 Abstract | | |
Background: Renal tumors constitute approximately 3% of all malignancies in adults. They form a heterogenous group with variable morphological, immunohistochemical, and molecular features. Aim: The objective of this study was to analyze the spectrum of adult renal tumors at a tertiary care center and study the demographic and histomorphological features. Materials and Methods: In this study, 55/87 nephrectomy specimens resected for adult renal tumors during a 1-year period were analyzed retrospectively. Results: There were 4 benign (7.2%) and 51 (92.7%) malignant tumors. There was a male preponderance with a male: female ratio of 3.42:1. The tumors were seen to occur equally in both kidneys. The most common tumor was clear cell renal cell carcinoma (RCC), the conventional type accounting for 65.5% of our study group. There were one each of multilocular cystic renal neoplasm of low malignant potential, papillary RCC, chromophobe RCC, Mit family RCC, oncocytoma and angiomyolipoma and two clear cell papillary RCC during this 1-year period. Uncommon tumors included neuroendocrine carcinoma (1), epithelioid angiomyolipoma (1), mixed epithelial stromal tumor (1), Ewings sarcoma (2), and glomangioma (1). Five cases of urothelial carcinoma of renal pelvis/ureter also were present. Conclusion: This article gives an overview of the spectrum of adult renal tumors at a tertiary care center with an in-depth literature review providing recent advances in each category of tumors.
Keywords: Carcinoma, nephrectomy, renal
How to cite this article:
Sheenu VS, Paul RS, Pushpa M, Ami EM, Rashmi R, Iona ML, Elizabeth M. Histopathological spectrum of adult renal tumours: A single center experience and review of literature. Indian J Pathol Microbiol 2023;66:307-13 |
How to cite this URL:
Sheenu VS, Paul RS, Pushpa M, Ami EM, Rashmi R, Iona ML, Elizabeth M. Histopathological spectrum of adult renal tumours: A single center experience and review of literature. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Jun 1];66:307-13. Available from: https://www.ijpmonline.org/text.asp?2023/66/2/307/346515 |
| Introduction | |  |
The annual incidence of renal cancer in 2018 has been reported to be over 400,000 new cases and accounts for 144,000 deaths worldwide.[1] It is the 9th and 14th most common cancer in men and women, respectively.[1] Incidence in males is higher than in females, approximately 2:1. With the increasing understanding of the molecular biology of renal tumors, we have witnessed tremendous progress in the classification of renal tumors. The contemporary classification of renal cell carcinoma (RCC) formulated at the 2016 meeting of the WHO Renal Tumor Classification Panel (World Health Organization Classification of Tumors, 2016)[2] encompasses several new entities based on cytological, architectural, immunohistochemical, and cytogenetic characteristics with resultant decline in the RCC, unspecified type.
| Materials and Methods | | |
This is a retrospective study that included 87 nephrectomy specimens that were received in our department during a period of 1 year from January 2019 to December 2019; 55/87 nephrectomy specimens resected for adult renal tumors formed the study group, and 32 nephrectomies performed for non-neoplastic lesions were excluded from the study.
Patient particulars, including age, sex, clinical diagnosis, radiological details, gross morphology, and microscopic details, were recorded from the hospital information system.
