroid-like follicular carcinoma of the kidney; translocated associated RCC; tuberous sclerosis-associated RCC; tubulocystic RCC
Introduction Recently, many new renal tumour entities and new concepts regarding the “established” renal tumour entities have been described and incorporated into the 2012 International Society of Urological Pathology (ISUP) classification of renal tumours.1 Several entities, including tubulocystic RCC, clear cell papillary RCC, and succinate dehydrogenase (SDH)-deficient RCC, have
Acquired cystic disease-associated renal cell carcinoma This tumour of unique morphology occurs exclusively in patients with acquired cystic disease (ACD).2 ACD-RCC accounts for 36% of renal epithelial tumours in the end-stage kidneys and often in patients on haemodialysis for more than 10 years.2,10,11 Histologically, it is characterized by cells with deeply eosinophilic cytoplasm forming multiple patterns including microcystic or cribriform. Intratumoral oxalate crystal deposition is characteristic (Figure 2).2,10e13 The nuclear atypia is usually ISUP Grade 3.11 Some cases have sarcomatoid or rhabdoid changes which correlate with adverse prognosis.14,15 Immunohistochemically, tumour cells are positive for AMACR, CD10 and RCC Ma, but negative for cytokeratin 7.12 Ultrastructurally, tumour cells contain abundant mitochondria.14 FISH, G-band karyotype and array CGH analysis show gain of chromosomes 3, 7, 16, 17 and sex chromosome.12,13,16 Hence, this tumour may be closely related to papillary RCC.12,17 Chromosomal aneuploidy, particularly gain
Naoto Kuroda MD is Director, Department of Diagnostic Pathology, Kochi Red Cross Hospital, Kochi, Japan. Conflicts of interest: none declared. Ondr ej Hess MD PhD is Professor, Department of Pathology, Faculty of Medicine, University Hospital Plzen, Charles University, Pilsen, Czech Republic; Biomedical Centre, Faculty of Medicine in Plzen, Charles University in Prague, Pilsen, Czech Republic. Conflicts of interest: none declared. Ming Zhou MD PhD is Professor, Surgical Pathology and Urologic Pathology, NYU Medical Center Tisch Hospital, New York City, USA. Conflicts of interest: none declared.
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PATHOLOGY OF KIDNEY TUMOURS
Figure 1 Clear cell papillary renal cell carcinoma. (a)Tumour cells with clear cytoplasm form cystic and papillary configuration. Nuclei are polarized away from the basement membrane (Courtesy of Dr. Kawakami F, Kobe, Japan). (b) Immunohistochemical stain for CAIX shows cup-shaped pattern (Courtesy of Dr. Watanabe R, Shizuoka, Japan).
1q34, NonO at Xq12 and CLTC at 17q23.19e22 Partner genes at chromosomes 3q23, 10q23 and 19q13.1 remain unidentified.23 e25 This tumour generally affects children and young adult and is the most common form of RCC in children. It also occurs in adults and accounts for 1% of all renal tumours in adults.1,19 e23,26e29 Patients may present with haematuria or abdominal mass.29 A previous exposure to cytotoxic chemotherapeutic agents in childhood may be a risk factor.30 Grossly, the tumour is well-marginated but unencapsulated. The cut surface displays yellow-tan colour with soft consistency. Histologically, this tumour is characterized by mixed papillary, nested and alveolar growth patterns. Tumour cells have voluminous clear and/or eosinophilic cytoplasm, distinct cell border, and large nuclei with vesicular chromatin and prominent nucleoli (Figure 3). Psammoma bodies or hyaline nodules are often identified in the stroma.23,26e28 Immunohistochemically, tumours cells underexpress and are usually focally and weakly positive for epithelial markers including keratins and EMA. It shows nuclear positivity for TFE3 protein which seems to be a highly sensitive and specific marker for this tumour (although it is also positive in alveolar soft part sarcoma). However, excessive antigen retrieval or use of concentrated antibody may lead to false positivity in other tumours.31 Ultrastructurally, rhomboid crystals or dense granules are identified in the cytoplasm of ASPL-TFE3 RCC.20,29 FISH using the TFE3 gene break-apart probe is helpful for establishing the diagnosis.32 Patients are usually treated with radical or partial nephrectomy.28 Extended lymphadenectomy is also performed. For metastatic lesions, VEGF or mTOR inhibitors may lead to improved outcome.29 Adult tumours seem to behave more aggressively than paediatric ones.26,28,29 Metastasis to lymph nodes is commonly observed.27e29 t(6;11)/TFEB translocation RCC is characterized by the fusion of TFEB gene at chromosome 6p21 to Alpha gene at chromosome 11q12. It generally occurs in children and young adults, but has been reported in adults.27,33e39 It is very rare and accounts for <1% of all renal tumours. The age ranges from 6 to 57 (mean 23) years. There is a slight female preponderance. The tumour ranges from 1 to 20 (mean 6.5) in size.38 Grossly, the tumour is
of chromosome 3 and 16, may be characteristic of this tumour.13,18 Radical or partial nephrectomy is usually performed. These tumours seem to have better prognosis than their sporadic counterparts as patients are under intense surveillance for their underlying medical kidney disease with various imaging studies. However, tumours with sarcomatoid or rhabdoid differentiation may behave aggressively.2,14,15
Microphthalmia/TFE (MiT) gene family translocation renal cell carcinoma MiT gene family translocation RCC includes Xp11.2/TFE3 translocation RCC and t(6;11)/TFEB translocation RCC. TFE3 and TFEB both belong to the MiT gene family. Xp11.2/TFE3 translocation RCC and t(6;11)/TFEB translocation RCC share clinical, pathological and genetic features and are therefore grouped together as MiT gene family translocation RCCs. Xp11.2/TFE3 translocation RCC is characterized by a translocation between the TFE3 gene at chromosome Xp11.2 and another gene including ASPL at 17q25, PRCC at 1q21, PSF at
Figure 2 Acquired cystic disease-associated renal cell carcinoma. The tumour cells with deeply eosinophilic to oncocytic cytoplasm form microcystic or cribriform pattern. Intratumoral oxalate crystals are present.
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PATHOLOGY OF KIDNEY TUMOURS
treatment. For metastatic diseases, VEGF and mTOR inhibitors may be used.37,38 Prognosis is uncertain due to small number of reported cases. Most cases in children and young adults seem to be indolent. However, some tumours in adults presented with metastasis and aggressive behaviour.34e38
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome HLRCC is an autosomal dominant inherited cancer syndrome characterized by multiple cutaneous leiomyomas, early onset uterine leiomyomas and renal tumours.41 Grossly, the renal tumour is usually solitary and unilateral, and forms a solid mass with frequent minor cystic component.41 Histologically, the tumour showed mixed architectural patterns with papillary, tubular, tubulopapillary, solid, and cystic configurations.41,42 Collecting duct carcinoma-like or tubulocystic carcinoma-like pattern may be observed.42 The most characteristic features, though, are large nuclei with very prominent eosinophilic nucleoli surrounded by clear halos, reminiscent of cytomegaloviral inclusions (Figure 5A).41e43 The similar nuclear features may be observed also in uterine leiomyomas. Immunohistochemically, HLRCC tumours show diffuse and strong nuclear and cytoplasmic S-(2-succino)-cysteine (2SC) protein (Figure 5B) and this staining pattern generally differs from that of other high grade RCCs and is considered diagnostic of HLRCC.42 However, this antibody is not commercially available. Genetically, somatic mutation of fumarate hydratase (FH ) gene or loss of heterozygosity is observed in addition to FH germline mutation in most cases.41e43 Radical nephrectomy including adrenal gland resection and regional lymphadenectomy is the choice of therapy.42,43 The tumour usually behaves in an aggressive fashion with frequent metastasis to regional lymph nodes, adrenal gland, liver or lung.41e43
Figure 3 Xp11.2/FEE3 renal cell carcinoma. Tumour cells with abundant clear/eosinophilic cytoplasm grow in nested and alveolar pattern. Psammoma bodies are present in the stroma.
