Like its sporadic counterpart, VHL clear cell RCC harbors defective VHL tumor suppressor genes. Genetic alteration in the VHL gene in the tumor can include deletion, nonsense or frame-shift mutations, mis-sense mutations or methylation.

Hereditary papillary RCC are typically bilateral, multifocal type 1 papillary RCC. Genetic alterations involve a proto-oncogene, c-MET, located at 7q31.1. Similar to what is found in sporadic papillary renal cell carcinoma, trisomy 7 and 17 are identified.

Hereditary leiomyomatosis associated-RCC patients develop cutaneous and uterine leiomyomas and one third of patients develop RCC. It was considered as a variant of type 2 papillary RCC. The pathologic findings in this disease are caused by germline mutations in the fumarate hydratase gene located at 1q42.

Architectural patterns are papillary, tubulo-papillary, tubular, solid or mixed. The morphologic hallmark of the hereditary leiomyomatosis-RCC, is the presence of large nucleus with a very prominent eosinophilic nucleolus, surrounded by a clear halo. These tumors are associated with poor prognosis.

It is now recognized a unique morphotype of RCC. The renal tumors have a papillary, alveolar, solid or tubular architecture with the characteristic features being a large nucleus and a prominent nucleolus, with a clear peripheral halo These tumors behave aggressively and have a poor prognosis when compared to other hereditary forms of RCC, or clear cell and papillary RCC (Fig. 1.1).

HLRCC leiomyomas frequently have increased cellularity, multinucleated cells, and atypia. All cases show tumor nuclei with large orangeophilic nucleoli surrounded by a perinucleolar halo similar to the changes found in HLRCC. Occasional mitoses may be seen; however, the tumors did not fulfill the criteria for malignancy.

Birt-Hogg-Dubé is an autosomal dominant cancer syndrome characterized by benign skin and renal tumors, and spontaneous pneumothorax. The disease related gene has been mapped to chromosome 17p11.2.

Birt-Hogg-Dubé is characterized by a spectrum of mutations, and clinical heterogeneity among and within families. Renal epithelial tumors with hybrid features are seen in this syndrome (Figs. 1.2 and 1.3).

Most clear cell RCC are variably sized solitary cortical neoplasms, rarely bilateral (<5 %) or multicentric (4 %), typically golden yellow. Necrosis, cystic degeneration, hemorrhage, calcification, ossification, and extension into the renal vein may occur. Clear cell tumors of any size are considered malignant.

Microvascular invasion and microscopic tumor coagulative necrosis may be relevant predictors in low stage RCC (Table 1.4). Clear cell RCC has a worse prognosis when compared with chromophobe or papillary subtypes, and may progress into a sarcomatoid carcinoma which is an ominous prognostic sign (Figs. 1.4 and 1.5).

The international Society of Urological Pathologists (ISUP) suggested that clear cell RCC grading should be based upon nucleolar features and not Fuhrman grading (Table 1.5). Sporadic clear cell RCC displays frequent chromosome 3p losses.

Clear cell RCC may have acidophilic cytoplasm, hemangioblastoma-like, angioleiomyoma-like stroma or pseudo-papillary architecture but retains the characteristic 3p loss.

The ISUP modification of the current 2004 WHO classification of kidney tumors recognizes multilocular cystic clear cell renal cell neoplasm of low malignant potential (MCNLMP) as a variant of clear cell RCC with a good prognosis.

This is a tumor entirely composed of cysts of variable size separated from the kidney by a fibrous capsule. The cyst are lined by a single layer of clear to pale cells but occasionally shows a few small papillae. The septa are composed of fibrous tissue that may have epithelial cells with clear cytoplasm that resemble those lining the cysts (Figs. 1.6, 1.7 and 1.8).

Cases with expansive nodules are excluded. VHL gene mutations in MCNLMP supports its classification as a type of clear cell RCC.

No progression of MCNLMP has been reported.

Papillary RCC has a less aggressive clinical course than clear cell RCC. Papillary RCC has variable proportions of papillae and may be bilateral or multifocal with hemorrhage, necrosis or cystic degeneration. The papillae contain a fibrovascular core with aggregates of foamy macrophages, calcified concretions and frequent hemosiderin granules.

Cellular type 1 and type 2 tumors have papillae covered by small cells with scanty cytoplasm arranged in a single layer in type1, and tumor cells of higher nuclear grade, eosinophilic cytoplasm and pseudostratified nuclei in type 2. Type 1 tumors have longer survival (Figs. 1.9, 1.10 and 1.11).

Trisomy or tetrasomy 7, trisomy 17 and loss of chromosome Y are the cytogenetic signature. Stage, tumor proliferation and sarcomatoid change being correlated with outcome. It has been suggested that papillary RCC grading should be based upon nucleolar features and not Fuhrman grading.

