Renal cell carcinomas with intratumoral fat and concomitant angiomyolipoma: potential pitfalls in staging and diagnosis

Intratumoral fat and angiomyolipomas (AMLs) occurring within renal cell carcinomas (RCCs) have rarely been reported but may be mistaken for tumor invasion into perinephric or renal sinus fat or misdiagnosed as tumor exhibiting sarcomatoid differentiation. We report 16 such cases. In 14 RCC cases, there was intratumoral fat, 9 of which had fat located peripherally near the capsule (n = 6), renal sinus (n = 1), or both (n = 2). Inflammatory infiltrates and osseous metaplasia were identified in the intratumoral fat in 7 and 8 cases, respectively. Two cases had intratumoral AML foci located at the periphery of RCC. Intratumoral fat or AML at the periphery of RCC simulated the invasion into the fat, while the smooth muscle component of AML resembled spindle cell, or sarcomatoid, differentiation. Our study highlights the potential pitfalls in staging and diagnosis when intratumoral fat or AML is found within RCC.     

Comparative Immunohistochemical Assessment of Craniopharyngioma and Related Lesions

Craniopharyngiomas (CP), Rathke’s cleft cysts (RCC), and sellar xanthogranulomas (XG) are closely related lesions. As expression of cytokeratins 8 (CK8) and 20 (CK20) was reported in RCC but not in CP, the present study investigates the reproducibility of immunohistochemical distinction between CP and RCC, attempting to identify the relationship of XG to these lesions. A comparative study of 55 patient specimens (25 CP, 28 RCC, and 2 XG) was analyzed for the histological features of xanthomatous changes and squamous metaplasia, and expression of CK8 and CK20. In the 25 CP cases, xanthomatous changes were seen in 5 (20%), with CK8 reactivity demonstrated in all 25 cases. A prominent xanthomatous component was identified in 13 of 28 RCC (46%), and squamous metaplasia was seen in 11 (39%), 9 of which also contained xanthomatous features. CK8 reactivity was demonstrated in all 28 RCC cases, whereas CK20 was seen only in 9 cases (32%). Of the two cases diagnosed as XG, none contained epithelium, and immunohistochemistry for cytokeratins was not observed. Overall, differential expression of cytokeratins cannot reliably distinguish CP from RCC. Furthermore, expression of CK20 in RCC is generally seen within a background of prominent squamous metaplasia and reactive xanthomatous changes.     

Synchronous chromophobe and papillary renal cell carcinoma. First report and review of the pathogenesis theories

The coexistence of different subtypes of renal cell carcinoma (RCC) within a single kidney is an extremely unusual entity. Presented herein is the case of a 57-year-old man with two RCC of chromophobe and papillary histology. Very few reports in the literature describe double or triple synchronous renal neoplasms. To our knowledge this is the first report of this RCC subtype combination, which might trigger further investigation on the RCC pathogenesis theories.     

Recent classification of renal epithelial tumors

The recent classification of renal tumors is based on genetic evidence as well as on histologic features. Malignant tumor includes clear cell renal carcinoma (RCC), multilocular cystic RCC, papillary RCC, chromophobe RCC, carcinoma of the collecting duct of Bellini, renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and mucinous tubular and spindle cell carcinoma. Benign tumor is subdivided into papillary adenoma, renal oncocytoma and metanephric adenoma. Recently, new disease entities such as acquired cystic disease-associated RCC, clear cell papillary RCC and renal carcinoma with t(6;11)(p21:q12) have been discovered. In this article, we briefly review and introduce the clinical, morphological and genetic features of these tumor entities.     

Immunohistochemical application of S100A1 in renal oncocytoma, oncocytic papillary renal cell carcinoma, and two variants of chromophobe renal cell carcinoma

S100A1 is a calcium-binding protein and a member of the S100 family. Recently, S100A1 immunohistochemistry may be an available marker in the differential diagnosis between renal oncocytoma and chromophobe renal cell carcinoma (RCC). However, there are no reports on S100A1 expression in oncocytic papillary RCC that has been recently identified. In this article, we immunohistochemically examined the expression of S100A1 protein in 18 renal tumors including 4 renal oncocytoma, 10 chromophobe RCCs, and 4 oncocytic papillary RCCs. All the cases of renal oncocytoma and oncocytic papillary RCC showed a positive reaction for S100A1 with cytoplasmic pattern. In chromophobe RCC, 3 of 4 tumors with typical variant and 4 of 6 tumors in eosinophilic variant were completely negative for S100A1. Finally, S100A1 immunohistochemistry may be useful in distinguishing renal oncocytoma from chromophobe RCC, but it may be of no use in the differential diagnosis between renal oncocytoma and oncocytic papillary RCC.     