well-circumscribed with frequent satellite nodules. The cut surface shows tan-brown to yellow colour. Cystic formation may be seen. Histologically, tumours comprise nests and sheets of cells with abundant clear to eosinophilic cytoplasm, round nuclei with vesicular chromatin and prominent nucleoli. The deposition of basement membrane materials in the stroma is common. The most characteristic finding, though, is the biphasic pattern with small lymphocyte-like tumour cells surrounding basement membrane material and outer large tumour cells with abundant eosinophilic to clear cytoplasm, resulting in rosette-like structures (Figure 4).33e39 Immunohistochemically, epithelial markers including EMA and cytokeratin AE1/3 are generally negative or at most focally and weakly positive. HMB45, Melan A and Cathepsin-K are positive. The nuclear expression of TFEB is highly sensitive and specific for this tumour.33e39 Ultrastructurally, tumour cells contain abundant mitochondria and lysosomeassociated structures.33,39 The fusion of TFEB gene to Alpha gene can be confirmed by cytogenetics, RT-PCR or DNA-PCR.33,34 FISH using TFEB gene break apart probe may be useful for the diagnosis.40 Radical or partial nephrectomy is the choice of
Succinate dehydrogenase (SDH)-deficient renal carcinoma This tumour is caused by germline mutations in one of the four subunits of SDH that form the mitochondrial complex 2 on the inner membrane of mitochondria. The complex plays a critical role in Krebs cycle. Mutation in any of the four subunits causes familial paraganglioma/pheochromocytoma syndrome which predisposes patients to pheochromocytoma, paraganglioma or gastrointestinal stromal tumour and RCC. SDHB is most commonly mutated. This tumour tends to affect young adults. The tumour is grossly well-marginated and the cut surface demonstrates tan to red colour. Cystic change may be seen. Histologically, the tumour is often described as “oncocytic tumour with bubbly appearance” as it is made up of cuboidal to oval cells with eosinophilic cytoplasm with bubbly change due to intracytoplasmic vacuoles or inclusions (Figure 6A). Ultrastructural studies have confirmed that the intracytoplasmic vacuoles are giant mitochondria. Nuclei are generally of low grade, but high grade including sarcomatoid change may occur. Immunohistochemically, tumour cells are positive for PAX8 and AMACR, but the negativity for SDHB. Because mutations in any of the SDH subunits destabilize the mitochondrial complex 2 and lead to loss of SDHB proteins, SDHB IHC has been shown to be a very effective way to screen
Figure 4 t(6;11) renal cell carcinoma. The characteristic feature of this tumour is “biphasic pattern” with small, lymphocyte-like and large tumour cells surrounding basement membrane materials creating rosette-like structures (Courtesy of Dr. Ishihara A, Miyazaki, Japan).
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PATHOLOGY OF KIDNEY TUMOURS
Figure 5 Hereditary leiomyomatosis and renal cell carcinoma syndrome. (a) Tumour cells with eosinophilic cytoplasm form papillary and solid architecture. The nuclei possess prominent nucleoli and resemble cytomegaloviral inclusion. (b) Immunohistochemical stain for S-(2-succino)cysteine (2SC) protein shows diffuse and strong nuclear and cytoplasmic positivity while the stromal cells and vessels are negative.
tubules/collecting ducts (cytokeratin 7, cytokeratin 19, Keratin 903 and parvalbumin).47e50 In FISH analysis, gain of chromosomes 7 and 17 and loss of chromosome Y are frequently seen. Therefore, tubulocystic carcinoma seems to be linked to papillary RCC genetically.48,50 Recently several studies show that tubulocystic RCC occasionally harbours high grade poorly differentiated components and these cases may in fact represent HLRCC syndrome.51e53 Patients are often treated with radical or partial nephrectomy and VEGF inhibitors may be effective for advanced tumours.47 This tumour seems to behave in an indolent fashion as a general rule.48,50 However, local recurrence and metastasis to lymph node, bone and liver have been reported in some cases, although it is unclear whether these cases actually represent HLRCC syndrome.49
for SDH mutation (Figure 6B). Surgical resection is the choice of treatment. Tumours without high grade component or coagulative necrosis behave in an indolent fashion, but those with dedifferentiation or in young adults are likely to behave aggressively.44e46
Tubulocystic carcinoma This tumour commonly occurs in the fifth and sixth decade of life and there is a strong male predilection. Most lesions are incidentally discovered, but some patients present with abdominal pain and mass and haematuria.47 On gross examination, the tumour shows well-defined multicystic lesion and the cut surface displays spongy or bubble wrap appearance (Figure 7A).47e50 Microscopically, the tumour consists of various sized cysts lined by flat, cuboidal, columnar and hobnail cells with eosinophilic cytoplasm, enlarged nuclei and prominent nucleoli (Figure 7B). Papillary components are observed in some tumours.48,50 Immunohistochemically, tumour cells show both phenotype of proximal tubules (AMACR and CD10) and distal
Anaplastic lymphoma kinase (ALK) renal cell carcinoma Seven cases have been reported in both paediatric and adult patients.54e58 It tends to affect relatively young patients. In US, paediatric ALK RCC is seen exclusively in patients with sickle
Figure 6 Succinate dehydrogenase-deficient renal cell carcinoma. The tumour cells have eosinophilic bubbly cytoplasm and indistinct cell border (a) and are negative for SDHB (b). The vascular endothelial cells are positive for SDHB and serve as the positive internal control.
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PATHOLOGY OF KIDNEY TUMOURS
Figure 7 Tubulocystic carcinoma. The cut surface shows spongy or bubble wrap appearance (a). Microscopically it consists of tubules and variably sized cysts lined by flat, cuboidal, and hobnail cells with eosinophilic cytoplasm (b, courtesy of Dr. Matsumoto H, Okinawa, Japan).
years. The ratio of male to female is 2:3. The tumour size ranges from 2 to 11 cm with a mean size of 6 cm.60 This tumour may resemble renal oncocytoma macroscopically and microscopically. Grossly, the tumour is well-marginated but unencapsulated. The cut surface displays a brown colour. Microscopically, the tumour is characterized by the proliferation of tubular or solid-sheet pattern of oncocytic cells with indistinct cell border and round centrally located nuclei lacking wrinkled appearance (Figure 9). Nested growth pattern typical of renal oncocytoma and perinuclear halo are absent. Immunohistochemically, tumour cells are diffusely positive for cytokeratin 7. Chromosomal analysis using FISH show chromosomal loss involving multiple chromosomes, including 7, 10, 13, 17 and 21, the chromosomal features suggestive of chromophobe RCC.59,60 Radical or partial nephrectomy is indicated. The core needle biopsy, however, may lead to diagnostic pitfalls, particularly if only routine H&E stain is examined without immunohistochemistry.60 The prognosis of this tumour remains uncertain because of the small number of reported cases, although previously reported cases showed excellent outcomes.60
cell traits and some are bona fide renal medullary carcinoma with loss of INI-1 protein expression. All cases harbour ALKVCL gene fusion.54,55 However, ALK RCC in adults seems to have a close link to ALK lung cancer, malignant lymphoma and inflammatory myofibroblastic tumour, demonstrating the fusion between ALK and EML4 or TMP3 gene.56 ALK RCC in paediatric patients comprises diffuse sheets of epithelioid cells with abundant eosinophilic cytoplasm and intracytoplasmic lumens and intratumoral inflammatory cells. Tumours in adults show mucinous cribriform pattern (Figure 8) or papillary configuration with mucinous background.56 ALK protein overexpression is detected by immunohistochemistry in some cases.54e56 Radical or partial nephrectomy, offers hope of cure. The presence of ALK gene fusion raises the possibility that this tumour may be amenable to the target therapy by ALK inhibitors, particularly for patients with the advanced stage disease.
Chromophobe renal cell carcinoma, oncocytic variant To date, five such cases have been reported.59,60 The age of patients’ ranges from 74 to 82 years with a mean age of 73.8
Atrophic kidney-like renal tumour Four cases have been reported.61,62 The gross picture shows well circumscribed tumour with capsule and honeycomb or spongy appearance. The cut surface of the tumour imparts a tan to brown colour. Histologically this tumour resembles an atrophic kidney or adenomatous goitre (Figure 10) and consists of microfollicles, psammoma bodies or amorphous dark-blue deposits and capsule containing smooth muscle cells. There is no cytological atypia. No significant chromosomal changes were identified using array comparative genomic hybridization (CGH) in one tumour. Prognostically, this tumour seems to show an indolent clinical behaviour.61,62
Biphasic alveolosquamoid renal cell carcinoma Two cases have been described to date.63 On gross examination, the tumour is well demarcated and the cut surface shows a grey
Figure 8 Anaplastic lymphoma kinase renal cell carcinoma. The tumour demonstrates cribriform growth pattern with a mucinous background (provided by Takeuchi K, Tokyo, Japan).