| Results | | |
In this study, 55/87 (63.2%) nephrectomy specimens received during the study period were resected for renal tumors. There were 34, 15, and 6 radical and partial nephrectomy and nephroureterectomy specimens, respectively. The highest incidence of renal tumors was seen in the middle aged population in the 4th–6th decade of life (mean age: 45 years) [Figure 1]. There was a male preponderance with a male: female ratio of 3.42:1. The tumors were seen to occur equally in both kidneys (left: right – 28:27). [Table 1] shows the absolute number and percentage distribution of the various categories of tumors encountered during our study period. There were 4 benign (7.2%) and 51 (92.7%) malignant tumors. The most common tumor was clear cell RCC, conventional type, accounting for 65.5%. There were one each of multilocular cystic renal neoplasm of low malignant potential, papillary RCC, chromophobe RCC, Mit family RCC, oncocytoma, and angiomyolipoma, and two clear cell papillary RCC during this 1-year period. Uncommon tumors included neuroendocrine carcinoma (1), epithelioid angiomyolipoma (1), mixed epithelial stromal tumor (1), Ewings sarcoma (2), and glomangioma (1). Five cases of urothelial carcinoma of renal pelvis/ureter also were present. Diagnosis was based on morphological features on hematoxylin and eosin stain in the majority (47) of cases. Additional immunohistochemical studies were performed for chromophobe RCC, oncocytoma, neuroendocrine carcinoma, epithelioid angiomyolipoma, Ewings sarcoma, glomangioma, and one urothelial carcinoma that showed divergent differentiation. | Table 1: Absolute number and percentage distribution of renal tumors during the study period
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| Discussion | | |
Similar to the worldwide distribution, clear cell renal cell carcinoma (CCRCC) represented the majority of the tumors in our study group, accounting to 65.5%. This tumor is known to originate from the proximal renal tubular epithelium. Sarcomatoid and rhabdoid features are seen in 5% of high-grade tumors and was present in 3.6% of our cases. The overall prognosis of CCRCC is worse than most other types of RCC.[3] These tumors can be sporadic (95% of cases) or familial as part of familial cancer syndrome von Hippel–Lindau disease. Interestingly, 98% of all cases, may it be sporadic or familial, are characterized by loss of genetic material on 3p, either loss of the whole chromosome or loss of function through hypermethylation. In parallel, the VHL gene located on chromosome 3p was described as the most frequently mutated gene (50%–75%) in CCRCC and later found to be silenced by promoter methylation in 5%–20% of cases.
Papillary RCC (PRCC) is also derived from the renal tubular epithelium and is the second most commonly encountered morphotype of RCC. It has traditionally been subdivided into two types. PRCC type 1 seems to be a distinct and compact histo-molecular entity and with a distinct CK7, CD10, racemase positive immunoprofile. The most common cytogenetic abnormalities are trisomies 7 and 17 and loss of Y in male patients in the sporadic form, and trisomy 7 in familial form.[4] Type 2 tumors appear to be a controversial entity, composed of a group of tumors sharing papillary/tubulopapillary architecture with different molecular and genetic features.[4] Fumarate hydratase-deficient RCCs, a high-grade PRCC which was previously categorized as PRCC “type 2,” have already been reclassified from type 2 PRCC owing to recent molecular and genetic studies. This entity should always be considered in high-grade papillary renal tumors occurring in young patients and ruled out using a combination of immunohistochemistry and FH mutation/LOH (loss of heterozygosity) analysis.[4] Oncocytic papillary RCC, the “third” subtype of papillary RCC included in the WHO 2016 blue book, is a poorly understood papillary RCC entity composed of oncocytic neoplastic cells with variable copy number variation patterns. We had two clear cell papillary RCC (CCPRCC) in our group. This tumor accounts for 1%–4% of renal tumors. It arises sporadically and with end-stage renal disease and VHL syndrome. They are typically detected incidentally in asymptomatic patients as small encapsulated tumors. Tumor cells have diffuse CK7 positivity, carbonic anhydrase IX positivity in cup-like distribution, and racemase negativity. CD10 is typically negative. In challenging cases where the morphology and/or immunohistochemical profile are not typical, genetic testing for VHL mutation/methylation and/or chromosome 3p loss are essential for rendering an accurate diagnosis of CCPRCC.