Chromosome changes in sarcomatoid renal carcinomas are different from those in renal cell carcinomas

Sarcomatoid renal carcinoma (SRC) is an uncommon and highly malignant renal tumor with sarcomatous morphology or with both sarcomatous and carcinomatous components. The tumors are generally referred to as dedifferentiated or transformed renal cell carcinomas (RCC). Information on their genomic changes is scarce. Data from a cytogenetic study of four cases of SRC are presented in this article. Combined with a few other cases from the literature, it appears that genomic changes in most cases of SRC have little in common with those characterizing conventional RCC. Sarcomatoid transformation thus may occur occasionally in RCC without the characteristic chromosome changes but also, and perhaps more frequently, in a subgroup of RCC without the characteristic chromosome changes.     

A case of chromophobe renal cell carcinoma with sarcomatoid foci and a small daughter lesion

Chromophobe renal cell carcinoma (RCC), which has recently been recognized to be a distinct type of RCC, comprises approximately 5% of renal cell tumors. It has been hypothesized that the cells that comprise chromophobe RCC show a phenotype similar to that of intercalated cells of the collecting duct Although the number of research reports on this type of tumor has recently been increasing, only nine cases of chromophobe RCC showing sarcomatoid transformation have been described. Herein, a case of chromophobe RCC with sarcomatoid foci and a small daughter lesion is reported.     

Recent advances of immunohistochemistry for diagnosis of renal tumors

The recent classification of renal tumors has been proposed according to genetic characteristics as well as morphological difference. In this review, we summarize the immunohistochemical characteristics of each entity of renal tumors. Regarding translocation renal cell carcinoma (RCC), TFE3, TFEB and ALK protein expression is crucial in establishing the diagnosis of Xp11.2 RCC, renal carcinoma with t(6;11)(p21;q12), and renal carcinoma with ALK rearrangement, respectively. In dialysis‐related RCC, neoplastic cells of acquired cystic disease‐associated RCC are positive for alpha‐methylacyl‐CoA racemase (AMACR), but negative for cytokeratin (CK) 7, whereas clear cell papillary RCC shows the inverse pattern. The diffuse positivity for carbonic anhydrase 9 (CA9) is diagnostic for clear cell RCC. Co‐expression of CK7 and CA9 is characteristic of multilocular cystic RCC. CK7 and AMACR are excellent markers for papillary RCC and mucinous tubular and spindle cell carcinoma. CD82 and epithelial‐related antigen (MOC31) may be helpful in the distinction between chromophobe RCC and renal oncocytoma. WT1 and CD57 highlights the diagnosis of metanephric adenoma. The combined panel of PAX2 and PAX8 may be useful in the diagnosis of metastatic RCC.     

Synchronous renal and adrenal masses: an analysis of 80 cases

Synchronous renal and adrenal masses are uncommon. Although adrenal masses in the context of renal cell carcinoma (RCC) are often suspected as metastasis, other adrenal lesions with different therapeutic and prognostic implications may coexist with RCC. In a retrospective review of 550 radical nephrectomies with ipsilateral adrenalectomy, 80 cases of coexisting renal and adrenal masses were identified. The renal masses included 76 RCCs, 3 oncocytomas, and 1 malignant pheochromocytoma of adrenal gland involving the kidney. Although the gross pathologic impression of adrenal masses in the presence of RCC was metastasis, on histologic examination, 56% of them were found to be benign lesions (mostly adrenal adenoma/hyperplasia), whereas malignant involvement from RCC was seen in 43%. The benign and malignant nature of the adrenal lesions in the context of RCC could not be discriminated based on the size of adrenal mass. Because of the prognostic implication of direct or metastatic involvement of adrenal gland in the setting of RCC and the possibility of finding small metastatic foci, a meticulous gross and microscopic examination of adrenal glands is emphasized. Rare unusual combinations of renal and adrenal lesions such as RCC and adrenal histoplasmosis, RCC and adrenal myelolipoma, renal oncocytoma, and adrenal pheochromocytoma are also described.     