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PATHOLOGY OF KIDNEY TUMOURS
cells are positive for PAX2 and PAX8, but negative for TTF-1 and thyroglobulin. CGH analysis of one tumour showed gain of 7q36, 8q24, 12, 16, 17p11-q11, 17q24, 19q, 20q13, 21q22.3, and Xp, and loss of 1p36.3 and 9q21-33.64 Radical or partial nephrectomy should be the therapeutic option. Clinically this tumour pursues an indolent course, but metastasis to lymph nodes or lung has been reported.64e66
syndrome (BHD)-associated renal BirteHoggeDube tumour BHD syndrome is characterized by a triad of skin lesions (fibrofolliculoma, trichodiscoma and acrochordon), pulmonary lesions (cyst and pneumothorax) and renal tumours. The culprit gene is folliculin (FLCN ) on chromosome 17p11.2. Diverse histological subtypes including hybrid oncocytic tumour, chromophobe RCC, oncocytoma, papillary RCC, clear cell RCC and unclassified RCC have been reported in this disease. Among them, hybrid oncocytic tumours are most frequent.67e70 Macroscopically, these tumours are well circumscribed without encapsulation and the cut surface shows homogenous tan to brown colour. Microscopically, hybrid oncocytic tumours possess areas that resemble both chromophobe RCC and renal oncocytoma (Figure 11).67e70 Some hybrid oncocytic tumours may show clear cell change.68 Intratumoral peripheral small papillary tufts may be a diagnostic clue to this tumour.69 Renal cysts or multiple renal oncocytosis are also often observed.69,70 The screening with annual ultrasonography or magnetic resonance imaging is recommended after the age of 20 years. The surgical resection and cryoablation/radiofrequency ablation may be suitable therapeutic option for solitary and multiple lesions. For advanced tumours, mTOR inhibitors may be beneficial. Prognostically, patients harbouring hybrid oncocytic tumour, chromophobe RCC and oncocytoma have an indolent clinical course, but the presence of clear cell component may harbinger a worse prognosis.70
Figure 9 Chromophobe renal cell carcinoma, oncocytic variant. The tumour consists of oncocytic cells with predominant tubular growth pattern (Courtesy of Dr. Yamaguchi T, Kyoto, Japan).
to tan colour. Microscopically, the tumor is characterized by two populations of large and small cells. The large cells have squamoid appearance and form solid-alveolar islands rimmed by smaller tumour cells. Interestingly, the expression pattern of cytokeratin 20 and high molecular weight cytokeratin 5/6 differs in large and small tumour cells. The array CGH performed in one tumour showed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22 and partial gains of chromosomes 1, 5, 11, 12 and 13. Regarding the clinical behaviour, one patient showed subcutaneous metastasis.63
Thyroid-like follicular carcinoma of the kidney This tumour is extremely rare. The age of patients ranges from 29 to 83 years. There is a slight female predilection.1 Grossly, the tumour is well-circumscribed with encapsulation and the cut surface is tan, brown to dark brown. Microscopically, the tumour resembles thyroid tissue and has to be distinguished from thyroid carcinoma metastatic to the kidney. It consists of micro- and macrofollicular structures that are lined by cells with amphophilic to eosinophilic cytoplasm and round nuclei. The follicles contain colloid-like substance. Immunohistochemically, tumour
Tuberous sclerosis-associated renal cell carcinoma RCC occurs in 2e4 % of tuberous sclerosis patients.71 Most tumours are found at young age and there is a female
patient. Figure 11 “Hybrid oncocytic tumour” from a BirteHoggeDube The tumour contains areas that resemble both chromophobe RCC and renal oncocytoma.
Figure 10 Atrophic kidney-like tumour. The tumour simulates the morphology of end-stage kidney (Courtesy of Dr. Oshiro Y, Ehime, Japan).
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PATHOLOGY OF KIDNEY TUMOURS
predominance.72 Half of the patients have multiple lesions.72 Histologically, there are wide array of tumours, including renal angiomyoadenomatous tumour (or RCC with smooth muscle stroma), chromophobe RCC-like, eosinophilic-solid cystic morphology and hybrid oncocytic/chromophobe tumour (HOCT) as well as previously reported histological types including clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC and renal oncocytoma. Concurrent renal angiomyolipoma is frequent. Immunohistochemically, tumour cells show positive stain for PAX8, cytokeratin 7, CD10, vimentin and carbonic anhydrase IX, but the negativity for HMB45, SDHB, TFE3 and AMACR.71,72 By FISH analysis, gain of chromosomes 7 and 17 was observed in a few cases.71 For treatment, surgical resection has been performed for the majority of patients.71,72 These tumours generally pursue an indolent clinical course, but metastasis to lymph nodes has been reported.68
undoubtedly critical for patient management. In the last decade, many renal tumours have been identified with clinical, pathological and genetic features distinct from other common, better characterized renal tumours.80e82 Several of the tumours are included in the 2016 WHO classifications as new histological subtypes, while others are considered emerging entities and require further characterization. A REFERENCES 1 Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol 2013; 37: 1469e89. 2 Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease. An experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol 2006; 30: 141e53. 3 Aydin H, Chen L, Cheng L, et al. Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol 2010; 34: 1608e21. 4 Rohan SM, Xiao Y, Liang Y, et al. Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol 2011; 24: 1207e20. 5 Adam J, Couturier J, Molinie V, Vieillefond A, Sibony M. Clear-cell papillary renal cell carcinoma: 24 cases of a distinct low-grade renal tumour and a comparative genomic hybridization array study of seven cases. Histopathology 2011; 58: 1064e71. 6 Williamson SR, Eble JN, Cheng L, Grignon DJ. Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile. Mod Pathol 2013; 26: 697e708. 7 Park JH, Lee C, Suh JH, Moon KC. Clear cell papillary renal cell carcinoma: a report of 15 cases including three cases of concurrent other-type renal cell carcinomas. Korean J Pathol 2012; 46: 541e7. 8 Alexiev BA, Drachenberg CB. Clear cell papillary renal cell carcinoma: incidence, morphological features, immunohistochemical profile, and biological behavior: a single institution study. Pathol Res Pract 2014; 210: 234e41. 9 Kuroda N, Ohe C, Kawakami F, et al. Clear cell papillary renal cell carcinoma: a review. Int J Clin Exp Pathol 2014; 15: 7312e8. 10 Nouh MAAM, Kuroda N, Yamashita M, et al. Renal cell carcinoma in patients with end-stage renal disease: relationship between histological type and duration of dialysis. BJU Int 2009; 105: 620e7. 11 Kuroda N, Ohe C, Mikami S, et al. Review of acquired cystic disease-associated renal cell carcinoma with focus on pathobiological aspects. Histol Histopathol 2011; 26: 1215e8. 12 Pan CC, Chen YJ, Chang LC, Chang YH, Ho DMT. Immunohistochemical and molecular genetic profiling of acquired cystic disease-associated renal cell carcinoma. Histopathology 2009; 55: 145e53. 13 Kunt E, Yusenko MV, Nagy A, Kovacs G. Oligoarray comparative genomic hybridization of renal cell tumors that developed in patients with acquired cystic renal disease. Hum Pathol 2010; 41: 1345e9.
PTEN hamartoma tumour syndrome This syndrome is an autosomal dominant inherited disorder and is associated with germline mutations in PTEN gene.73,74 Clinically, patients afflicted by this syndrome have increased cancer risk of breast, endometrium and thyroid gland. Skin lesions such as acral keratosis and facial trichilemmoma may be observed.74 Reported renal tumours include papillary RCC, chromophobe RCC and clear cell RCC.73,74 Immunohistochemically, tumour cells show loss of PTEN protein.73 Loss of heterozygosity at PTEN gene locus is common.74 Partial or radical nephrectomy is the best therapeutic option ad multifocal disease is rare.73,74 For advanced tumours, mTOR inhibitors may benefit patients.74 The biological behaviour seems to be indolent, although reported cases are scarce.74
Renal hemangioblastoma Fourteen renal hemangioblastomas have been reported.75e78 The incidence may, however, be higher as some clear cell RCC, especially those without VHL gene mutation, may represent renal hemangioblastomas. This tumour can occur sporadically without association with von HippeleLindau disease. Histologically, tumour cells have clear to eosinophilic cytoplasm with vacuolation resembling lipoblasts admixed with spindle cells. The stroma contains complex capillary network with occasional hemangiopericytomatous vascular pattern. Immunohistochemically, tumour cells are positive for alphainhibin and S-100 protein, but negative for HMB45, Melan A. PAX2, PAX8, CD10, carbonic anhydrase IX may be positive in these tumours.75e78 G-band karyotype and array CGH analysis of one tumour showed no chromosomal changes. Recently, clear cell RCCs with hamangioblastoma-like features have been reported,79 suggestive of its close relationship with clear cell RCC. This tumour is benign.75e78 If an accurate diagnosis can be established on needle biopsy, patients can be managed by active surveillance.
Conclusions Renal cell carcinomas are heterogeneous in their clinical, pathological and genetic features. Their accurate classification is
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PATHOLOGY OF KIDNEY TUMOURS
M, Ballard ET, et al. Translocation carcinomas of the 30 Argani P, Lae kidney after chemotherapy in childhood. J Clin Oncol 2006; 24: 1529e33. 31 Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003; 27: 750e61. 32 Rao Q, Williamson SR, Zhang S, et al. TFE3 break-apart FISH has a higher sensitivity for Xp11.2 translocation-associated renal cell carcinoma compared with TFE3 or Cathepsin K immunohistochemical staining alone. Expanding the morphologic spectrum. Am J Surg Pathol 2013; 37: 804e15. 33 Argani P, Hawkins A, Griffin CA, et al. A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6; 11)(p21;q12) chromosomal translocation. Am J Pathol 2001; 158: 2089e96. M, Hutchinson B, et al. Renal carcinomas with the 34 Argani P, Lae t(6;11)(p21;q12). Clinicopathologic features and demonstration of the specific Alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA-PCR. Am J Surg Pathol 2005; 29: 230e40. c ek T, Michal M, et al. A distinctive trans35 Petersson F, Vane location carcinoma of the kidney; “rosette forming,” t(6;11), HMB45-positive renal tumor: a histomophologic, immunohistochemical, ultrastructural, and molecular genetic study of 4 cases. Hum Pathol 2012; 43: 726e36. 36 Inamura K, Fujiwara M, Togashi Y, et al. Diverse fusion patterns and heterogenous clinicopathologic features of renal cell carcinoma with t(6;11) translocation. Am J Surg Pathol 2012; 36: 35e42. 37 Ishihara A, Yamashita T, Takamori H, Kuroda N. Renal carcinoma with t(6;11)(p21;q12) translocation. Report of an adult case. Pathol Int 2011; 61: 539e45. 38 Kuroda N, Tanaka A, Sasaki N, et al. Review of renal carcinoma with t(6;11)(p21;q12) with focus on clinical and pathobiological aspects. Histol Histopathol 2013; 28: 685e90. 39 Matuura K, Inoue T, Kai T, et al. Molecular analysis of a case of renal cell carcinoma with t(6;11)(p21;q12) reveals a link to a lysosome-like structure. Histopathology 2014; 64: 306e9. 40 Argani P, Yonescu R, Morsberger L, et al. Molecular confirmation of t(6;11)(p21;q12) renal cell carcinoma in archival paraffinembedded material using a break-apart TFEB FISH assay expands its clinicopathologic spectrum. Am J Surg Pathol 2012; 36: 1516e26. 41 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; 31: 1578e85. 42 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. Am J Surg Pathol 2014; 38: 627e37. 43 Udagar AM, Alva A, Chen YB, et al. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). A rapid autopsy report of metastatic renal cell carcinoma. Am J Surg Pathol 2014; 38: 567e77.
