Kidney

THE UNREMARKABLE AND NONNEOPLASTIC KIDNEY

Entire volumes are written on the subject of nonneoplastic renal disease,¹ so this chapter will not attempt to cover medical renal disease in its entirety. However, a few aspects of normal renal anatomy and histology are very relevant to renal cancer staging. Likewise, a few of the more common medical renal diseases may be relevant to the surgical or genitourinary pathologist when evaluating kidney specimens for surgical or oncologic disease.

ANATOMY AND HISTOLOGY

The Glomerulus

The glomerulus is composed of a complex network of capillaries that plays a key role in the kidney’s filtration of blood. The normal adult glomerulus is composed of numerous capillary loops with thin walls and open lumens (Figures 3.1 and 3.2). The mesangium or mesangial matrix shows pale eosinophilic staining in hematoxylin and eosin sections and in the normal state should be inconspicuous with usually only one to two mesangial cell nuclei (not more than three, Figure 3.3). Blood enters and leaves the glomerulus through the afferent and efferent arterioles, although only one or neither may be visualized in a given tissue section due to the plane of cutting (Figure 3.4).² For the surgical pathologist examining tissue adjacent to a tumor, usually it is reasonable to briefly assess the glomeruli in tissue away from the tumor. (Tissue immediately adjacent to the tumor can have unusual changes that may be difficult to assess as indicative of systemic disease or not.) If the glomeruli appear largely normal, in most cases more extensive evaluation (with special stains or full medical renal evaluation) is probably unnecessary. When the amount of mesangial matrix is increased, the most common etiology is diabetic nephropathy, discussed later.³,⁴,⁵,⁶ Global glomerular sclerosis or obsolescence results in a consolidated nodule with complete loss of the glomerular architecture (Figure 3.5). It is relatively common to have some degree of global glomerular sclerosis that increases with age; however, evaluating areas immediately adjacent to the renal mass likely would be an overestimate due to compressive mass effect. At the same time, we have encountered end-stage or atrophic kidneys that histologically have large areas of tissue appearing near-normal, so detailed quantification of glomerular sclerosis is probably unnecessary for routine cases.

Renal Tubules

The proximal tubules have taller and more eosinophilic epithelial cells than those of the distal nephron (Figure 3.7). Over the years, most subtypes of renal neoplasm have been assigned a putative “cell of origin” from one of the renal tubular compartments, in which most renal cell carcinomas (RCCs) are regarded as of proximal tubular origin or phenotype.⁷ Oncocytoma and chromophobe RCC are hypothesized to be of intercalated cell origin or phenotype, whereas a few aggressive carcinomas are thought to have the phenotype of the principal cells of the distal nephron, including collecting duct carcinoma and renal medullary carcinoma.⁷ For routine surgical pathology practice, there is not usually great significance to recognizing proximal versus distal tubules; however, the proximal tubules may serve as a helpful internal control for immunohistochemistry, usually showing very strong staining for alpha-methylacyl-CoA racemase (AMACR, Figure 3.8), which corresponds to what is expected in papillary RCC.

Renal Arteries and Veins

Renal blood vessels have major significance for staging of renal cancer, especially involvement of veins. Therefore, it is worthwhile for the surgical pathologist handling renal specimens to be familiar with their normal structure and appearance.⁸ Although there is classically a main artery and vein which are taken as margin sections in staging of a renal cancer, numerous anatomic variations can occur, with additional arteries or vein branches present at the specimen margin. The larger veins and tributaries will have a recognizable smooth muscle media histologically (Figure 3.9); however, smaller vein tributaries will not necessarily have smooth muscle in their walls (Figures 3.10 and 3.11), which has led to the removal of the requirement from the American Joint Committee on Cancer (AJCC) staging system⁹ that vein invasion be into “muscle-containing” branches. Staging is discussed more in a section on renal cancer staging.

The Renal Sinus

The renal sinus is the central compartment of adipose tissue that contains the renal vasculature around the hilum of the kidney (Figures 3.13,3.14,3.15). Since the renal sinus does not have a discrete capsule separating the kidney from the fat and since this contains the renal vein and tributaries, this is one of the most common pathways for extrarenal spread of renal cancer.¹⁰,¹¹ As discussed in the section on renal cancer staging, multiple sections should be submitted from the renal sinus, especially for larger renal tumors. In radical nephrectomy specimens, often there are few or no lymph nodes in the hilar area unless specifically dissected by the surgeon, often as separate specimens. Therefore, attempt should be made to identify any readily appreciable lymph nodes; however, it is not a failure if none are identified in a radical nephrectomy specimen without a specified lymph node dissection.

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).

Figure 3.3. The mesangial matrix stains red-purple in this periodic acid Schiff-stained section. It should be relatively inconspicuous in normal kidneys, whereas it is increased with diabetes. There are only two to three nuclei at most in the mesangial areas. Four or more cells are generally considered abnormal.