[4] Diagnostic criteria for multilocular cystic renal neoplasm of low malignant potential (MCRCNLMP) were defined by the 2004 WHO classification of kidney tumors based on the suggestions of Eble and Bonsib[5] as a tumor of low malignant potential that can be mistaken for cystic degeneration of conventional CCRCC. This tumor accounts for less than 1% of renal tumors. As many as 90% of cases are discovered incidentally on radiological evaluation for other purposes. The tumor is surrounded by fibrous pseudocapsule and composed of cysts with septae lined by clear epithelial cells with small nuclei without nucleoli and with no expansile solid nodules. Prognosis is excellent; recurrence or metastases have not been reported in bona fide cases. The single case in our study group was incidentally detected in a 54-year-old male patient. He underwent partial nephrectomy which revealed a multiloculated cystic neoplasm measuring 5.5 cm × 4.5 cm × 4.5 cm without solid component [Figure 2]. He is stable after 1 year follow-up with no recurrence. Chromosome 3p deletions and VHL mutations are the most frequently found genetic alterations in these tumors, similar to CCRCC but no specific genetic alterations have so far been identified.[4] Thus, careful macroscopic evaluation and sampling are pivotal for accurate diagnosis. | Figure 2: Multilocular cystic renal neoplasm of low malignant potential composed of muliple cysts lined by clear cells without expansile nodules, H and E 20× (Inset: high power 40×)
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Chromophobe RCC (ChRCC) constitutes 5%–7% of all renal cell carcinoma. Initially described by Thoenes et al. in 1985,[6] these are well circumscribed and unencapsulated tumors with a homogenous light tan to brown color and a central scar. Microscopy shows confluent solid growth with nests, sheets, or trabeculae composed of two types of cells: large pale cells with voluminous reticular cytoplasm and sharply defined plant-like cell membranes (type 1) which predominate in the classic ChRCC, and smaller cells with finely granular eosinophilic cytoplasm (type 2), predominant in eosinophilic variant. They show distinctive irregular wrinkled, raisinoid nucleus with coarse chromatin and characteristic perinuclear halo due to accumulation of cytoplasmic microvesicles, which is a unique ultrastructural feature in these tumors. Immunohistochemically, these tumors are positive for CD117 and CK7 and are negative for vimentin and CD10, which distinguish these tumors from clear cell RCC. These tumors have a favorable prognosis with a 5-year survival rate of 78%–100%.[3] Validation studies failed to demonstrate a correlation between grade and outcome for the WHO/ISUP grading classification, and it has been recommended that these tumors not be graded.[7] In addition to classic and eosinophilic ChRCCs, there are several other variants that have been recently described in the literature, including pigmented microcystic adenomatoid, multicystic variant, and ChRCC with neuroendocrine differentiation.[8],[9],[10] With the exception of ChRCC with neuroendocrine features, it seems that such variability has no influence on biological behavior. However, ChRCC with neuroendocrine features is a more aggressive variant. Usually associated with multiple chromosomal losses, including chromosomes Y, 1, 2, 6, 10, 13, 17, and 21, molecular genetic ancillary tests are not useful for diagnosing ChRCC in daily practice.
Oncocytoma is the most frequent benign epithelial tumor. It is a well-circumscribed, typically mahogany brown to tan or yellow-colored tumor with a central stellate scar. The oncocytic cells are arranged in solid-nested architecture within loose hypocellular connective tissue. Atypical features such as focal nuclear atypia, hemorrhage, and rarely fat invasion and vascular invasion may occur. These tumors show CD 117 + vimentin + CK7- (differentiates from chromophobe RCC) CD10- immunoprofile. Cytogenetically, these tumors may not show any abnormalities (48%) or show loss of chromosome 1, X, or Y (52%) and are closely related to chromophobe RCC.[3] Birt–Hogg–Dubé syndrome is associated with the development of numerous and bilateral oncocytic renal neoplasms. It is now acknowledged that these tumors may also arise de novo in those without constitutional features of Birt–Hogg–Dubé.[11] Currently, it is proposed that the term oncocytosis be confined to those tumors that occur sporadically and that the tumor complex be known as multifocal oncocytoma-like tumors associated with oncocytosis.