Acquired cystic disease-associated renal cell carcinoma with gain of chromosomes 3, 7, and 16, gain of chromosome X, and loss of chromosome Y

Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) has been recently described. To date, there are no reports on genetic findings of G-band karyotype of ACD-associated RCC. In this article, we report the first report of G-band karyotype of ACD-associated RCC. A 66-year-old Japanese man was found to have a left renal tumor during the follow-up of hemodialysis consequent to chronic renal failure. Left nephrectomy was performed. Histological examination of three tumors in the left kidney showed the cribriform or microcystic growth pattern of neoplastic cells with eosinophilic cytoplasm, and many oxalate crystals were observed. The G-band karyotype of ACD-associated RCC showed 49, X, +X, −Y, +3, +7, +16. These chromosomal abnormalities resemble those of sporadic papillary RCC that has been previously reported. Finally, we suggest that this tumor may show a close relationship between ACD-associated RCC and papillary RCC, but a large-scale study will be needed to clarify the relationship between ACD-associated RCC and papillary RCC.     

Renal cell carcinoma and the renal sinus

Renal sinus fat invasion was incorporated as one of the parameters for pT stage definition of renal cell carcinoma (RCC) only in the latest 2002 American Joint Committee on Cancer/tumor-node-metastasis staging protocol. The current pT3a subcategory (in addition to adrenal gland involvement) groups 2 modes of extrarenal extension by RCC, either by peripheral perinephric fat extension or by renal sinus fat invasion. Recent prospective studies have shown that with more directed gross sampling and histologic evaluation, renal sinus invasion is actually more commonly diagnosed than previously reported, or when compared with retrospectively sampled RCC nephrectomy specimens. These studies have demonstrated that renal sinus invasion is the principal pathway for extrarenal extension for clear cell RCC; the incidence of which is related to size (tumors greater than 4 cm more frequently involve the renal sinus). More significantly, a recent retrospective study of pT3a clear cell RCC nephrectomy specimens showed that tumors invading the renal sinus fat portend a more aggressive outcome than tumors invading only the peripheral perinephric fat. Clear cell RCCs invading the renal sinus are more likely to have higher nuclear grade, regional lymph node involvement and sarcomatoid transformation than tumors invading only the perinephric fat. Given the importance of renal sinus invasion, sampling strategies for nephrectomy specimens should be modified to focus in this region as appropriate and pathologists should be familiar with the histologic criteria for staging renal sinus invasion.     

GATA3 aids in distinguishing fumarate hydratase-deficient renal cell carcinoma from papillary renal cell carcinoma

GATA3 has been reported to be positive in clear cell papillary renal cell carcinoma and papillary renal neoplasm with reverse polarity. However, its features in high-grade RCC remain unclear. Despite the emergence of novel renal entities, FH-deficient RCC remains one of the most aggressive renal neoplasms. The diagnosis is mainly based on the loss of FH at the protein level. Previous studies have shown that inclusion-like nuclei, multiple architectural patterns, FH loss, and 2SC positivity can differentiate FH-deficient RCC from other RCC. In some FH-deficient RCC cases, FH is normally expressed and is difficult to diagnose. This study included 11 FH-deficient RCC, and GATA3 showed different expression in seven cases. However, 147 papillary renal cell carcinomas were included, and GATA3 expression was negative. A comparison of clinicopathological aspects between 11 FH-deficient RCC and 30 high-grade PRCC showed statistical significance in age, size, multiple architectural patterns, inclusion-like nuclei, and prognosis. However, PRCC exhibited similar characteristics. CK7, GATA3, and FH profiles were also statistically significant. Different chromosomal alterations were found in FH-deficient RCC, and chromosomal alterations were not different between FH-deficient RCC and PRCC. GATA3 was positive in 33 % (7/21) of collecting duct carcinomas and negative in other high-grade renal neoplasms. GATA3 is negative in PRCC, but can be positive in FH-deficient RCC and collecting duct carcinoma. GATA3 expression may indicate a worse outcome in high-grade RCC with papillary architecture. We recommend GATA3 IHC for the differential diagnosis and prognostic assessment of high-grade RCC with papillary architecture.     