Age and sex distribution of papillary RCC is similar to clear cell RCC. Recent molecular genetic studies provide evidences for the independent origin of multifocal papillary tumors in patients with papillary RCC. An oncoytic variant of papillary RCC has been reported. One patient died of metastases on follow-up (Figs. 1.12 and 1.13).

Less aggressive than other RCC, the chromophobe type is characterised by huge pale cells with reticulated cytoplasm and prominent cell membrane. It accounts for 5 % of renal epithelial tumors.

Chromophobe RCC is solid and appears orange turning grey or sandy after fixation. The eosinophilic variant needs to be differentiated from oncocytoma. Sarcomatoid transformation is associated to aggressive disease. Diffuse cytoplasmic Hale’s iron colloid stain is characteristic (Figs. 1.14, 1.15 and 1.16).

The relationship between oncocytoma and chromophobe RCC is still unclear. Both seems to derive from the intercalated cell of the collecting duct, both have rearrangement of mitochondrial DNA, increased mitochondria in oncocytoma and numerous mitochondria-derived microvesicles in chromophobe RCC, and both are frequently observed in oncocytosis with or without Birt-Hogg-Dubé syndrome.

There are reports of hybrid tumor composed of oncocytic and chromophobe elements. Therefore, oncocytoma might be the benign counterpart of chromophobe RCC. Loss of several chromosomes characterises chromophobe RCC. Recognising occassional occurrence of metastases and 10 % mortality is of clinical relevance.

At diagnosis most patients are in the sixth decade, stage T1 or T2 (86 %) and similar gender incidence. Fuhrman grading is not appropriated to grade chromophome RCC with an international consensus on that chromophobe RCC should not be graded at present.

Described as tumors having a mixture of cells with the morphologic features of those seen in chromophobe RCC and renal oncocytoma (Figs. 1.17 and 1.18).

HOCTs occur in three clinical situations: (i) being sporadic, (ii) in association with renal oncocytosis/oncocytomatosis, and (iii) in patients with the Birt-Hogg-Dubé syndrome (BHD). It seems that tumors from all three groups share similar morphologic features but that they have a differing molecular genetic background.

Sporadic HOCTs are composed of neoplastic cells predominantly arranged in a solid-alveolar pattern, with nuclei showing mild nuclear pleomorphism and abundant granular eosinophilic to oncocytic cytoplasm. Neoplastic cells have a perinuclear halo and are occasional binucleate. No raisinoid nuclei of the type seen in classic chromophobe RCC are present. Usually tumor cells resemble cells of oncocytoma with perinuclear cytoplasmic clearing, and, occasional, small tubules may be present.

HOCTs in oncocytosis/oncocytomatosis are almost identical to those tumors that occur sporadically, being composed of sheets of cells separated by a delicate vasculature. The cells are round to polygonal with finely granular cytoplasm, and the nuclei are slightly pleomorphic and irregular with visible nucleoli. No typical raisinoid nuclei are seen, and mitotic figures are rare.

HOCTs associated with BHD typically show three morphologic patterns: (i) an admixture of areas typical of oncocytoma and chromophobe RCC; (ii) scattered chromophobe cells in the background of a typical oncocytoma; and (iii) large eosinophilic cells with intracytoplasmic vacuoles. In these tumors, the nuclei are often more pleomorphic than other forms of HOCT and occasionally have a “raisinoid” morphology.

The majority of the tumors express parvalbumin, antimitochondrial antigen, CK7, and CD117 by immunohistochemistry. Monosomy of chromosome 20 is the most frequent genetic alteration, a finding highly unusual for both oncocytoma and chromophobe RCC.

HOCTs usually occur in adult patients, with no sex predilection; some are associated with long term hemodialysis. Can be unilateral and solitary or being bilateral and multiple lesions. Necrosis is not frequently, but central fibrotic strands/scars may be occasionally present. Tumors are usually well circumscribed and nonencapsulated with homogenous tan to brown cut surface.

HOCT, regardless of clinical association, seems to behave indolently and no evidence of aggressive behavior has been documented.

Collecting duct carcinoma (CDC), also known as Bellini’s tumor, accounts for <1 % of renal malignancies and derives from the “principal cells” of the collecting duct; ranges 2.5–12 cm, is centraly located and shows a firm grey-white appearance.

Mean patient age is 55 years with male predominance. When small, origin within a medullary pyramid may be seen at gross examination. At diagnosis, most tumors are in advanced stage with metastasis and morphologic criteria for diagnosis are the presence of an infiltrative tubular or tubulopapillary pattern, associated with desmoplastic stromal reaction, necrosis and cells displaying high Fuhrman grade (Figs. 1.19, 1.20 and 1.21).