[11] Although these tumors resemble the oncocytic component of tumors seen in Birt–Hogg–Dubé syndrome (which include chromophobe RCC and the so-called hybrid tumor, as well as oncocytoma), the tumors of oncocytosis have genetic changes associated with typical oncocytoma but not that seen in Birt–Hogg–Dubé renal lesions.[12] The immunoexpression of oncocytosis does, however, differ from typical oncocytoma in that approximately 50% of tumors show diffuse positivity to cytokeratin 7—a feature associated with sporadic chromophobe RCC. Despite the progressive nature of oncocytosis, there is no evidence that these tumors have metastatic potential, although recurrence is common. Recently Trpkov et al. described an additional group of a distinct low-grade oncocytic renal tumors that demonstrate CD117 negative/cytokeratin 7-positive immunoprofile with indolent behavior.[13]
One case in our study group that occurred in a 45-year-old man showed morphologic features suggestive of microphthalmia-associated transcription (MiT) family translocation RCC. Gross finding was that of an encapsulated tumor measuring 6.5 cm × 6 cm × 6 cm located in the interpolar region with a variegated cut surface, similar to conventional CCRCC. On histological examination, it showed a biphasic growth pattern with large epithelioid cells with eosinophilic cytoplasm forming predominant papillary architecture with hyalinized cores and focal areas showing groups of smaller cells clustered around basement membrane-like material [Figure 3]. In the 2016 WHO classification, MiT family tRCC, comprising Xp11 tRCC and t(6;11) RCC, was newly defined as a RCC subtype. These tumors are characterized by the rearrangement of the MiT transcription factors TFE3 and TFEB. Xp11 tRCC comprises 20%–40% of childhood RCC and 1%–4% of adult RCC with an average age of onset of 50 years.[14],[15] It frequently shows lymph node metastasis and has a worse prognosis than papillary RCC and similar prognosis with clear cell RCC and has the potential to metastasize as late as 20–30 years after diagnosis.[16] However, Xp11 tRCC in childhood patients is generally considered to have a better prognosis.[16] t(6;11) RCC is very rare, with approximately 60 cases reported thus far with an average age of onset of approximately 30 years and is considered to have a good prognosis, but the number of reported cases is too small to reach a definitive answer. These tumors do not have a distinctive gross or histological appearance; therefore, a definitive diagnosis cannot be made using morphology alone. The most specific antibodies for Xp11 tRCC and t (6;11) RCC are the anti-TFE3 antibody and anti-TFEB antibody, respectively. However, results must be cautiously interpreted because of the false-positive or false-negative results caused by the technical issues of fixation and immunostaining and should utilize an immunohistochemical panel.[17] Because the MiT family are transcription factors that play a role in melanocyte or osteoclast differentiation, these tumors often express melanosome-related antigens that are positive for HMB45 and/or Melan A and Cathepsin K which is expressed in osteoclasts. They are typically negative for EMA, cytokeratin AE1/AE3, and CK7.[2] Primary neuroendocrine tumor (NET) of kidney is exceedingly rare, with <100 cases reported so far.[18],[19],[20] Our study group included one large cell neuroendocrine carcinoma in a 46-year-old female patient who presented with a mass in the right kidney measuring 4 cm, involving the interpolar region. The tumor had ill-defined margins and gross infiltration of renal sinus fat. Microscopy showed cells having moderate to abundant eosinophilic granular cytoplasm, round to ovoid nuclei with stippled chromatin pattern, arranged in trabeculae, nests, and cords [Figure 4]a. In addition, 3–4 mitoses/10 HPF, foci of necrosis, and lymphovascular invasion were present. Immunohistochemical studies showed diffuse staining for synaptophysin, focal staining for chromogranin [Figure 4]b, and focal Golgi staining for CD10 with a ki-67 labeling index of 21%. The pathogenesis of this tumor is uncertain because neuroendocrine cells are found in renal pelvis but not in the normal adult renal parenchyma. Different theories support the fact that NETs arise from primitive totipotential stem cells that subsequently differentiate in a neuroendocrine direction. These are usually not associated with carcinoid syndromes. Approximately 50% of the cases present with metastasis, most commonly to lymph nodes, followed by liver, lung, and bone.