De novo concurrent papillary renal cell carcinoma and angiomyolipoma in a kidney allograft: evidence of donor origin

In the general population, renal cell carcinoma (RCC) is a relatively common neoplasm; however, the papillary RCC subtype is infrequent and represents only 10 to 15% of all RCC. Angiomyolipoma is a well-known common benign tumor. The occurrence of RCC in association with angiomyolipoma is a rare event, with only approximately 50 cases reported in the nontransplantation setting. In transplant recipients, RCC can develop in native kidneys, but its occurrence "de novo" in the renal allograft is very rare with an estimated incidence of less than 0.5%. We report here the case of a 39-year-old woman who underwent cadaveric renal transplantation in 1990. No lesion was observed in the allograft during the pre- and perioperative period or on early postoperative ultrasounds. No graft rejection occurred under a standard triple immunosuppressive therapy. Thirteen years later, during a routine ultrasonography, 2 solid masses were discovered in the allograft, both of them richly vascularized. She underwent allograft nephrectomy and the histologic findings revealed that one of the tumors was a chromophilic (type 1) papillary RCC (2.5 cm in diameter) and the other, an angiomyolipoma (1.5 cm). Microsatellite analysis of the allograft, as compared with the recipient peripheral blood leukocytes, demonstrated that the 2 tumors (1 malignant and 1 benign) were of donor origin. To our knowledge, this is the first report of de novo concurrent papillary RCC and angiomyolipoma in a renal allograft.     

Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: an immunohistochemical and genetic study

Clear cell papillary renal cell carcinoma (RCC) is a recently established disease entity. However, there are few reports on genetic study of this entity. We report such a case with focus on genetic study. A 57-year-old Japanese man was found to have 3 renal tumors. Histologically, two tumors showed findings of clear cell RCC; and the other tumor showed findings of clear cell papillary RCC that was characterized by papillary growth pattern of neoplastic cells in cystic space with purely clear cell cytology. Immunohistochemically, tumor cells of clear cell papillary RCC were diffusely positive for PAX2 and cytokeratin 7, but negative for CD10, RCC Ma, and AMACR. In fluorescence in situ hybridization study for one clear cell papillary RCC, we detected polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20. In addition, we detected mutation of VHL gene in clear cell RCC, but found no VHL gene mutation in clear cell papillary RCC. Finally, our results provide further evidence that clear cell papillary RCC may be both morphologically and genetically distinct entity from clear cell RCC and papillary RCC.     

Distinct Cytoplasmic Expression of KL-6 Mucin in Chromophobe Renal Cell Carcinoma: A Comparative Immunohistochemical Study with Other Renal Epithelial Cell Tumors

The presence of cytoplasmic sialyl glycoproteins is a conspicuous feature in chromophobe renal cell carcinoma (RCC). We compared the immunohistochemical expression of sialyl glycoproteins in chromophobe RCC with that in other types of renal tumors. Formalin-fixed, paraffin-embedded tissues of surgically resected renal tumors (chromophobe RCC, 14 cases [10 cases of classic type and 4 cases of eosinophilic variant]; oncocytoma, 7 cases; and clear cell RCC, 9 cases) and kidneys from immature infants (4 cases) were immunostained with antibodies against sialyl glycoproteins (anti-KL-6 and anti-sialyl MUC1 antibodies). Cytoplasmic expression of KL-6 and sialyl MUC1 was distinctive in the chromophobe RCC and renal oncocytoma cells, and in the intercalated cells in collecting duct epithelia. Apical-surface staining of these sialyl glycoproteins was predominantly observed in clear RCC, in the epithelia of the distal tubule and collecting duct, and in the neonatal renal proximal tubule, but not in those of the adult renal proximal tubule. The above-mentioned observations provide additional evidence for similar phenotypic profiles of chromophobe RCC and renal oncocytoma, and the intercalated cells in collecting ducts and the oncofetal expression of sialyl glycoproteins in clear cell RCC. KL-6 is a potential tumor marker for renal tumors.     