CDC is positive for low and high molecular weight keratins, CD117 and vimentin, EMA, p63, CK7, Pax 2, Pax 8, but molecular alterations of CDC are poorly understood (Table 1.3). The main differential diagnoses of CDC include type 2 PRCC, renal pelvic adenocarcinoma or urothelial carcinoma with glandular differentiation. Immunohistochemistry is a valuable adjunct in this setting (Table 1.6).

One recent experience identified complete loss of expression of INI1 in 15 % and focal/weak expression of INI1 in up to 30 % of CDC, with no difference in survival by INI1 status.

It is a rapidly growing rare tumor of the renal medulla regarded as an aggressive variant of collecting duct carcinoma that was initially considered of renal pelvis origin. Some may have solid, spindled or rhabdoid phenotype (Figs. 1.22 and 1.23).

Immunohistochemistry analysis shows that the neoplastic cells are positive for CEA (7/8), AE1/3 (8/8), CAM5.2 (7/7), CK7 (5/5), CK20 (4/6), and vimentin (6/6)

Essentially all cases of RMC show loss of nuclear expression of the transcriptional regulator INI1/SMARCB1, reflecting prevalent mutation of the gene.

With few exceptions this tumor is seen in young male blacks with sickle cell trait (mean age 22 years), presenting with hematuria, flank pain, weight loss and palpable mass.

Metastatic disease may be the initial clinical evidence and the reported prognosis is poor.

Low-grade carcinoma composed of tightly packed tubules separated by pale mucinous stroma and a spindle cell component. It seems to derive from the distal nephron (Figs. 1.24, 1.25, 1.26, 1.27 and 1.28).

This tumor has a combination of losses involving chromosomes 1, 4, 6, 8, 13 and 14 and gains of chromosome 7, 11, 16 and 17. Immunohistochemical analysis found a significant overlap with papillary RCC, and some authors believe this is a variant of papillary RCC with spindle cell differentiation.

There is a female predominance and the mean age is 50 years at diagnosis. One patient developed metastases on follow-up.

A few cases of RCC arise in long term survivors of childhood neuroblastoma. This group is heterogeneous that shows oncocytoid features.

Allelic imbalances occur at the 20q13 locus. The prognosis is similar to other RCC. Uni- or bilateral lesions develop at mean age of 13 years.

Current WHO classification does not consider sarcomatoid RCC as an entity but rather as a progression of any RCC main type. Pure sarcomatoid morphology without recognizable epithelial elements falls into the unclassified RCC category (Figs. 1.29 and 1.30).

RCC with sarcomatoid elements show higher proliferative activity than other renal cell carcinoma types and usually exhibit highly malignant behavior with a predilection for increased local invasiveness and a higher likelihood of distant metastasis.

Sarcomatoid components may be seen in clear cell, papillary, chromophobe and collecting duct carcinomas. It is speculated that the sarcomatoid components of RCC represent areas of dedifferentiation or epithelial-mesenchymal transition.

Patterns of allelic loss and of nonrandom X-chromosome inactivation in clear cell and sarcomatoid components of RCC from 22 patients and concluded that both clear cell and sarcomatoid components of RCC are derived from the same progenitor cell.

The specific molecular mechanisms responsible for sarcomatoid transformation of a renal tumor are unknown, although some studies suggest a link with mutations of the TP53 tumor suppressor gene.

RCC with rhabdoid differentiation is a rare and aggressive neoplasm with poor prognosis. Most patients are at high stage at diagnosis, develop metastases soon after and died of the disease within a year of diagnosis.

Rhabdoid cells are large with eccentric atypical nucleus and eosinophilic intracytoplasmic inclusion that is positive for vimentin, EMA, and cytokeratin. Sarcomatoid change and rhabdoid features may coexist. Rhabdoid cells show loss of nuclear expression of the transcriptional regulator INI1/SMARCB1

It represents 4–6 % of renal tumors. At diagnosis, most are of high grade and stage with poor survival (Figs. 1.31 and 1.32).

The WHO criteria include: (i) composites of recognised types, (ii) pure sarcomatoid morphology, (iii) mucin production, (iv) rare mixtures of epithelial and stromal elements, and (v) unrecognisable cell types.

Reported data suggests that it is an aggressive form of RCC as confirmed in a recent study based on 56 cases. The prognosis of these patients is mainly related to pT stage, tumor size, vascular invasion, tumor necrosis or recurrence after surgery.

Is a rare renal tumor composed of tubular and cystic structures. The genomic alterations of tubulocystic carcinoma are alike but not identical to those of papillary RCC (Fig. 1.33).

