Capillary loops with thin walls
Mesangial matrix material not conspicuous
Maximum of two to three nuclei in mesangial areas
Inflammatory cells rare in capillary lumens, if any
No fibrin thrombi in arteriolar or capillary lumens (Figure 3.6)
Figure 3.1. The normal glomerulus is composed of multiple capillary loops with thin walls. The Bowman capsule separating the glomerulus from the renal tubules and interstitium is also thin and inconspicuous.
Figure 3.2. In this high magnification H&E stain of a glomerulus, the mesangial matrix is light pink with a normal number of nuclei (1-2 cells).
thorough medical renal evaluation is needed, some laboratories can perform immunofluorescence from formalin-fixed, paraffin-embedded tissues, and tissue for electron microscopy can be either extracted from the paraffin block (with some artifact) or processed from the gross specimen.
Figure 3.7. Proximal tubules, occupying most of this field, typically have voluminous eosinophilic cytoplasm. Distal tubules (circled) have slightly less cytoplasm and more cuboidal cells.
Figure 3.8. Using immunohistochemistry, this stain for AMACR shows extremely bright staining in the proximal tubules, which would mirror that seen in papillary renal cell carcinomas.
Figure 3.9. This field shows a paired renal artery (a) and vein (v). Both have smooth muscle in their walls, although the smooth muscle of the vein is variable in thickness and focally absent.
Figure 3.11. At high magnification, this artery (a) and vein (v) pair shows no muscle in the small vein.
Figure 3.12. An elastic layer (arrow) can be helpful in recognizing arteries. This example shows some multilayering, suggesting hypertension.
Figure 3.13. The renal sinus is the fatty compartment that surrounds the renal hilar vasculature and renal pelvis (arrows). This area should be carefully examined for staging renal cancer.
Figure 3.14. Microscopically, the renal sinus is composed of loose fibrous tissue, fat, and vascular structures. This large vein branch has a thin wall.
Figure 3.15. Higher magnification of the interface of the kidney and renal sinus shows loose fibrous tissue, fat, and a vein wall.
Figure 3.16. This case of amyloidosis shows focal eosinophilic nodularity (arrow) within the glomerulus.
Figure 3.17. Congo red staining in the same case from Figure 3.16 shows positive staining of an arteriole, supporting amyloidosis. This case was AL (light chain type).
Mesangial matrix expanded or nodular (Kimmelstiel-Wilson nodules)
Hyalinosis in both afferent and efferent arterioles (if both are visualized, Figure 3.24)
Glomerular or Bowman capsule hyalinosis
Mesangial matrix positive (black) on silver stain (Figure 3.25), in contrast to amyloid (pink)
Congo red negative in nodules, in contrast to amyloid (positive)
Figure 3.20. Hyaline arteriolosclerosis (arrow) is associated with diabetes and hypertension. This arteriole shows asymmetrical thickening with eosinophilic material. There are small “bubbles” which differ from the usual pattern of amyloid.
Figure 3.21. In diabetic nephropathy, the mesangial matrix is expanded, forming Kimmelstiel-Wilson nodules.
Figure 3.22. Microaneurysms are a feature of diabetic nephropathy, in which it appears that multiple capillary loops have merged to form one large loop (arrow), shown in this Jones silver stain.
Figure 3.23. Hyalinosis can also be present in glomeruli with diabetic nephropathy. This example shows eosinophilic material with “bubbles,” (arrow) differing from the waxy/cracked appearance of amyloid.
Figure 3.24. Classically, diabetic nephropathy will show hyaline arteriolosclerosis of both the afferent and efferent arterioles (arrows), although both cannot always be visualized due to the plane of sectioning.
Figure 3.25. The expanded mesangial matrix in diabetic nephropathy is black in Jones silver stain, compared with pink in amyloidosis.
Clear cell versus non-clear cell: Clinical guidelines do distinguish clear cell from non-clear cell RCC for treatment pathways in the metastatic setting.16 So, pathologists should make the best attempt possible to discern clear cell from non-clear cell RCC. In some cases, this may not be possible, however, especially for small biopsies of a metastatic lesion with atypical morphology (Figures 3.29 and 3.30). One of the most helpful immunohistochemical markers for this purpose is carbonic anhydrase IX (showing diffuse membrane labeling in clear cell RCC); however, this should be interpreted with caution in the setting of unknown primary cancer or absence of a renal mass, as its specificity is lower in these scenarios.