14 Kuroda N, Tamura M, Taguchi T, et al. Sarcomatoid acquired cystic disease-associated renal cell carcinoma. Histol Histopathol 2008; 23: 1327e31. 15 Kuroda N, Tamura M, Hamaguchi N, et al. Acquired cystic disease-associated renal cell carcinoma with sarcomatoid change and rhabdoid features. Ann Diagn Pathol 2011; 15: 462e6. 16 Kuroda N, Shiotsu T, Hes O, Michal M, Shuin T, Lee GH. Acquired cystic disease-associated renal cell carcinoma with gain of chromosomes 3, 7, and 16, gain of chromosome X, and loss of chromosome Y. Med Mol Morphol 2010; 43: 231e4. 17 Yamaguchi T, Kuroda N, Kawada T, Imamura Y. Imprint cytological findings of acquired cystic disease-associated renal-cell carcinoma: a close relationship to papillary renal-cell carcinoma. Diagn Cytopathol 2012; 40: 844e6. 18 Kuroda N, Yamashita M, Kakehi Y, Hes O, Michal M, Lee GH. Acquired cystic disease-associated renal cell carcinoma: an immunohistochemical and fluorescence in situ hybridization study. Med Mol Morphol 2011; 44: 228e32. 19 Clark J, Lu YJ, Sidhar SK, et al. Fusion of splicing factor genes PSF and NonO(p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene 1997; 15: 2233e9. 20 Argani P, Antonescu CR, Illei PB, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and young adults. Am J Pathol 2001; 159: 179e92. 21 Argani P, Antonescu CR, Couturier J, et al. PRCC-TFE3 renal carcinomas: morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X1; 1)(p11.2;q21). Am J Surg Pathol 2002; 26: 1553e66. 22 Argani P, Lui MY, Coutrier J, Bouvier R, Foumet JC, Ladanyi M. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 2003; 22: 5374e8. 23 Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007; 31: 1149e60. 24 Dijkhuizen T, van den Berg E, Wilbrink M, et al. Distinct Xp11.2 breakpoints in two renal cell carcinomas exhibiting X: autosome translocations. Genes Chromosomes Cancer 1995; 14: 43e50. 25 Armah HB, Parwani AV, Surti U, Bastacky SI. Xp11.2 translocation renal cell carcinoma occurring during pregnancy with a novel translocation involving chromosome 19: a case report with review of the literature. Diagn Pathol 2009; 4: 15. 26 Meyer PN, Clark JI, Flanigan RC, Picken MM. Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults. Am J Clin Pathol 2007; 128: 70e9. 27 Campero P, Vasiliu V, Molinie V, et al. Renal translocation carcinomas. Clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol 2008; 35: 656e70. 28 Komai Y, Fujisawa M, Fuji Y, et al. Adult Xp11 translocation renal cell carcinoma diagnosed by cytogenetic and immunohistochemistry. Clin Cancer Res 2009; 15: 1170e6. 29 Kuroda N, Mikami S, Pan CC, et al. Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect. Histol Histopathol 2012; 27: 133e40.
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PATHOLOGY OF KIDNEY TUMOURS
44 Gill AJ, Pachter NS, Chou A, et al. Renal tumors associated with germline SDHB mutation show distinctive morphology. Am J Surg Pathol 2011; 35: 1578e85. 45 Ricketts CJ, Shurch B, Vocke CD, et al. Succinate dehydrogenase kidney cancer (SDH-RCC): an aggressive example of the Warburg effect in cancer. J Urol 2012; 188: 2063e71. 46 Gill AJ, Hes O, Papathomas T, et al. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity. A clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol 2014; 38: 1588e602. 47 Kuroda N, Matsumoto H, Ohe C, et al. Review of tubulocystic carcinoma of the kidney with focus on clinical and pathobiological aspects. Pol J Pathol 2013; 64: 233e7. 48 Yang XJ, Zhou M, Hes O, et al. Tubulocystic carcinoma of the kidney: clinicopathologic and molecular characterization. Am J Surg Pathol 2008; 32: 177e87. 49 Amin MB, MacLennan GT, Gupta R, et al. Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma. Am J Surg Pathol 2009; 33: 384e92. 50 Zhou M, Yang XJ, Lopez JI, et al. Renal tubulocystic carcinoma is closely related to papillary renal cell carcinoma: implications for pathological classifications. Am J Surg Pathol 2009; 33: 1840e9. 51 Al-hussain TO, Change L, Zhang S, et al. Tubulocystic carcinoma of the kidney with poorly differentiated foci: a series of 3 cases with fluorescence in situ hybridization analysis. Hum Pathol 2013; 44: 1406e11. 52 Zhao M, Teng X, Ru G, et al. Tubulocystic renal cell carcinoma with poorly differentiated foci is indicative of aggressive behavior: clinicopathological study of two cases and review of the literature. Int J Clin Exp Pathol 2015; 8: 11124e31. 53 Smith S, Trpkov K, Mehra R, et al. Is tubulocystic carcinoma with dedifferentiation a form of HLRCC/Fumarate hydratase-deficient RCC? USCAP abstract. Mod Pathol 2015; 28: 260A. 54 Debelenko LV, Raimondi SC, Daw N, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALKassociated tumor spectrum. Mod Pathol 2011; 24: 430e42. 55 Marino-Enriquez A, Ou WB, Weldon CB, Flecher JA, PerezAtayde AR. ALK rearrangement in sickle cell trait-associated renal medullary carcinoma. Genes Chromosomes Cancer 2011; 50: 146e53. 56 Sugawara E, Togashi Y, Kuroda N, et al. Identification of anaplastic lymphoma kinase fusions in renal cancer. Cancer 2012; 118: 4427e36. 57 Sukov WR, Hodge JC, Lohse CM, et al. ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients. Mod Pathol 2012; 25: 1516e25. 58 Lee C, Park JW, Suh JH, Nam KH, Moon KC. ALK-positive renal cell carcinoma in a large series of consecutively resected Korean renal cell carcinoma patients. Korean J Pathol 2013; 47: 452e7. 59 Yamaguchi T, Kuroda N, Imamura Y, et al. Imprint cytologic features of chromophobe renal cell carcinoma morphologically resembling renal oncocytoma: is this an oncocytic variant of chromophobe renal cell carcinoma? Diagn Cytopathol 2010; 38: 509e13. 60 Kuroda N, Tanaka A, Yamaguchi T, et al. Chromophobe renal cell carcinoma, oncocytic variant: a proposal of a new variant giving a critical diagnostic pitfall in diagnosing renal oncocytic tumors. Med Mol Morphol 2013; 46: 49e55.