Like papillary RCC, it often exhibits trisomy of chromosome 17, but it does not show trisomy 7. It does not exhibit monosomy of chromosomes 1, 6, 14, 15, and 22 and frequent allelic loss on chromosomal arms 1q, 6p, 8p, 13q, and 21q, which are frequently seen in collecting duct cancer.

Immunohistochemistry showed variable expression of CD10, AMACR, parvalbumin, 34βE12, PAX-2, CAIX, CK8, 18, CK19 and occasionally for CK7 and 34βE12.

Rare cases may present with lymph node metastasis. Some may coexist with papillary RCC.

These are composed of cells with abundant eosinophilic cytoplasm and variably solid, cribriform, tubulocystic and papillary architecture. It shows no VHL gene deletions, although gains of chromosomes 7 and 17 are present in some cases.

Deposits of calcium oxalate crystals are frequent finding in each tumor. One study based on FISH analysis showed no losses or gains of chromosomes 1, 2, 6, 10, or 17 in one tumor; gains of chromosomes 1, 2, and 6 were noted in two tumors, one of these also showed gains of chromosome 10 (Fig. 1.34).

These are renal carcinomas composed mainly of papillary structures proliferating within cystic spaces, lined by cells with clear cytoplasm.

All tumors lacked the gains of chromosome 7 and loss of Y that are typical for papillary renal cell carcinoma and furthermore lack the 3p deletion which is typical of clear cell RCC (Figs. 1.35 and 1.36).

These tumors also occur in patients unrelated to end-stage renal disease.

This type of RCC is defined by different translocations involving chromosome Xp11.2, all resulting in gene fusions involving the TFE3 gene. This carcinoma predominantly affects children and young adults, but may be seen in adults.

The ASPL-TFE3 translocation carcinomas characteristically present at an advanced stage associated with lymph node metastases. RCC associated with Xp11.2 translocations resemble clear cell RCC on gross examination and seems to have an indolent evolution, even with metastasis (Figs. 1.37 and 1.38).

The histopathologic appearance is that of a papillary carcinoma with clear cells and cells with granular eosinophilic cytoplasm with foci of calcifications regardless of the type of translocation.

TFE3 immunostainings were positive in only 82 % of TFE3 translocation carcinomas. Both TFE3 and TFEB renal translocation carcinomas expressed CD10 and alpha-methylacyl-coenzyme-A racemase.

Another subset of renal tumors are associated with a translocation t(6;11)(p21;q12) involving the transcription factor EB (TFEB). Translocation involving TFE3 and TFEB can be specifically identified by immunohistochemistry, but diagnosis may also be performed by FISH analysis (Fig. 1.39).

Labeling for PAX8 distinguishes the t(6;11) RCC from epithelioid angiomyolipoma, which otherwise shares a similar immunoprofile.

It is a rare variant of RCC resembling well differentiated follicular carcinoma of the thyroid gland. These tumors are well circumscribed, tan brown and homogenous.

Microscopically they consist of tumor follicles of varying size containing dense eosinophilic colloid-like material (Fig. 1.40). The genetics and immunohistochemical expression of these tumors are, as yet, not fully characterized although thyroid follicular cell markers, thyroglobulin and TTF-1 are negative.

The majority of cases reported to date have shown an indolent behavior, although metastases to lymph nodes in two cases and a single case with pulmonary metastases have been reported.

These tumors are seen in patients within germline Succinate Dehydrogenase B mutation, which is associated with a syndrome characterized by pheochromocytoma, paraganglioma and type 2 gastrointestinal stromal tumors.

Microscopically these tumors are characterized by the presence of compact nests of eosinophilic polygonal cells. Cytoplasmic vacuoles and pale eosinophilic cytoplasmic inclusions are commonly seen and these represent giant mitochondria.

Less than ten cases have been reported to date and follow-up is limited. Of note, sarcomatoid change was identified in two patients with metastatic disease, one of whom died of tumor related causes.

A fusion of the anaplastic lymphoma kinase (ALK) gene with the gene for the cytoskeletal protein vinculin (VCL) resulting from the translocation t(2:10)(p23;q22) has been reported in two tumors observed in young patients.

VCL–ALK translocation RCC appear to have a characteristic appearance, consisting of cells with a polygonal to spindled morphology with abundant eosinophilic cytoplasm and frequent intracytoplasmic lumina.

While these two cases were associated with sickle cell trait, two further RCCs showing ALK fusion with different partner genes have been described in older patients, although neither of these showed a sickle cell association.

Two additional cases of RCC demonstrating ALK fusion (fusion partner unknown) have been reported in adult patients that behave aggressively.

A recent case showing VCL–ALK RCC in a child with sickle-cell trait has been recently reported.