RCC versus urothelial carcinoma: RCC will typically be treated markedly differently than urothelial carcinoma (such as with tyrosine kinase inhibitors, vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (MTOR) pathway agents, in contrast to conventional chemotherapy, i.e., gemcitabine/cisplatin for urothelial carcinoma). In most cases, the clinical impression of a renal pelvis mass versus spherical renal mass will correctly predict urothelial carcinoma versus RCC, but occasionally patterns of growth can be deceptive. Helpful immunohistochemical markers are
PAX8—in general favors RCC; however, caution is necessary, as upper tract urothelial carcinoma can also be positive17
GATA3—favors urothelial carcinoma18
P63—strongly favors urothelial carcinoma19
Fumarate hydratase-deficient/hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)-associated renal cancer: This aggressive form of renal cancer, discussed later, is beginning to be recognized as potentially necessitating specific therapy.16 In brief, findings that suggest this diagnosis include an eosinophilic (“type 2”) papillary RCC with extremely prominent nucleoli or heterogeneous architectural patterns, such as tubulocystic, papillary, and infiltrative growth.20,21,22
Renal medullary carcinoma: Cytotoxic chemotherapy, such as platinum-based regimens, is generally recommended for this aggressive and rare form of renal cancer.16
Sarcomatoid RCC: A specific treatment is not explicitly recommended for sarcomatoid RCC at present; however, some studies have investigated a conventional chemotherapy approach (such as gemcitabine, sometimes in combination with RCC-directed therapies, such as sunitinib or bevacizumab).16 Distinguishing sarcomatoid RCC from mimics is discussed further under the spindle cell tumors pattern.
Hereditary syndromes: Renal cancers of hereditary syndromes are generally treated similarly to their sporadic counterparts. However, multiple masses, such as in von Hippel-Lindau (VHL) disease or other syndromes, may be treated with more conservative renal sparing surgery, such as enucleation. Conversely, HLRCC-associated tumors require aggressive treatment, even if solitary, and may require specific chemotherapeutic considerations.16 Finally, pathologist recognition of hereditary renal cancer syndromes is important to trigger follow-up for metachronous tumors and tumors of other organs in the patient and family members. A summary of the best established syndromes associated with renal tumors is listed in Table 3.1.14,23
Figure 3.27. In this case of focal segmental glomerular sclerosis, the periodic acid Schiff stain highlights the area of segmental sclerosis (arrow).
Figure 3.28. Interstitial inflammation is relatively common in the areas immediately around a renal mass, and we generally do not use the terminology “interstitial nephritis” to avoid confusion with allergic-type reactions to drugs.
Figure 3.29. This renal mass biopsy shows a renal cell carcinoma tumor that was positive for PAX8 and negative for AMACR and cytokeratin 7.
Figure 3.30. Immunohistochemistry of the same biopsy from Figure 3.29 shows negative staining for carbonic anhydrase IX. Although this does not lend support to diagnosis of clear cell renal cell carcinoma (RCC), a comment was given for this specimen indicating that clear cell RCC was favored based on the morphology and difficult to entirely exclude due to the small amount of tissue.
TABLE 3.1: Hereditary Renal Cancer Syndromes
Figure 3.31. The classic gross appearance of clear cell renal cell carcinoma is golden-yellow or orange. This tumor also has some small hemorrhagic areas. It is circular and very well circumscribed.
Figure 3.32. This clear cell renal cell carcinoma shows a mixture of yellow and red-brown gross appearances, likely resulting from hemorrhage.
Figure 3.33. This large clear cell renal cell carcinoma includes yellow areas (red arrow) but also white-tan areas (white arrow). The latter should always be sampled histologically, as this can represent higher-grade areas or sarcomatoid change.
Figure 3.34. The classic appearance of clear cell renal cell carcinoma histologically is nested growth of cells with optically clear cytoplasm and an extremely intricate capillary fibrovascular network.