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61 Hes O, de Souza TG, Pivovarcikova K, et al. Distinctive renal cell tumor simulating atrophic kidney with 2 types of microcalcifications. Report of 3 cases. Ann Diagn Pathol 2014; 18: 82e8. 62 Oshiro Y, Hida AI, Tamiya S, et al. Bilateral atrophic kidney-like tumors. Pathol Int 2014; 64: 478e80. 63 Petersson F, Bulimbasic S, Hes O, et al. Biphasic alveolosquamoid renal carcinoma: a histomorphological, immunohistochemical, molecular genetic, and ultrastructural study of a distinctive morphologic variant of renal cell carcinoma. Ann Diagn Pathol 2012; 16: 459e69. 64 Jung SJ, Chung JI, Park SH, Ayala AG, Ro JY. Thyroid follicular carcinoma-like tumor of kidney. A case report with morphologic, immunohistochemical, and genetic analysis. Am J Surg Pathol 2006; 30: 411e5. 65 Amin MB, Gupta R, Hes O, et al. Primary thyroid-like follicular carcinoma of the kidney. Report of 6 cases of a histologically distinctive adult renal epithelial neoplasm. Am J Surg Pathol 2009; 33: 393e400. 66 Dhillon J, Tannir NM, Matin SF, et al. Thyroid-like follicular carcinoma of the kidney with metastases to the lung and retroperitoneal lymph nodes. Hum Pathol 2011; 42: 146e50. 67 Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the syndrome. Am J Surg Pathol 2002; 26: BirteHoggeDube 1542e52. syn68 Adley BP, Smith ND, Nayar R, Yang XJ. BirteHoggeDube drome. Clinicopathologic findings and genetic alterations. Arch Pathol Lab Med 2006; 130: 1865e70. 69 Kuroda N, Furuya M, Nagashima Y, et al. Intratumoral peripheral small papillary tuft: a diagnostic clue of renal tumors associated syndrome. Ann Diagn Pathol 2014; 18: with BirteHoggeDube 171e6. 70 Kuroda N, Furuya M, Nagashima Y, et al. Review of renal tumors syndrome with focus on associated with BirteHoggeDube clinical and pathobiological aspects. Pol J Pathol 2002; 26: 1542e52. 71 Yang P, Cornejo KM, Sadow PM, et al. Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol 2014; 38: 895e909. 72 Guo J, Tretiakova MS, Troxell ML, et al. Tuberous sclerosisassociated renal cell carcinoma. A clinicopathologic study of 57 separate carcinomas in 18 patients. Am J Surg Pathol 2014; 38: 1457e67. 73 Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology 2012; 79: 1187.e1e7. 74 Shurch B, Ricketts CJ, Vocke CD, et al. Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer. J Urol 2013; 190: 1990e8. 75 Ip YT, Yuan JQ, Cheung H, Chan JKC. Sporadic hemangioblastoma of the kidney: an underrecognized pseudomalignant tumor? Am J Surg Pathol 2010; 34: 1695e700. 76 Verine J, Sandid W, Miquel C, Vignaud JM, Mangiat-Artus P. Sporadic hemangioblastoma of the kidney: an underrecognized pseudomalignant tumor? Am J Surg Pathol 2011; 35: 623e4. 77 Doyle LA, Fletcher CDM. Peripheral hemangioblastoma. Clinicopathologic characterization in a series of 22 cases. Am J Surg Pathol 2014; 38: 119e27. 78 Kuroda N, Agatsuma Y, Tamura M, et al. Sporadic renal hemangioblastoma with CA9, PAX2 and PAX8 expression: diagnostic
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pitfall in the differential diagnosis from clear cell renal cell carcinoma. Int J Clin Exp Pathol 2015; 8: 2131e8. Montironi R, Lopez-Beltran A, Cheng L, Galosi AB, Montorsi F, Scarpelli M. Clear cell renal cell carcinoma (ccRCC) with hemangioblastoma-like features: a previously unreported pattern of ccRCC with possible clinical significance. Eur Urol 2014; 66: 806e10. Kuroda N, Tanaka A, Ohe C, Nagashima Y. Recent advances of immunohistochemistry for diagnosis of renal tumors. Pathol Int 2013; 63: 381e90. Kuroda N, Tanaka A. Recent classification of renal epithelial tumors. Med Mol Morphol 2014; 47: 68e75. Nagashima Y, Kuroda N, Yao M. Transition of organizational category of renal cancer. Jpn J Clin Oncol 2013; 43: 233e42.
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Five new RCC entities are included in the 2016 WHO classification as new histological subtypes: HLRCC, t(6;11)/TFEB RCC, SDH deficient RCC, tubulocystic RCC, ACD-associated RCC and clear cell papillary RCC
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Clear cell papillary RCC is a benign or indolent tumour with tubulopapillary structures lined with low grade clear cells that are positive for CK7 and CA9 but negative for CD10 t(6;11)/TFEB RCC is characterized by translocation between TFEB gene and Alpha gene and overexpression of TFEB protein. It predominantly affects young children. “Biphasic” pattern is characteristic. HLRCC is an inherited cancer syndrome caused by germline mutations in FH gene. RCC is highly aggressive and characterized by cytomegaloviral inclusion-like prominent nucleoli SDH-deficient RCC is most commonly caused by mutations in SDHB gene. Renal tumours have “bubbly” cytoplasm due to accumulation of macromitochondria. Loss of SDHB protein is diagnostic Tubulocystic RCC is composed entirely of tubules and cysts of variable sizes. It may be part of the manifestation of HLRCC, especially when there is “poorly differentiated” component ACD -associated RCC is characterized by pseudocribriform or tubulocystic architecture lined with cells with abundant eosinophilic cytoplasm. Calcium oxalate crystals in the tumour are characteristic
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New and emerging renal tumour entities
distinct clinicopathological features and are therefore recognized as new RCC subtypes. Other entities, such as anaplastic lymphoma kinase associated RCC and thyroid like follicular carcinoma of the kidney, are considered emerging RCC entities and additional studies are needed to further elucidate their clinical, pathological and molecular characteristics. Correct diagnosis of these tumours is, however, critical for not only understanding of their pathogenesis but also patient management.
Naoto Kuroda Ondrej Hess Ming Zhou
Clear cell papillary renal cell carcinoma
Abstract
Although initially reported in end-stage kidneys, this tumour is now most commonly sporadic in otherwise normal kidneys.2e9 It accounts for 1e4.3% of all epithelial neoplasms. The patient’s age ranges from 18 to 88 (mean 70) years. There is no gender predilection. Patients are usually asymptomatic.9 Tumours are usually small.3e6 Grossly, the tumour shows variable cystic formation with focal solid consistency and the cut surface is white-tan, pale yellow, or red-brown. Histologically, the tumour is composed of clear cells forming a variety of growth patterns including papillary, tubular, acinar, solid and cystic. Branching tubules and papillae are common.6 Nuclear grade is low, typically ISUP nucleolar grade 1 or 2 in most cases. Nuclei often show linear arrangement away from the basement membrane (Figure 1A).5e7 Smooth muscle is often identified within the stroma. Immunohistochemically, neoplastic cells are positive for cytokeratin 7 and carbonic anhydrase IX with characteristic “cup-shaped pattern” (Figure 1B), but negative for AMACR, CD10 and RCC Ma.2e9 TFE3 is consistently negative.5,7 This tumour shows no genetic characteristics of clear cell RCC or papillary RCC.3,4 The array CGH analysis showed no chromosomal imbalances.5 Partial nephrectomy may be best therapeutic option for a solitary lesion. Active surveillance may be considered if a correct diagnosis is rendered on needle core biopsy.9 Prognostically there has been no reports of local recurrence or distant metastasis.6e8 Further studies are needed to ascertain its biological behaviour; however, this tumour is best regarded as having an indolent clinical behaviour.
In this review, we discuss new and emerging renal cell carcinoma (RCC) entities, including anaplastic lymphoma kinase (ALK) RCC, oncocytic variant of chromophobe RCC, atrophic kidney-like renal tumour, biphasic alveolosquamoid RCC, tubulocystic RCC, thyroidlike follicular carcinoma of the kidney, succinate dehydrogenase syndrome-associated renal tumour, deficient RCC, BirteHoggeDube hereditary leiomyomatosis/renal cell carcinoma associated RCC, tuberous sclerosis-associated RCC, PTEN hamartoma tumour syndrome, clear cell papillary RCC, acquired cystic disease-associated RCC, Xp11.2 RCC, t(6;11) RCC and renal hemangioblastoma. These tumours have clinical, pathological and genetic features distinct from other common RCCs and therefore are important to recognize. Some of them have been recognized as distinct histological subtypes in the 2016 World Health Organization Classification. However, further studies are needed to elucidate their clinicopathologic features and molecular mechanisms.
Keywords Acquired cystic disease-associated RCC; ALK; anaplastic lymphoma kinase; atrophic kidney-like renal tumour; BirteHoggeDube syndrome-associated renal tumour; clear cell papillary RCC; HLRCC associated RCC; succinate dehydrogenase-deficient RCC; thyroid-like follicular carcinoma of the kidney; translocated associated RCC; tuberous sclerosis-associated RCC; tubulocystic RCC
Introduction Recently, many new renal tumour entities and new concepts regarding the “established” renal tumour entities have been described and incorporated into the 2012 International Society of Urological Pathology (ISUP) classification of renal tumours.1 Several entities, including tubulocystic RCC, clear cell papillary RCC, and succinate dehydrogenase (SDH)-deficient RCC, have
Acquired cystic disease-associated renal cell carcinoma This tumour of unique morphology occurs exclusively in patients with acquired cystic disease (ACD).2 ACD-RCC accounts for 36% of renal epithelial tumours in the end-stage kidneys and often in patients on haemodialysis for more than 10 years.2,10,11 Histologically, it is characterized by cells with deeply eosinophilic cytoplasm forming multiple patterns including microcystic or cribriform. Intratumoral oxalate crystal deposition is characteristic (Figure 2).2,10e13 The nuclear atypia is usually ISUP Grade 3.11 Some cases have sarcomatoid or rhabdoid changes which correlate with adverse prognosis.14,15 Immunohistochemically, tumour cells are positive for AMACR, CD10 and RCC Ma, but negative for cytokeratin 7.12 Ultrastructurally, tumour cells contain abundant mitochondria.14 FISH, G-band karyotype and array CGH analysis show gain of chromosomes 3, 7, 16, 17 and sex chromosome.12,13,16 Hence, this tumour may be closely related to papillary RCC.12,17 Chromosomal aneuploidy, particularly gain
Naoto Kuroda MD is Director, Department of Diagnostic Pathology, Kochi Red Cross Hospital, Kochi, Japan. Conflicts of interest: none declared. Ondr ej Hess MD PhD is Professor, Department of Pathology, Faculty of Medicine, University Hospital Plzen, Charles University, Pilsen, Czech Republic; Biomedical Centre, Faculty of Medicine in Plzen, Charles University in Prague, Pilsen, Czech Republic. Conflicts of interest: none declared. Ming Zhou MD PhD is Professor, Surgical Pathology and Urologic Pathology, NYU Medical Center Tisch Hospital, New York City, USA. Conflicts of interest: none declared.