Chromophobe cell carcinoma and renal cell neoplasms with mucin-like changes

Hale's colloidal iron staining of 8 chromophobe cell carcinomas (CCC) was compared with that of non-chromophobe renal cell carcinomas (RCC), renal oncocytomas, and renal adenomas. Six non-chromophobe RCC showing diffuse and moderate cytoplasmic staining contained extensive areas with translucent cytoplasm as observed in CCC. Seventeen of 25 conventional RCC of the clear cell variant (randomly chosen from 130 cases), 21 of 26 RCC with areas of chromophilic cytoplasm, and 16 of 20 papillary RCC, 7 of 14 adenomas and 14 of 16 oncocytomas displayed focal areas with mild to moderate staining of the cytoplasm. Hale's colloidal iron staining was partially reduced by digestion with neuramidase but not with hyaluronidase. This positive staining demonstrated glycoproteins containing sialylated glycoconjugates, probably a type of acid epithelial mucin. We suggest that there is a spectrum of mucin-like changes in typical CCC representing RCC with extensive and marked "mucin-like changes". The eosinophilic variant of CCC and some RCC with extensive chromophobe cell features represent renal neoplasms with moderate changes. The other RCC, oncocytomas and papillary renal neoplasms with mild to moderate staining with Hale's colloidal iron represent renal neoplasms with focal mucin-like changes. RCC with extensive chromophobe cell features may pose a differential diagnostic problem with CCC.     

Mucin-secreting clear cell renal cell carcinoma. A rare variant of conventional renal cell carcinoma

We report herein one case of conventional renal cell carcinoma (RCC) producing extensive extracellular mucinous secretion in a 71-year-old man. To the best of our knowledge, the presence of mucinous secretion in this tumor has not been documented. Mucin production, despite its low frequency, can be considered an additional feature of conventional RCC. Therefore, clear cell RCC should be added to the list of parenchymal renal tumors that can show significant mucin secretion; and it should be included in the inventory of morphologic variations of this tumor, which may cause diagnostic difficulties. It is of primary importance to distinguish mucin-secreting clear cell RCC from the metastasis of a mucin-secreting tumor to conventional RCC. Presence of mucin in a clear cell carcinoma does not exclude a renal origin.     

New and emerging renal tumour entities

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, thyroid-like follicular carcinoma of the kidney, succinate dehydrogenase-deficient RCC, Birt–Hogg–Dubé syndrome-associated renal tumour, 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.     

High endogenous avidin binding activity: an inexpensive and readily available marker for the differential diagnosis of kidney neoplasms

It has been documented that some tissues, such as salivary gland, liver, cardiac and skeletal muscles and kidney, have high level endogenous biotin or endogenous avidin binding activity (EABA). Limited data is available on EABA in renal cell neoplasms. A tissue microarray (TMA) was constructed that included oncocytoma (n=30), chromophobe renal cell carcinoma (RCC) (n=18), clear cell RCC (n=45), clear cell RCC with granular/eosinophilic (G/E) features (n=19), papillary RCC (n=21), papillary RCC with G/E features (n=29) and benign renal tissues (n=31). The TMA slides were stained with or without biotin blocker and analyzed using the automated cellular imaging system (ACIS(R)). Without biotin blocker, a high positive rate of EABA was found in oncocytoma (56/60, 93%) and normal renal tubules (46/60, 77%). A moderate positive rate of EABA was found in clear cell and papillary RCCs with G/E features (13/39, 33% and 19/55, 35%, respectively). Chromophobe RCC and RCC without G/E features had essentially no EABA. With biotin blocker, benign renal tissue and clear cell RCC were negative for EABA; but a significant number of renal oncocytoma (29/60, 48%) and a few papillary RCC with G/E features (5/52, 10%) remained positive for EABA. In conclusion, high EABA may be used to differentiate oncocytoma from chromophobe RCC, and the staining results must be interpreted with caution when avidin-biotin detection system is used in diagnosing renal neoplasms.