May have eosinophilic cytoplasm (Figures 3.36 and 3.37) or bizarre features26,27 (Figures 3.38,3.39,3.40,3.41,3.42) with higher-grade tumors
Scarring, infarct-type necrosis, or fibrosis is common,28 which may contain inconspicuous tumor cells and may be deceptive if captured in a biopsy (Figures 3.43 and 3.44)
Immunohistochemistry is consistently positive for carbonic anhydrase IX with membranous pattern (Figure 3.47), but may be decreased or negative in high-grade areas (Figure 3.48)26
Cytokeratin 7 staining usually negative, minimal, or focal (Figure 3.49), but rarely can be more diffuse in true clear cell RCC (Figure 3.50)29
Often positive for vimentin, especially higher-grade tumors (Figure 3.51)
Negative for KIT (contrasting to oncocytoma/chromophobe RCC)30
Minimal or negative staining for high molecular weight cytokeratin (contrasting to clear cell papillary RCC)
Chromosome 3p loss detected via fluorescence in situ hybridization (FISH) or copy number assessment techniques is very common and often used as a surrogate (Figure 3.52)35 but may not be 100% specific for clear cell RCC36,37,38
Much of the molecular knowledge of renal cancer comes from clear cell RCC, particularly the role of the VHL gene and chromosome 3p25 where it is located, which is often deleted as a “second hit”47
Multiple treatment approaches have been established based on key molecular pathways in clear cell RCC, especially those targeting VEGF, tyrosine kinases in general, and the MTOR pathway16
It is therefore relatively important for the pathologist to attempt to subtype metastatic renal cancer, as the treatment algorithms are different for clear cell and non-clear cell tumors16
PAX8 is currently the most helpful marker to support a metastasis being of renal origin (Figure 3.54),48 although this should be interpreted cautiously if there is not clinical evidence of a renal mass or a known history of a high-stage (or large) renal mass, as it is rare for RCC to present with metastases and a subtle or unidentified primary tumor
Carbonic anhydrase IX diffuse membrane immunohistochemical staining is supportive of clear cell subtype of RCC49,50,51,52
However, staining can be found in nonrenal cancers,53 so this should again be interpreted cautiously if there is no renal mass
Staining can also be decreased or negative in the poorly differentiated component of clear cell RCC tumors. Therefore, a negative result does not entirely exclude clear cell RCC
Metastatic renal cell carcinoma—see Comment
Figure 3.35. Other patterns in clear cell renal cell carcinoma can also include an alveolar hemorrhagic growth pattern.
Figure 3.36. Rarely clear cell renal cell carcinoma (RCC) can have large areas of eosinophilic cell pattern, mimicking an oncocytic neoplasm. This tumor also had classic areas of clear cell RCC elsewhere in the tumor.
Figure 3.37. Eosinophilic areas of clear cell renal cell carcinoma can contain hyaline globules of various sizes and shapes. This case includes dense globules of variable size.
Cells often have vacuolated rather than empty cytoplasm (Figure 3.56)
Foamy macrophages often present, with similar consistency of cytoplasm compared to the tumor cells (Figure 3.57)54
Psammoma bodies may be present (Figure 3.56) (very rare in clear cell RCC)
Very strong immunohistochemical staining for AMACR (Figure 3.59), similar intensity to proximal tubules, supports papillary RCC
Carbonic anhydrase IX usually negative or minimal (labeling only areas of necrosis or hypoxia) (Figures 3.61 and 3.62)
Trisomy of chromosome 7 or 17 by FISH or copy number assessment would favor papillary RCC, but likely not necessary in most cases54
Loss of chromosome 3p, although generally favoring clear cell RCC, may not be entirely specific, with some losses reported in papillary RCC with clear cell change37,54
Markers of MITF family translocation RCC negative (TFE3 or TFEB proteins, cathepsin K, melanocytic markers)55
Cells with pale staining or flocculent eosinophilic cytoplasm, often with admixture of both cell types (Figure 3.67)
Often prominent cell borders, resembling plant cells (Figure 3.66)
Figure 3.39. Occasional high-grade clear cell renal cell carcinoma tumors can contain syncytial-type giant cells with numerous nuclei.
Figure 3.40. Rhabdoid features in clear cell renal cell carcinoma manifest as central eosinophilic globules within the cytoplasm that mimic rhabdomyoblastic cells (although without immunohistochemical evidence of skeletal muscle differentiation).
Figure 3.41. Higher magnification in this case of rhabdoid clear cell renal cell carcinoma shows clear cytoplasm with central eosinophilic material, mimicking rhabdomyoblasts.
Figure 3.42. Sarcomatoid changes in renal cell carcinoma may also be deceptive. This case shows a hint of clear cytoplasm but otherwise resembles a spindle cell sarcoma.
Figure 3.44. Other areas of the same tumor from Figure 3.43 show transition to typical clear cell renal cell carcinoma.