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PATHOLOGY OF KIDNEY TUMOURS
Figure 1 Clear cell papillary renal cell carcinoma. (a)Tumour cells with clear cytoplasm form cystic and papillary configuration. Nuclei are polarized away from the basement membrane (Courtesy of Dr. Kawakami F, Kobe, Japan). (b) Immunohistochemical stain for CAIX shows cup-shaped pattern (Courtesy of Dr. Watanabe R, Shizuoka, Japan).
1q34, NonO at Xq12 and CLTC at 17q23.19e22 Partner genes at chromosomes 3q23, 10q23 and 19q13.1 remain unidentified.23 e25 This tumour generally affects children and young adult and is the most common form of RCC in children. It also occurs in adults and accounts for 1% of all renal tumours in adults.1,19 e23,26e29 Patients may present with haematuria or abdominal mass.29 A previous exposure to cytotoxic chemotherapeutic agents in childhood may be a risk factor.30 Grossly, the tumour is well-marginated but unencapsulated. The cut surface displays yellow-tan colour with soft consistency. Histologically, this tumour is characterized by mixed papillary, nested and alveolar growth patterns. Tumour cells have voluminous clear and/or eosinophilic cytoplasm, distinct cell border, and large nuclei with vesicular chromatin and prominent nucleoli (Figure 3). Psammoma bodies or hyaline nodules are often identified in the stroma.23,26e28 Immunohistochemically, tumours cells underexpress and are usually focally and weakly positive for epithelial markers including keratins and EMA. It shows nuclear positivity for TFE3 protein which seems to be a highly sensitive and specific marker for this tumour (although it is also positive in alveolar soft part sarcoma). However, excessive antigen retrieval or use of concentrated antibody may lead to false positivity in other tumours.31 Ultrastructurally, rhomboid crystals or dense granules are identified in the cytoplasm of ASPL-TFE3 RCC.20,29 FISH using the TFE3 gene break-apart probe is helpful for establishing the diagnosis.32 Patients are usually treated with radical or partial nephrectomy.28 Extended lymphadenectomy is also performed. For metastatic lesions, VEGF or mTOR inhibitors may lead to improved outcome.29 Adult tumours seem to behave more aggressively than paediatric ones.26,28,29 Metastasis to lymph nodes is commonly observed.27e29 t(6;11)/TFEB translocation RCC is characterized by the fusion of TFEB gene at chromosome 6p21 to Alpha gene at chromosome 11q12. It generally occurs in children and young adults, but has been reported in adults.27,33e39 It is very rare and accounts for <1% of all renal tumours. The age ranges from 6 to 57 (mean 23) years. There is a slight female preponderance. The tumour ranges from 1 to 20 (mean 6.5) in size.38 Grossly, the tumour is
of chromosome 3 and 16, may be characteristic of this tumour.13,18 Radical or partial nephrectomy is usually performed. These tumours seem to have better prognosis than their sporadic counterparts as patients are under intense surveillance for their underlying medical kidney disease with various imaging studies. However, tumours with sarcomatoid or rhabdoid differentiation may behave aggressively.2,14,15
Microphthalmia/TFE (MiT) gene family translocation renal cell carcinoma MiT gene family translocation RCC includes Xp11.2/TFE3 translocation RCC and t(6;11)/TFEB translocation RCC. TFE3 and TFEB both belong to the MiT gene family. Xp11.2/TFE3 translocation RCC and t(6;11)/TFEB translocation RCC share clinical, pathological and genetic features and are therefore grouped together as MiT gene family translocation RCCs. Xp11.2/TFE3 translocation RCC is characterized by a translocation between the TFE3 gene at chromosome Xp11.2 and another gene including ASPL at 17q25, PRCC at 1q21, PSF at
Figure 2 Acquired cystic disease-associated renal cell carcinoma. The tumour cells with deeply eosinophilic to oncocytic cytoplasm form microcystic or cribriform pattern. Intratumoral oxalate crystals are present.
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treatment. For metastatic diseases, VEGF and mTOR inhibitors may be used.37,38 Prognosis is uncertain due to small number of reported cases. Most cases in children and young adults seem to be indolent. However, some tumours in adults presented with metastasis and aggressive behaviour.34e38
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome HLRCC is an autosomal dominant inherited cancer syndrome characterized by multiple cutaneous leiomyomas, early onset uterine leiomyomas and renal tumours.41 Grossly, the renal tumour is usually solitary and unilateral, and forms a solid mass with frequent minor cystic component.41 Histologically, the tumour showed mixed architectural patterns with papillary, tubular, tubulopapillary, solid, and cystic configurations.41,42 Collecting duct carcinoma-like or tubulocystic carcinoma-like pattern may be observed.42 The most characteristic features, though, are large nuclei with very prominent eosinophilic nucleoli surrounded by clear halos, reminiscent of cytomegaloviral inclusions (Figure 5A).41e43 The similar nuclear features may be observed also in uterine leiomyomas. Immunohistochemically, HLRCC tumours show diffuse and strong nuclear and cytoplasmic S-(2-succino)-cysteine (2SC) protein (Figure 5B) and this staining pattern generally differs from that of other high grade RCCs and is considered diagnostic of HLRCC.42 However, this antibody is not commercially available. Genetically, somatic mutation of fumarate hydratase (FH ) gene or loss of heterozygosity is observed in addition to FH germline mutation in most cases.41e43 Radical nephrectomy including adrenal gland resection and regional lymphadenectomy is the choice of therapy.42,43 The tumour usually behaves in an aggressive fashion with frequent metastasis to regional lymph nodes, adrenal gland, liver or lung.41e43
Figure 3 Xp11.2/FEE3 renal cell carcinoma. Tumour cells with abundant clear/eosinophilic cytoplasm grow in nested and alveolar pattern. Psammoma bodies are present in the stroma.
well-circumscribed with frequent satellite nodules. The cut surface shows tan-brown to yellow colour. Cystic formation may be seen. Histologically, tumours comprise nests and sheets of cells with abundant clear to eosinophilic cytoplasm, round nuclei with vesicular chromatin and prominent nucleoli. The deposition of basement membrane materials in the stroma is common. The most characteristic finding, though, is the biphasic pattern with small lymphocyte-like tumour cells surrounding basement membrane material and outer large tumour cells with abundant eosinophilic to clear cytoplasm, resulting in rosette-like structures (Figure 4).33e39 Immunohistochemically, epithelial markers including EMA and cytokeratin AE1/3 are generally negative or at most focally and weakly positive. HMB45, Melan A and Cathepsin-K are positive. The nuclear expression of TFEB is highly sensitive and specific for this tumour.33e39 Ultrastructurally, tumour cells contain abundant mitochondria and lysosomeassociated structures.33,39 The fusion of TFEB gene to Alpha gene can be confirmed by cytogenetics, RT-PCR or DNA-PCR.33,34 FISH using TFEB gene break apart probe may be useful for the diagnosis.40 Radical or partial nephrectomy is the choice of
Succinate dehydrogenase (SDH)-deficient renal carcinoma This tumour is caused by germline mutations in one of the four subunits of SDH that form the mitochondrial complex 2 on the inner membrane of mitochondria. The complex plays a critical role in Krebs cycle. Mutation in any of the four subunits causes familial paraganglioma/pheochromocytoma syndrome which predisposes patients to pheochromocytoma, paraganglioma or gastrointestinal stromal tumour and RCC. SDHB is most commonly mutated. This tumour tends to affect young adults. The tumour is grossly well-marginated and the cut surface demonstrates tan to red colour. Cystic change may be seen. Histologically, the tumour is often described as “oncocytic tumour with bubbly appearance” as it is made up of cuboidal to oval cells with eosinophilic cytoplasm with bubbly change due to intracytoplasmic vacuoles or inclusions (Figure 6A). Ultrastructural studies have confirmed that the intracytoplasmic vacuoles are giant mitochondria. Nuclei are generally of low grade, but high grade including sarcomatoid change may occur. Immunohistochemically, tumour cells are positive for PAX8 and AMACR, but the negativity for SDHB. Because mutations in any of the SDH subunits destabilize the mitochondrial complex 2 and lead to loss of SDHB proteins, SDHB IHC has been shown to be a very effective way to screen
Figure 4 t(6;11) renal cell carcinoma. The characteristic feature of this tumour is “biphasic pattern” with small, lymphocyte-like and large tumour cells surrounding basement membrane materials creating rosette-like structures (Courtesy of Dr. Ishihara A, Miyazaki, Japan).