[20],[21] Due to lack of randomized trials, because of the very low number of reported cases, there is no standard guideline for the treatment of renal NET.[21] Angiomyolipoma (AML) is a benign mesenchymal tumor belonging to the family of perivascular epithelioid cell tumors (PEComas). Most of these neoplasms are found incidentally on imaging. Prevalence varies between 0.2% and 0.6% with a strong female predilection. They occur as sporadic, isolated entities in 80% of cases. The remaining 20% develop in association with tuberous sclerosis complex (TSC) or pulmonary lymphangioleiomyomatosis.[22],[23] Hereditary lesions affect both genders equally and usually manifest at a younger age, and are usually large, bilateral, and tend to be more aggressive.[24] There have been infrequently reported cases of AML, especially of the classic type, with lymph node involvement and extension into the IVC. The current thinking behind this extension is based on multifocal tumorigenesis rather than metastasis.[25],[26] Epithelioid angiomyolipoma is a rare variant of angiomyolipoma that consists of at least 80% epithelioid cells. These tumors have a tendency toward malignant transformation and can be locally aggressive. Histologically, they can resemble and be misdiagnosed as RCC. Both classic and epithelioid variants show immunohistochemical coexpression of melanocytic (HMB45, Melan A) and smooth muscle markers (SMA, Calponin). Recently, aberrant immunoreactivity for TFE3 protein and TFE3 gene fusions have been reported in a subset of PEComas. Although numbers are small, distinctive features of these cases include a tendency to young age, the absence of association with tuberous sclerosis, predominant alveolar architecture and epithelioid cytology, minimal immunoreactivity for muscle markers, and strong (3+) TFE3 immunoreactivity.[27] However, most of the renal epithelioid angiomyolipomas expressing TFE3 by immunohistochemistry do not show TFE3 gene rearrangement by FISH. The single case of epithelioid angiomyolipoma we encountered occurred in a 56-year-old male patient and posed the differential diagnosis of tRCC due to diffuse epithelioid morphology with eosinophilic granular cytoplasm [Figure 5]. | Figure 3: (a and b) Mit family translocation RCC showing a biphasic growth pattern with large epithelioid cells with eosinophilic cytoplasm forming papillary architecture with hyalinised cores (a) and focal areas showing groups of smaller cells clustered around basement membrane-like material (b), H and E 40×
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 | Figure 4: (a and b) Large cell neuroendocrine carcinoma showing trabeculae of cells having moderate to abundant eosinophilic granular cytoplasm and round to ovoid nuclei with stippled chromatin pattern, H and E 40× (a) with diffuse staining for Chromogranin, IHC 40 × Bond polymer refine detection method using Leica BOND MAX fully automated IHC machine (b)
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 | Figure 5: Epithelioid angiomyolipoma showing diffuse epithelioid morphology with eosinophilic granular cytoplasm, H and E 40×
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The mixed epithelial and stromal tumor family encompasses a spectrum of tumors ranging from predominantly cystic tumors (adult cystic nephromas) to tumors that are variably solid (MESTs) and contain biphasic epithelial and stromal components, all sharing similar immunohistochemical and gene expression profiles.[2] Michal and Syrucek first proposed MEST designation in 1998. It usually occurs in post-menopausal women (F: M ratio – 7:1). Until now, 132 cases have been reported in the literature, 116 of which occurred in females with a median age of 54 years (8–84). Three pediatric cases have also been reported. Size varies from 0.3 to 30.5 cm with a predilection for right side. The proposed pathogenesis is due to embryological proximity of Mullerian derived and renal tissue, renal stromal cells undergo neoplastic differentiation with Mullerian features under appropriate hormonal milieu (hyperoestrogenemia) with entrapment of normal renal tubules which then undergo neoplastic transformation to cysts and primitive tubules. They are solitary unencapsulated but well-circumscribed tumors involving the medulla. Most of these tumors follow a benign course, but 13 cases with malignant transformation have been reported in the literature.[28] Our case was interesting in that it occurred in a 15-year-old boy as a large cystic neoplasm measuring 14 cm × 11 cm × 11 cm, confined within the kidney but replacing approximately 50% of the kidney. Histopathology showed a multiloculated cystic neoplasm with a biphasic pattern with cysts of varying sizes lined by flattened to cuboidal to hobnail cells and intervening septae showing sheets of spindle cells with variable cellularity [Figure 6]. | Figure 6: (a and b) Mixed epithelial-stromal tumor with a biphasic pattern with cysts of varying sizes lined by flattened to cuboidal cells, H and E 20× (a) High power, H and E 40× (b)