Figure 3.46. Higher magnification of cystic clear cell renal cell carcinoma shows solid areas adjacent to cysts lined by similar cells.
Figure 3.47. Carbonic anhydrase IX typically shows diffuse membranous staining in clear cell renal cell carcinoma.
Figure 3.50. Rarely, clear cell renal cell carcinoma can have greater amounts of cytokeratin 7 staining.
Nuclear size variation, from small to large (Figure 3.68)
Large, wrinkled nuclei with dark, smudged nuclear chromatin (“raisinoid”) (Figure 3.66)
May have intranuclear cytoplasmic invaginations (Figure 3.69)
Perinuclear clearing (“halo”) (Figure 3.70)
Solid or trabecular growth pattern (Figure 3.71)
“Missing nuclei:” cytoplasm is so voluminous that some cells appear to have no nuclei (plane of section entirely misses the nucleus, Figure 3.72)
Colloidal iron stain—positive in cytoplasm (Figures 3.73 and 3.74) but variable results depending on laboratory technical conditions
Negative for vimentin, in contrast to clear cell or papillary RCC (Figure 3.75)
Often substantial staining for cytokeratin 7 (but decreased in eosinophilic variant) (Figure 3.76)
Figure 3.51. Vimentin is often positive in clear cell renal cell carcinoma, especially higher-grade areas. In this case, low-grade areas (right) are negative, whereas high-grade areas (left) are positive.
Figure 3.53. Clear cell renal cell carcinoma has an unusual predilection to metastasize to the pancreas (left).
Positive for KIT (CD117, Figure 3.77)
Carbonic anhydrase IX negative or minimal, in contrast to clear cell RCC (Figure 3.78)
with anaplastic nuclear features.66 However, this system has not gained widespread usage at present and is not required in reporting schemes.13
Figure 3.55. This papillary renal cell carcinoma (RCC) has heterogeneous gross cut surfaces with some areas appearing yellow, mimicking clear cell RCC, likely due to foamy cells.
Figure 3.56. In contrast to clear cell renal cell carcinoma (RCC), the cytoplasm of papillary RCC with clear cell change is usually highly vacuolated. This example also has psammoma bodies, which are rare for clear cell RCC.
Figure 3.57. In this papillary renal cell carcinoma with clear cell change, the tumor cells have a similar cytoplasmic quality to intermingled foamy macrophages.
Figure 3.59. AMACR is diffusely positive in this papillary renal cell carcinoma with clear cell change in a core biopsy sample.
Figure 3.60. Cytokeratin 7 staining is also diffuse in the same case from Figure 3.59.
Figure 3.62. Focal staining for carbonic anhydrase IX can be observed in non-clear cell renal cell carcinomas, usually in areas of ischemia or necrosis. In this case, there is some staining in cystic areas, but large solid areas are negative.
Figure 3.63. This chromophobe renal cell carcinoma has a central scar, which is not specific for oncocytoma.
Figure 3.64. Some chromophobe renal cell carcinomas (RCCs) have a pale tan color that differs from the golden-yellow or orange cut surface of clear cell RCC.
Figure 3.65. This chromophobe renal cell carcinoma has a red-brown color, similar to the normal renal parenchyma, which would raise a differential diagnosis with oncocytoma.
Figure 3.66. Chromophobe tumors are often unencapsulated or incompletely encapsulated, contrasting to clear cell renal cell carcinoma, which usually has a fibrous pseudocapsule.
Figure 3.67. Typical cytologic features of chromophobe renal cell carcinoma include cells with prominent borders (resembling plant cells), variable pale to eosinophilic cytoplasm, and scattered wrinkled nuclei (“raisinoid”).
Figure 3.69. Intranuclear cytoplasmic invaginations (pseudoinclusions) are sometimes present in chromophobe renal cell carcinoma.
Figure 3.70. Perinuclear cytoplasmic clearing (“halos”) are often present in chromophobe cells with eosinophilic cytoplasm.
Figure 3.71. The growth of chromophobe renal cell carcinoma (RCC) may be diffuse or trabecular, contrasting to the discrete packets of cells circumscribed by a capillary vascular network in clear cell RCC.
Figure 3.72. In chromophobe tumors, some cells often appear to have no nuclei, likely because the cytoplasm is so voluminous the nucleus was entirely missed in the plane of section.