Figure 3.4. In this periodic acid Schiff-stained section, the arteriole (arrow) is well visualized, although only one (afferent or efferent) is visible due to the plane of section.

NONNEOPLASTIC RENAL DISEASE

Several studies have investigated the incidence of nonneoplastic renal disease in tumor nephrectomy specimens, finding mostly that diabetic nephropathy and vascular disease (hypertensive changes, etc.) are the most common incidental abnormalities.³,⁴,⁵,⁶,¹² However, a variety of other diseases have been reported, including amyloidosis (Figures 3.16 and 3.17), focal segmental glomerular sclerosis (FSGS, Figure 3.18), atheroembolism, and thrombotic microangiopathy, among others.³,⁴,⁵,⁶,¹² Ideally, if a suspicion of medical renal disease is known at the time of surgery for a renal mass, coordination between the pathologist and surgeon can facilitate collection of samples for full medical renal evaluation (including direct immunofluorescence and electron microscopy). However, in the vast majority of cases, medical renal disease is not particularly suspected and no such samples are taken. If the surgical pathologist is familiar with some general principles, then the appropriate cases for medical renal consultation can be selected. It is worthwhile to submit at least one to two sections of normal appearing renal parenchyma away from the neoplasm in specimens with sufficient tissue, to aid in screening for clinically relevant medical renal disease. If more
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 3.5. Global glomerular sclerosis is a generally nonspecific pattern of injury. This glomerulus (arrow) is consolidated into a nonspecific fibrous nodule in a patient with hypertension as the presumed etiology of renal disease. The below glomerulus is largely normal.

Figure 3.6. Fibrin thrombi can sometimes be encountered in glomerular capillary loops or arterioles. This generally is considered a thrombotic microangiopathy pattern. In the setting of kidneys collected for organ donation, it is thought that this often results from donor head trauma and does not necessarily contraindicate use of the kidney for transplantation. The fibrin (arrow) is a light pink color, in contrast to erythrocytes, which are darker red.

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.

Hypertensive Changes/Arterial Thickening

Some degree of arterial thickening is quite common in nephrectomy specimens (Figure 3.19) and generally considered to reflect hypertensive changes. The elastic layer may be irregular or duplicated. In addition to intimal thickening of large arteries, arterioles may show hyalinosis, which is associated most often with hypertension or diabetes (Figure 3.20). These findings may be documented either in the main diagnoses or in the nonneoplastic disease section of cancer checklists,¹³ since hypertension is relatively common in patients with typical demographics for renal cancer (i.e., age 50+). Hypertension, obesity, smoking, etc. are also considered risk factors for renal cancer.¹⁴

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 3.10. This smaller paired artery (a) and vein (v) shows no significant smooth muscle in the vein wall. The requirement that veins contain muscle to diagnose pT3a vein branch invasion has been removed in the 8th edition AJCC staging, as even grossly visible renal vein branches may have inconspicuous muscle.

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).

Figure 3.18. Focal segmental glomerular sclerosis is characterized by partial sclerosis of the glomerulus (arrow). In this example, the opposite side of the same glomerulus is essentially normal.

Diabetic Nephropathy

Diabetic nephropathy is one of the most common incidental abnormalities in tissue from tumor nephrectomy specimens.³,⁴,⁵,⁶,¹² Typical features include expansion of the mesangial matrix. If severe, mesangial matrix is expanded to the point of forming nodules (Kimmelstiel-Wilson nodules, Figure 3.21). There may also be capillary microaneurysms in which the capillaries form wide, flat loops, in contrast to the normal thin individual loops, presumably from loss of connection to the mesangium, in which multiple loops become confluent (Figure 3.22). Other classic features of diabetic nephropathy include “capsular drop” with nodules of hyalinosis on the Bowman capsule and “hyaline cap” with hyalinosis in the glomerulus (Figure 3.23).

Changes Adjacent to Tumor

Several morphologic changes can be found in the renal parenchyma adjacent to a neoplasm, and therefore we would hesitate to make overarching diagnoses for findings that are only present immediately around the mass. For example, there can be more prominent tubulointerstitial inflammation in the areas around the mass. We have also encountered glomerular abnormalities resembling those of FSGS, which we would again hesitate to diagnose as the disease FSGS if not present in tissue away from the mass (Figure 3.26), and especially so if there is not clinically appreciable proteinuria.

Focal Segmental Glomerular Sclerosis

FSGS is a pattern of glomerular injury caused by diverse potential etiologies,¹⁵ ranging from glomerulonephritis to FSGS as a primary disease. This injury pattern is characterized histologically by segmental scarring of the glomerular tuft, such that part of the glomerulus appears relatively normal and another part is sclerotic (Figure 3.27). FSGS as a disease is classically associated with significant proteinuria. As noted in the previous paragraph, we have encountered some lesions that resemble glomerular segmental sclerosis in the tissue immediately adjacent to a mass. If the patient has no definite chronic renal disease or proteinuria and these are found only adjacent to the mass, then it is probably reasonable to disregard them. If there is clinical evidence of renal disease or these lesions are found away from the mass (Figure 3.26), it is likely worthwhile to comment on them or request a more detailed medical renal evaluation of the specimen, either internally or externally.