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Glomus tumors of the kidney are rare tumors, and only 22 cases of primary renal glomus tumors have been described in the literature, of which 17 were benign (with no evidence of recurrence or metastasis), three cases were malignant glomus tumors, and two cases were uncertain malignant potential.[29] The 2016 WHO classification system of the kidney tumors does not include the pericytic tumors and the exceptionally rare glomus tumors. Most benign glomus tumors were diagnosed in adults (age range 32–81 years), with a male: female ratio of 2:1, and are discovered incidentally during regular follow-up. Our case was diagnosed in a 29-year-old female patient who presented with a left renal mass. Grossly the tumor was well circumscribed, located in the upper pole of the kidney and measuring 2.7 cm × 2.5 cm × 2.2 cm, without the involvement of renal pelvis, sinus fat, or renal capsule. Microscopy showed fairly circumscribed neoplasm composed of nests, cords, and trabeculae of cells having ovoid vesicular nuclei, small nucleoli, and scanty to moderate amount of eosinophilic to vacuolated cytoplasm [Figure 7]a. The stroma showed extensive hyalinization with prominence of thin-walled vascular channels [Figure 7]c. Tumor cells showed positive staining for vimentin and SMA [Figure 7]b and patchy staining for H caldesmon. They were negative for cytokeratins, S100, synaptophysin, HMB-45, CD34, and desmin. Folpe et al. suggested the following criteria for malignancy in glomus tumors of soft tissue: (1) size >2cm and subfascial or deep location; (2) atypical mitotic figures; and (3) moderate-to-high nuclear grade and mitotic activity (5 mitoses/50 high-power fields).[30] However, it should be noted that the criteria associated with soft tissue glomus tumor aggression may not be predictive for those in the kidney. | Figure 7: (a-c) Glomus tumor showing trabeculae of cells having ovoid vesicular nuclei, small nucleoli, and scanty to moderate amount of eosinophilic cytoplasm, H and E 20× (a) IHC for SMA 40 × Bond polymer refine detection method using Leica BOND MAX fully automated IHC machine (b) IHC for CD34 20 × highlighting rich vasculature (c)
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Primary renal Ewing sarcoma is extremely rare and behaves more aggressively than Ewing sarcoma arising at other sites. The presence of this entity was first described in the kidneys in 1975 and thereafter has been addressed in only a few small case series. The mean age of presentation is 26 years, while the youngest patient reported so far was 3-years-old at the time of diagnosis.[31] Our study group included two cases diagnosed as Ewings sarcoma; both showed a small round cell neoplasm with brisk mitotic activity and necrosis, staining diffusely for CD99 and FLI 1. Cytokeratin, synaptophysin, WT1, desmin, and LCA were negative. Cytogenetic studies were not performed.
Further, 9% (5/55) of the tumors in our group were urothelial carcinoma, two arising from renal pelvis and three from the ureter. Patient age ranged from 56 to 86 years, and all patients underwent nephroureterectomy. All tumors were high grade and one showed sarcomatoid and divergent differentiation with glandular and squamous areas. All except the latter spared renal parenchyma.
| Conclusion | | |
Over the years, the histological diversity of RCC has been acknowledged, and unique morphological subtypes with characteristic histological features, immunoprofiles, and distinctive molecular alterations have been described and studied. It is now evident with the available data that the histological subtyping and understanding of the molecular alterations of renal tumors has significance in therapeutic approaches and prognosis.
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Conflicts of interest
There are no conflicts of interest.
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Correspondence Address:
Renu S Paul
Senior Consultant Pathologist, VPS Lakeshore Hospital and Research Centre, Kochi, Kerala
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijpm.ijpm_53_21
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1] |