Figure 3.73. Classically, the colloidal iron stain (modified Mowry shown here) will show diffuse cytoplasmic staining of chromophobe renal cell carcinoma, although ideal staining conditions can be technically challenging.
Figure 3.74. To verify a well-stained colloidal iron stain, there should be outlining of glomerular cells with minimal to no staining of proximal tubules.
Figure 3.75. Vimentin immunohistochemistry is consistently negative in chromophobe renal cell carcinoma (RCC), contrasting to the expected pattern of many other RCC types.
Figure 3.76. In classic chromophobe renal cell carcinoma, cytokeratin 7 often shows diffuse staining with membranous accentuation. However, the extent of staining is often markedly lower in eosinophilic chromophobe tumors.
Figure 3.77. KIT (CD117) staining is often positive with a membranous pattern in chromophobe renal cell carcinoma (RCC), contrasting to clear cell RCC.
Figure 3.78. This case of chromophobe renal cell carcinoma (RCC) (same case from Figures 3.76 and 3.77) raised a differential diagnosis with clear cell RCC due to the nested arrangement of cells with prominent capillary vascular network and less conspicuous nuclear size variation than usual. However, the immunohistochemistry in this case clarified the diagnosis.
Figure 3.79. Aggressive features in chromophobe renal cell carcinoma include sarcomatoid change, as shown in this case with transition from chromophobe morphology (left) to spindle cell pattern (right).
Solid areas nearly identical to clear cell RCC (Figure 3.85)
Glandular structures with a branching configuration (Figures 3.86,3.87,3.88), in contrast to solid round nests of clear cell RCC
Figure 3.81. Vascular invasion is also a potential adverse feature in chromophobe renal cell carcinoma. This example shows a large polypoid protrusion of tumor into a renal sinus vein (arrow).
Figure 3.83. This example of clear cell papillary renal cell carcinoma in a partial nephrectomy forms a small extensively cystic mass with almost no grossly appreciable solid component (scale bar 1 cm).
Figure 3.84. This example of clear cell papillary renal cell carcinoma shows a more solid white-tan to red mass.
Figure 3.86. Branched glandular structures are a clue to possible recognition of clear cell papillary renal cell carcinoma.
Figure 3.87. This field of a clear cell papillary renal cell carcinoma (RCC) shows tubular or glandular structures with predominantly clear cytoplasm. There is slightly more branching than a usual clear cell RCC, which may be a clue to the diagnosis.
Figure 3.88. This clear cell papillary renal cell carcinoma demonstrates some branching glands, edematous stroma, and focal papillary structures in a cystic space at the left edge.
Cells with nuclear alignment above the basement membrane, resembling the subnuclear vacuoles of early secretory endometrium or “piano keys” (Figures 3.89,3.90,3.91)
Cysts with small or more complex papillary structures (Figures 3.92,3.93,3.94,3.95), usually blunt rather than elongated
Fibrous stroma between glands (Figure 3.85)
Carbonic anhydrase IX diffuse membrane staining, similar to clear cell RCC, sometimes with “cup-shaped” pattern (Figure 3.96)
Diffuse, uniform positive for cytokeratin 7 (Figure 3.97), unexpected for clear cell RCC
Negative for CD10 (Figure 3.98), in contrast to clear cell RCC
Negative or minimal weak staining for AMACR (Figure 3.99), contrasting to papillary RCC
Often staining for GATA3 (Figure 3.100), suggesting distal nephron phenotype
Often staining for high molecular weight cytokeratin (Figure 3.101), suggesting distal nephron phenotype
Occasional clear cell RCCs can have overlapping features of clear cell papillary RCC,29,90,91 such as branched glands, nuclear alignment, and focal papillary structures (Figures 3.102,3.103,3.104)
Typically, the immunohistochemistry in these tumors does not show the expected pattern of clear cell papillary RCC, such as with positive AMACR or CD10 (Figure 3.103)
This has a high rate of correlation with chromosome 3p deletion using FISH,29,91 suggesting that these are better classified as clear cell RCCs
Aggressive behavior, higher tumor stage, and necrosis have also been noted in these tumors with imperfect features,90 supporting classification as clear cell RCC
Patients with VHL disease may also have tumors resembling clear cell papillary RCC (Figure 3.105), but similarly the immunohistochemical profile usually shows an imperfect staining pattern, favoring classification as clear cell RCC91
Some translocation RCCs, such as those with NONO fusion, may have nuclear alignment mimicking clear cell papillary RCC (Figure 3.106), although usually accompanied by higher-grade nuclear features
Psammoma bodies would be atypical for clear cell papillary RCC
Kidney, left, partial nephrectomy:
Clear cell papillary RCC, 2.5 cm greatest dimension
ISUP/WHO grade 2
Confined to the kidney (pT1a)
appears distinct from both clear cell RCC and papillary RCC. To date, we are not aware of any tumor with this constellation of features that has metastasized or otherwise demonstrated aggressive behavior, suggesting that the malignant potential of these tumors is low, if any. It is estimated that these tumors make up as much as 4% of adult RCCs. Previously most were likely classified as low-grade, low-stage clear cell RCCs.