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PATHOLOGY OF KIDNEY TUMOURS
Figure 5 Hereditary leiomyomatosis and renal cell carcinoma syndrome. (a) Tumour cells with eosinophilic cytoplasm form papillary and solid architecture. The nuclei possess prominent nucleoli and resemble cytomegaloviral inclusion. (b) Immunohistochemical stain for S-(2-succino)cysteine (2SC) protein shows diffuse and strong nuclear and cytoplasmic positivity while the stromal cells and vessels are negative.
tubules/collecting ducts (cytokeratin 7, cytokeratin 19, Keratin 903 and parvalbumin).47e50 In FISH analysis, gain of chromosomes 7 and 17 and loss of chromosome Y are frequently seen. Therefore, tubulocystic carcinoma seems to be linked to papillary RCC genetically.48,50 Recently several studies show that tubulocystic RCC occasionally harbours high grade poorly differentiated components and these cases may in fact represent HLRCC syndrome.51e53 Patients are often treated with radical or partial nephrectomy and VEGF inhibitors may be effective for advanced tumours.47 This tumour seems to behave in an indolent fashion as a general rule.48,50 However, local recurrence and metastasis to lymph node, bone and liver have been reported in some cases, although it is unclear whether these cases actually represent HLRCC syndrome.49
for SDH mutation (Figure 6B). Surgical resection is the choice of treatment. Tumours without high grade component or coagulative necrosis behave in an indolent fashion, but those with dedifferentiation or in young adults are likely to behave aggressively.44e46
Tubulocystic carcinoma This tumour commonly occurs in the fifth and sixth decade of life and there is a strong male predilection. Most lesions are incidentally discovered, but some patients present with abdominal pain and mass and haematuria.47 On gross examination, the tumour shows well-defined multicystic lesion and the cut surface displays spongy or bubble wrap appearance (Figure 7A).47e50 Microscopically, the tumour consists of various sized cysts lined by flat, cuboidal, columnar and hobnail cells with eosinophilic cytoplasm, enlarged nuclei and prominent nucleoli (Figure 7B). Papillary components are observed in some tumours.48,50 Immunohistochemically, tumour cells show both phenotype of proximal tubules (AMACR and CD10) and distal
Anaplastic lymphoma kinase (ALK) renal cell carcinoma Seven cases have been reported in both paediatric and adult patients.54e58 It tends to affect relatively young patients. In US, paediatric ALK RCC is seen exclusively in patients with sickle
Figure 6 Succinate dehydrogenase-deficient renal cell carcinoma. The tumour cells have eosinophilic bubbly cytoplasm and indistinct cell border (a) and are negative for SDHB (b). The vascular endothelial cells are positive for SDHB and serve as the positive internal control.
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PATHOLOGY OF KIDNEY TUMOURS
Figure 7 Tubulocystic carcinoma. The cut surface shows spongy or bubble wrap appearance (a). Microscopically it consists of tubules and variably sized cysts lined by flat, cuboidal, and hobnail cells with eosinophilic cytoplasm (b, courtesy of Dr. Matsumoto H, Okinawa, Japan).
years. The ratio of male to female is 2:3. The tumour size ranges from 2 to 11 cm with a mean size of 6 cm.60 This tumour may resemble renal oncocytoma macroscopically and microscopically. Grossly, the tumour is well-marginated but unencapsulated. The cut surface displays a brown colour. Microscopically, the tumour is characterized by the proliferation of tubular or solid-sheet pattern of oncocytic cells with indistinct cell border and round centrally located nuclei lacking wrinkled appearance (Figure 9). Nested growth pattern typical of renal oncocytoma and perinuclear halo are absent. Immunohistochemically, tumour cells are diffusely positive for cytokeratin 7. Chromosomal analysis using FISH show chromosomal loss involving multiple chromosomes, including 7, 10, 13, 17 and 21, the chromosomal features suggestive of chromophobe RCC.59,60 Radical or partial nephrectomy is indicated. The core needle biopsy, however, may lead to diagnostic pitfalls, particularly if only routine H&E stain is examined without immunohistochemistry.60 The prognosis of this tumour remains uncertain because of the small number of reported cases, although previously reported cases showed excellent outcomes.60
cell traits and some are bona fide renal medullary carcinoma with loss of INI-1 protein expression. All cases harbour ALKVCL gene fusion.54,55 However, ALK RCC in adults seems to have a close link to ALK lung cancer, malignant lymphoma and inflammatory myofibroblastic tumour, demonstrating the fusion between ALK and EML4 or TMP3 gene.56 ALK RCC in paediatric patients comprises diffuse sheets of epithelioid cells with abundant eosinophilic cytoplasm and intracytoplasmic lumens and intratumoral inflammatory cells. Tumours in adults show mucinous cribriform pattern (Figure 8) or papillary configuration with mucinous background.56 ALK protein overexpression is detected by immunohistochemistry in some cases.54e56 Radical or partial nephrectomy, offers hope of cure. The presence of ALK gene fusion raises the possibility that this tumour may be amenable to the target therapy by ALK inhibitors, particularly for patients with the advanced stage disease.
Chromophobe renal cell carcinoma, oncocytic variant To date, five such cases have been reported.59,60 The age of patients’ ranges from 74 to 82 years with a mean age of 73.8
Atrophic kidney-like renal tumour Four cases have been reported.61,62 The gross picture shows well circumscribed tumour with capsule and honeycomb or spongy appearance. The cut surface of the tumour imparts a tan to brown colour. Histologically this tumour resembles an atrophic kidney or adenomatous goitre (Figure 10) and consists of microfollicles, psammoma bodies or amorphous dark-blue deposits and capsule containing smooth muscle cells. There is no cytological atypia. No significant chromosomal changes were identified using array comparative genomic hybridization (CGH) in one tumour. Prognostically, this tumour seems to show an indolent clinical behaviour.61,62
Biphasic alveolosquamoid renal cell carcinoma Two cases have been described to date.63 On gross examination, the tumour is well demarcated and the cut surface shows a grey
Figure 8 Anaplastic lymphoma kinase renal cell carcinoma. The tumour demonstrates cribriform growth pattern with a mucinous background (provided by Takeuchi K, Tokyo, Japan).
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PATHOLOGY OF KIDNEY TUMOURS
cells are positive for PAX2 and PAX8, but negative for TTF-1 and thyroglobulin. CGH analysis of one tumour showed gain of 7q36, 8q24, 12, 16, 17p11-q11, 17q24, 19q, 20q13, 21q22.3, and Xp, and loss of 1p36.3 and 9q21-33.64 Radical or partial nephrectomy should be the therapeutic option. Clinically this tumour pursues an indolent course, but metastasis to lymph nodes or lung has been reported.64e66
syndrome (BHD)-associated renal BirteHoggeDube tumour BHD syndrome is characterized by a triad of skin lesions (fibrofolliculoma, trichodiscoma and acrochordon), pulmonary lesions (cyst and pneumothorax) and renal tumours. The culprit gene is folliculin (FLCN ) on chromosome 17p11.2. Diverse histological subtypes including hybrid oncocytic tumour, chromophobe RCC, oncocytoma, papillary RCC, clear cell RCC and unclassified RCC have been reported in this disease. Among them, hybrid oncocytic tumours are most frequent.67e70 Macroscopically, these tumours are well circumscribed without encapsulation and the cut surface shows homogenous tan to brown colour. Microscopically, hybrid oncocytic tumours possess areas that resemble both chromophobe RCC and renal oncocytoma (Figure 11).67e70 Some hybrid oncocytic tumours may show clear cell change.68 Intratumoral peripheral small papillary tufts may be a diagnostic clue to this tumour.69 Renal cysts or multiple renal oncocytosis are also often observed.69,70 The screening with annual ultrasonography or magnetic resonance imaging is recommended after the age of 20 years. The surgical resection and cryoablation/radiofrequency ablation may be suitable therapeutic option for solitary and multiple lesions. For advanced tumours, mTOR inhibitors may be beneficial. Prognostically, patients harbouring hybrid oncocytic tumour, chromophobe RCC and oncocytoma have an indolent clinical course, but the presence of clear cell component may harbinger a worse prognosis.70
Figure 9 Chromophobe renal cell carcinoma, oncocytic variant. The tumour consists of oncocytic cells with predominant tubular growth pattern (Courtesy of Dr. Yamaguchi T, Kyoto, Japan).
to tan colour. Microscopically, the tumor is characterized by two populations of large and small cells. The large cells have squamoid appearance and form solid-alveolar islands rimmed by smaller tumour cells. Interestingly, the expression pattern of cytokeratin 20 and high molecular weight cytokeratin 5/6 differs in large and small tumour cells. The array CGH performed in one tumour showed partial or complete losses of chromosomes 2, 5, 6, 9, 12, 15, 16, 17, 18 and 22 and partial gains of chromosomes 1, 5, 11, 12 and 13. Regarding the clinical behaviour, one patient showed subcutaneous metastasis.63
Thyroid-like follicular carcinoma of the kidney This tumour is extremely rare. The age of patients ranges from 29 to 83 years. There is a slight female predilection.1 Grossly, the tumour is well-circumscribed with encapsulation and the cut surface is tan, brown to dark brown. Microscopically, the tumour resembles thyroid tissue and has to be distinguished from thyroid carcinoma metastatic to the kidney. It consists of micro- and macrofollicular structures that are lined by cells with amphophilic to eosinophilic cytoplasm and round nuclei. The follicles contain colloid-like substance. Immunohistochemically, tumour
Tuberous sclerosis-associated renal cell carcinoma RCC occurs in 2e4 % of tuberous sclerosis patients.71 Most tumours are found at young age and there is a female
patient. Figure 11 “Hybrid oncocytic tumour” from a BirteHoggeDube The tumour contains areas that resemble both chromophobe RCC and renal oncocytoma.