Figure 3.91. This example of clear cell papillary renal cell carcinoma demonstrates prominent nuclear alignment and slight branching of the glands.
Figure 3.93. In extensively cystic examples of clear cell papillary renal cell carcinoma, there are often small stubby papillae that protrude into the cystic spaces.
Figure 3.94. Papillary structures in clear cell papillary renal cell carcinoma are often small, with branching resembling fingers from a hand.
Figure 3.95. Occasional clear cell papillary tumors can have more florid papillary architecture, leading to confusion with papillary renal cell carcinoma.
Figure 3.96. Carbonic anhydrase IX is diffusely positive in clear cell papillary renal cell carcinoma and sometimes shows a “cup-shaped” staining pattern, where the basal and lateral cell borders are positive but the apical staining is absent.
Figure 3.97. Cytokeratin 7 consistently shows diffuse positive staining in clear cell papillary renal cell carcinoma.
Figure 3.98. CD10 is negative in clear cell papillary renal cell carcinoma, although focal labeling of cystic areas has been reported.
Figure 3.99. AMACR is consistently negative or extremely minimal in clear cell papillary renal cell carcinoma.
Figure 3.100. GATA3 is often positive in clear cell papillary renal cell carcinoma, suggesting a possible distal nephron phenotype.
Figure 3.101. Like GATA3, high molecular weight cytokeratin positivity in clear cell papillary is suggestive of a distal nephron phenotype.
Figure 3.102. This renal mass biopsy case shows a tumor with branched glands and prominent stroma, suggestive of clear cell papillary renal cell carcinoma (RCC). Although substantial cytokeratin 7 staining was present (not pictured), there was strong staining for AMACR (Figure 3.103), arguing against clear cell papillary RCC.
Figure 3.103. The same biopsy from Figure 3.102 shows strong staining for AMACR, arguing against clear cell papillary renal cell carcinoma (RCC). Our approach is to regard tumors with imperfect features as clear cell RCCs due to the greater potential for aggressive behavior. This tumor also showed diffuse membranous staining for carbonic anhydrase IX and negative staining for high molecular weight cytokeratin in the final resection, which had a similar borderline morphology.
May have abnormally voluminous clear cytoplasm, greater than expected for clear cell RCC
Alternating between clear cell and papillary patterns, or clear cell and eosinophilic patterns, raises consideration of MITF family translocation RCC (Figures 3.107 and 3.108)
Rarely may have multilocular cystic-like morphology (Figure 3.109)
Other clues to MITF family translocation RCC:
Psammoma bodies (Figure 3.110)
Young age (suggestive but not necessary) (Figure 3.111)
Carbonic anhydrase IX—negative or minimal, in contrast to clear cell RCC96
HMB45 or melan-A—positivity may be a clue to the diagnosis (Figure 3.114)
TFE3 or TFEB proteins—positive, depending on the fusion (although optimal staining may be technically challenging)92,93 (Figure 3.115)
Keratin, EMA, or vimentin—may be negative or decreased (but not required, may be positive)96
TFE3 or TFEB break-apart FISH (Figure 3.116)—typically shows an abnormal split signal pattern; however, a few translocations occur by chromosomal inversion and may have a false-negative result, particularly NONO, GRIPAP1, RBMX, and RBM10 partners of TFE399-104
Reverse transcriptase polymerase chain reaction or next-generation sequencing—may detect those with false-negative FISH. Depending on the assay, this may require knowledge of both partners
of cells with clear cytoplasm surrounding smaller cells with hyaline globules, forming a rosette-like pattern (Figure 3.117).105 This finding is neither uniformly present, nor is it entirely specific for the diagnosis, as it can sometimes be mimicked in TFE3 tumors and is not always observed (Figure 3.118).93 The optimal treatment for translocation RCC is not entirely known at present, due to their rarity.