Figure 10 Atrophic kidney-like tumour. The tumour simulates the morphology of end-stage kidney (Courtesy of Dr. Oshiro Y, Ehime, Japan).
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PATHOLOGY OF KIDNEY TUMOURS
predominance.72 Half of the patients have multiple lesions.72 Histologically, there are wide array of tumours, including renal angiomyoadenomatous tumour (or RCC with smooth muscle stroma), chromophobe RCC-like, eosinophilic-solid cystic morphology and hybrid oncocytic/chromophobe tumour (HOCT) as well as previously reported histological types including clear cell RCC, papillary RCC, chromophobe RCC, unclassified RCC and renal oncocytoma. Concurrent renal angiomyolipoma is frequent. Immunohistochemically, tumour cells show positive stain for PAX8, cytokeratin 7, CD10, vimentin and carbonic anhydrase IX, but the negativity for HMB45, SDHB, TFE3 and AMACR.71,72 By FISH analysis, gain of chromosomes 7 and 17 was observed in a few cases.71 For treatment, surgical resection has been performed for the majority of patients.71,72 These tumours generally pursue an indolent clinical course, but metastasis to lymph nodes has been reported.68
undoubtedly critical for patient management. In the last decade, many renal tumours have been identified with clinical, pathological and genetic features distinct from other common, better characterized renal tumours.80e82 Several of the tumours are included in the 2016 WHO classifications as new histological subtypes, while others are considered emerging entities and require further characterization. A REFERENCES 1 Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol 2013; 37: 1469e89. 2 Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease. An experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol 2006; 30: 141e53. 3 Aydin H, Chen L, Cheng L, et al. Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol 2010; 34: 1608e21. 4 Rohan SM, Xiao Y, Liang Y, et al. Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol 2011; 24: 1207e20. 5 Adam J, Couturier J, Molinie V, Vieillefond A, Sibony M. Clear-cell papillary renal cell carcinoma: 24 cases of a distinct low-grade renal tumour and a comparative genomic hybridization array study of seven cases. Histopathology 2011; 58: 1064e71. 6 Williamson SR, Eble JN, Cheng L, Grignon DJ. Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile. Mod Pathol 2013; 26: 697e708. 7 Park JH, Lee C, Suh JH, Moon KC. Clear cell papillary renal cell carcinoma: a report of 15 cases including three cases of concurrent other-type renal cell carcinomas. Korean J Pathol 2012; 46: 541e7. 8 Alexiev BA, Drachenberg CB. Clear cell papillary renal cell carcinoma: incidence, morphological features, immunohistochemical profile, and biological behavior: a single institution study. Pathol Res Pract 2014; 210: 234e41. 9 Kuroda N, Ohe C, Kawakami F, et al. Clear cell papillary renal cell carcinoma: a review. Int J Clin Exp Pathol 2014; 15: 7312e8. 10 Nouh MAAM, Kuroda N, Yamashita M, et al. Renal cell carcinoma in patients with end-stage renal disease: relationship between histological type and duration of dialysis. BJU Int 2009; 105: 620e7. 11 Kuroda N, Ohe C, Mikami S, et al. Review of acquired cystic disease-associated renal cell carcinoma with focus on pathobiological aspects. Histol Histopathol 2011; 26: 1215e8. 12 Pan CC, Chen YJ, Chang LC, Chang YH, Ho DMT. Immunohistochemical and molecular genetic profiling of acquired cystic disease-associated renal cell carcinoma. Histopathology 2009; 55: 145e53. 13 Kunt E, Yusenko MV, Nagy A, Kovacs G. Oligoarray comparative genomic hybridization of renal cell tumors that developed in patients with acquired cystic renal disease. Hum Pathol 2010; 41: 1345e9.
PTEN hamartoma tumour syndrome This syndrome is an autosomal dominant inherited disorder and is associated with germline mutations in PTEN gene.73,74 Clinically, patients afflicted by this syndrome have increased cancer risk of breast, endometrium and thyroid gland. Skin lesions such as acral keratosis and facial trichilemmoma may be observed.74 Reported renal tumours include papillary RCC, chromophobe RCC and clear cell RCC.73,74 Immunohistochemically, tumour cells show loss of PTEN protein.73 Loss of heterozygosity at PTEN gene locus is common.74 Partial or radical nephrectomy is the best therapeutic option ad multifocal disease is rare.73,74 For advanced tumours, mTOR inhibitors may benefit patients.74 The biological behaviour seems to be indolent, although reported cases are scarce.74
Renal hemangioblastoma Fourteen renal hemangioblastomas have been reported.75e78 The incidence may, however, be higher as some clear cell RCC, especially those without VHL gene mutation, may represent renal hemangioblastomas. This tumour can occur sporadically without association with von HippeleLindau disease. Histologically, tumour cells have clear to eosinophilic cytoplasm with vacuolation resembling lipoblasts admixed with spindle cells. The stroma contains complex capillary network with occasional hemangiopericytomatous vascular pattern. Immunohistochemically, tumour cells are positive for alphainhibin and S-100 protein, but negative for HMB45, Melan A. PAX2, PAX8, CD10, carbonic anhydrase IX may be positive in these tumours.75e78 G-band karyotype and array CGH analysis of one tumour showed no chromosomal changes. Recently, clear cell RCCs with hamangioblastoma-like features have been reported,79 suggestive of its close relationship with clear cell RCC. This tumour is benign.75e78 If an accurate diagnosis can be established on needle biopsy, patients can be managed by active surveillance.
Conclusions Renal cell carcinomas are heterogeneous in their clinical, pathological and genetic features. Their accurate classification is
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pitfall in the differential diagnosis from clear cell renal cell carcinoma. Int J Clin Exp Pathol 2015; 8: 2131e8. Montironi R, Lopez-Beltran A, Cheng L, Galosi AB, Montorsi F, Scarpelli M. Clear cell renal cell carcinoma (ccRCC) with hemangioblastoma-like features: a previously unreported pattern of ccRCC with possible clinical significance. Eur Urol 2014; 66: 806e10. Kuroda N, Tanaka A, Ohe C, Nagashima Y. Recent advances of immunohistochemistry for diagnosis of renal tumors. Pathol Int 2013; 63: 381e90. Kuroda N, Tanaka A. Recent classification of renal epithelial tumors. Med Mol Morphol 2014; 47: 68e75. Nagashima Y, Kuroda N, Yao M. Transition of organizational category of renal cancer. Jpn J Clin Oncol 2013; 43: 233e42.
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Practice points C
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Five new RCC entities are included in the 2016 WHO classification as new histological subtypes: HLRCC, t(6;11)/TFEB RCC, SDH deficient RCC, tubulocystic RCC, ACD-associated RCC and clear cell papillary RCC
DIAGNOSTIC HISTOPATHOLOGY --:-
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Clear cell papillary RCC is a benign or indolent tumour with tubulopapillary structures lined with low grade clear cells that are positive for CK7 and CA9 but negative for CD10 t(6;11)/TFEB RCC is characterized by translocation between TFEB gene and Alpha gene and overexpression of TFEB protein. It predominantly affects young children. “Biphasic” pattern is characteristic. HLRCC is an inherited cancer syndrome caused by germline mutations in FH gene. RCC is highly aggressive and characterized by cytomegaloviral inclusion-like prominent nucleoli SDH-deficient RCC is most commonly caused by mutations in SDHB gene. Renal tumours have “bubbly” cytoplasm due to accumulation of macromitochondria. Loss of SDHB protein is diagnostic Tubulocystic RCC is composed entirely of tubules and cysts of variable sizes. It may be part of the manifestation of HLRCC, especially when there is “poorly differentiated” component ACD -associated RCC is characterized by pseudocribriform or tubulocystic architecture lined with cells with abundant eosinophilic cytoplasm. Calcium oxalate crystals in the tumour are characteristic
Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Kuroda N, et al., New and emerging renal tumour entities, Diagnostic Histopathology (2016), http://dx.doi.org/ 10.1016/j.mpdhp.2016.01.005