Figure 3.107. This translocation renal cell carcinoma shows papillary architecture with mixed eosinophilic and clear cells.
Figure 3.108. Higher magnification of the same case from Figure 3.107 shows papillary architecture and a mixture of clear and eosinophilic cells in translocation renal cell carcinoma.
Figure 3.109. Some MITF family translocation renal cell carcinomas may have a multilocular cystic morphology. This case resembled multilocular cystic neoplasm of low malignant potential; however, there is a psammoma body within one of the septa.
Figure 3.110. This MITF family translocation renal cell carcinoma (RCC) closely resembles clear cell RCC; however, numerous psammoma bodies are a clue to the diagnosis.
Figure 3.111. This MITF family translocation-associated renal cell carcinoma (RCC) occurred in a child, which is a clue to distinction from clear cell RCC.
Figure 3.112. Stromal hyalinization can be a clue to the diagnosis of translocation (TFE3 or TFEB) renal cell carcinoma (RCC). This example has subtly increased stromal hyalinization between the cells, which otherwise would resemble clear cell RCC.
Figure 3.113. This translocation renal cell carcinoma (RCC) from a child has very abundant uniform hyalinization around the nests, which would be an odd pattern in clear cell RCC and should prompt consideration of MITF family translocation RCC.
Figure 3.114. Melanocytic marker positivity raises suspicion for MITF family translocation renal cell carcinoma. This example shows focal staining for HMB45 (red chromogen).
Figure 3.118. This TFEB translocation tumor otherwise would be most likely confused with clear cell renal cell carcinoma, as the rosette-like pattern is not conspicuous.
Figure 3.120. At higher magnification, adrenal rests are composed of cells with numerous cytoplasmic vacuoles rather than entirely clear cytoplasm.
difficulty in the brain.118,119,120,121,122 Hemangioblastomas are associated with VHL syndrome, which may raise both clear cell RCC and hemangioblastoma in the differential diagnosis of a renal mass in such a patient.
Figure 3.122. Higher magnification of the same case from Figure 3.121 shows the adrenal cortical adenoma abutting benign renal parenchyma without a clear plane of separation.
Hemangioblastoma cells may be more flocculent or vacuolated (Figures 3.124,3.125,3.126) than the entirely clear pattern of clear cell RCC
Inhibin is characteristically positive; S100 or neuron-specific enolase is often present in hemangioblastoma
Lesser staining for keratin or epithelial membrane antigen is often found in hemangioblastoma
Figure 3.124. Rarely hemangioblastomas may occur in the kidney, which is especially deceptive in distinguishing from renal cell carcinoma. A potential clue in this case is the predominant solid architecture without arrangement into separate nests.
May have a sheet-like growth pattern, lacking the discrete nests of clear cell RCC
Cells may be partly clear and partly eosinophilic (Figure 3.132), sometimes with a central eosinophilic globule
Figure 3.125. Other areas of hemangioblastoma may have edematous or fibrotic stroma, which can also be found in sclerotic areas of renal cell carcinoma.
Figure 3.127. Epithelioid angiomyolipoma may closely mimic a clear cell renal cell carcinoma (RCC). This tumor occurred in a very young patient and contains scattered calcifications, which are atypical for clear cell RCC.
Figure 3.128. Prominent stromal hyalinization in this case of epithelioid angiomyolipoma/PEComa is a clue to the diagnosis, similar to MITF family translocation renal cell carcinoma.
Figure 3.129. In contrast to conventional angiomyolipoma, epithelioid angiomyolipoma/PEComa is considered as having malignant potential. This case metastasized to lymph nodes (lymph node tissue at right).
May contain multinucleated tumor giant cells (Figure 3.132)
May have a lesser spindle-shaped cell component, focal thick blood vessels or fat
Melanocytic markers positive
Often positive for smooth muscle markers, such as smooth muscle actin and less frequently desmin127
Scant data available, but likely PAX8 and carbonic anhydrase IX negative
Figure 3.131. In angiomyolipoma, epithelioid cells are most often arranged around blood vessels (arrow), giving rise to the “perivascular epithelioid” name of this tumor family.
Figure 3.132. Occasional cells in angiomyolipoma can have a Touton cell-like appearance (arrow) with a central globule of hyaline material surrounded by a pale/clear zone.
Figure 3.134. Foamy cells in xanthogranulomatous pyelonephritis can lead to confusion with renal cell carcinoma. Admixture of other inflammatory cells may be a clue to the diagnosis.
Gross appearance may be variable: yellow (foamy cells or necrosis), red (hemorrhage), or brown (hemosiderin), usually round and well circumscribed (Figures 3.139,3.140,3.141,3.142)
Often basophilic appearance at low magnification microscopically (Figure 3.143)
Variable encapsulation, sometimes with tumor herniating through the pseudocapsule (Figure 3.144)
Cytoplasm variable from pale eosinophilic to clear (vacuolated)37,54 or containing hemosiderin (Figure 3.147)
Architecture: papillary, glomeruloid structures, solid, or cystic
Cytokeratin 7—typically substantial positivity (but may be decreased with eosinophilic cells) (Figures 3.148 and 3.149)
AMACR—consistently diffuses strong staining, with intensity similar to that of proximal tubules (Figure 3.150)
Carbonic anhydrase IX—negative or minimal staining in areas of necrosis/ischemia (Figure 3.151)
High molecular weight cytokeratin—variable positive137
Figure 3.135. Xanthogranulomatous pyelonephritis can also include spindle cell areas, which could lead to confusion with sarcomatoid renal cell carcinoma.
Figure 3.136. The 2016 WHO Classification now allows papillary adenomas to be up to 15 mm. This is a large papillary adenoma diagnosed under these new criteria.
Figure 3.137. Requirements for papillary adenoma include lack of encapsulation and nuclear grade 1 to 2.
Figure 3.138. This small papillary adenoma includes psammoma bodies, like papillary renal cell carcinoma, and blends with the adjacent benign renal tissue.
Figure 3.139. Papillary renal cell carcinoma can have variable gross appearances. This example is predominantly pink-tan with some yellow streaks likely corresponding to foamy cells.
Figure 3.140. This large papillary renal cell carcinoma is grossly friable-appearing and hemorrhagic centrally, corresponding to necrosis.
Figure 3.141. This papillary renal cell carcinoma (RCC) appears yellow, mimicking the gross appearance of clear cell RCC.
Figure 3.142. Some papillary renal cell carcinomas can be recognized grossly as very granular, a hint to their papillary architecture.
Figure 3.143. At low magnification, type 1 papillary renal cell carcinoma is typically basophilic. This tumor has some foamy macrophages at left.
Figure 3.144. Papillary renal cell carcinoma is variably encapsulated and sometimes herniates beyond the tumor capsule.
Figure 3.145. Tumor cells in papillary renal cell carcinoma are often cuboidal or low columnar. This example shows classic papillary formations.
Figure 3.146. This papillary renal cell carcinoma is composed of cuboidal eosinophilic cells with focal foamy macrophages.
Figure 3.147. Some papillary renal cell carcinoma tumors contain prominent intracytoplasmic hemosiderin.
Figure 3.148. This renal mass biopsy shows a papillary renal cell carcinoma with somewhat deceptive morphology, raising a differential diagnosis of clear cell renal cell carcinoma.
Figure 3.149. Immunohistochemistry shows substantial staining for cytokeratin 7 in the same tumor from Figure 3.148.
Figure 3.152. Occasional papillary renal cell carcinomas can be predominantly solid, potentially obscuring the diagnosis.
Figure 3.153. The same tumor from Figure 3.152 also contained more classic areas of papillary morphology with foamy cells and psammoma bodies.
TABLE 3.2: Differential Diagnosis of Type 1 Papillary Renal Cell Carcinoma (RCC)
TABLE 3.3: Differential Diagnosis of Type 2 Papillary Renal Cell Carcinoma (RCC)
to discriminate them from other papillary RCCs (Figure 3.159). Staining for cytokeratin 7 is frequently present but variable in extent and AMACR does not always show the diffuse strong pattern of typical papillary tumors (Figure 3.160).150,152 Recent work has found frequent KRAS mutations, which contrasts to type 1 and type 2 papillary RCC, supporting the consideration of this as a distinct type of renal neoplasm.151
Figure 3.155. Occasional papillary renal cell carcinomas contain mucin, as in this example, within the fibrovascular cores.
Figure 3.156. Type 2 papillary renal cell carcinoma has become almost a diagnosis of exclusion in current practice. It is composed of columnar eosinophilic cells with pseudostratified nuclei.
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