Inflammation

It is not unusual to find some inflammation in the tissue adjacent to a renal mass, which again may be related to compressive or obstructive mass effect (Figure 3.28). We generally avoid use of the term tubulointerstitial nephritis or similar to avoid potentially implying acute tubulointerstitial nephritis, which is presumptively an allergic-type reaction. Instead, terminology such as chronic interstitial inflammation can be used descriptively to indicate the lack of a definite etiology. Several inflammatory pseudotumors and other distinct entities are discussed later in the inflammatory pattern section.

Figure 3.19. This artery with hypertensive changes shows multilayering of the elastic layer (red arrow). Normally, the intima should be inconspicuous, with endothelial cells just above the elastic layer; however, this case shows substantial intimal thickening (black bar).

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.

Figure 3.26. With focal segmental glomerular sclerosis, part of the glomerulus is sclerotic (arrow), whereas the remainder appears relatively normal. This biopsy came from a 16-year-old with proteinuria.

TUMORS

RENAL CANCER GENERAL

FAQ: What are the Most Important Aspects of Renal Cancer Classification for Clinical Treatment?

Although the classification of renal cancer has expanded greatly with numerous recognized subtypes and variants, in general there are only a few major diagnostic branch points that have significant implications for treatment at present. Unless specified here, most other subtypes of RCC are currently categorized with “non-clear cell” for treatment purposes.

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.

CLEAR/PALE CELL PATTERN

Clear Cell Renal Cell Carcinoma

Clear cell RCC is overwhelmingly the most common subtype of renal cancer, typically accounting for at least 60% to 70% of adult renal tumors.²⁴ However, with increasing understanding of the molecular features of renal cancer and immunohistochemistry, it is now known that there are several other “clear cell” tumors that must be distinguished from clear cell RCC.²⁵ Clear cell RCC characteristically has a golden-yellow or orange cut surface grossly (Figure 3.31), although this can be variable, depending on features such as hemorrhage or sarcomatoid dedifferentiation, which may influence the gross appearance to more red-brown (Figure 3.32) or white-tan (Figure 3.33). Microscopically, clear cell RCC can have many patterns, some of which can be diagnostically deceptive.

TABLE 3.1: Hereditary Renal Cancer Syndromes

	Gene/Chromosome	Renal Tumors	Other Manifestations
Von Hippel-Lindau disease	VHL/3p25	Clear cell renal cell carcinoma (RCC), multiple, and renal cysts	Hemangioblastoma (nervous system and retina), pheochromocytoma, pancreatic neuroendocrine tumors, pancreatic cysts, cystadenomas of epididymis/broad ligament, endolymphatic sac tumor of inner ear
Hereditary leiomyomatosis and renal cell carcinoma syndrome	FH/1q42	Aggressive RCC with prominent nucleoli, multiple patterns (papillary, infiltrative, tubulocystic)	Cutaneous leiomyomas, uterine leiomyomas (at a young age)
Hereditary papillary RCC	MET/7p31	Papillary RCC, type 1, numerous
Birt-Hogg-Dubé syndrome	FLCN/17p11	Oncocytic neoplasms, multiple	Lung cysts, skin fibrofolliculomas
Tuberous sclerosis	TSC1/9q34 TSC2/16p13	Angiomyolipomas, renal cysts, and RCCs (eosinophilic solid and cystic RCC, smooth muscle stroma, and oncocytic)	Cardiac rhabdomyoma, intestinal polyps, pulmonary cysts, brain tubers and subependymal giant cell astrocytoma
Hereditary pheochromocytoma/paraganglioma syndromes	Succinate dehydrogenase subunits (most common SDHB)	SDH-deficient RCC (oncocytic with cytoplasmic vacuoles)	Paraganglioma/pheochromocytoma, gastrointestinal stromal tumor
Constitutional chromosome 3 translocations	3p	Clear cell RCC
Cowden syndrome	PTEN/10q23	Clear cell, papillary, chromophobe RCC	Cancers of breast, thyroid, endometrium, and prostate; colon polyps, facial trichilemmomas, macrocephaly
Hyperparathyroid jaw tumor syndrome	CDC73/1q31.2	Papillary RCC, mixed epithelial and stromal tumor	Parathyroid tumors, jaw fibromas
BAP1 cancer syndrome	BAP1/3p21	Clear cell RCC	Melanoma and mesothelioma
MITF cancer syndrome	MITF/3p14	Unknown	Melanoma, pancreatic cancer, pheochromocytoma

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.

KEY FEATURES: Clear Cell Renal Cell Carcinoma

Nested or alveolar architecture, composed of cells with clear cytoplasm (Figures 3.34 and 3.35)
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)
Cystic changes may be variably present (Figures 3.45 and 3.46)
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)
PAX8 consistently positive, supporting renal cell origin³¹,³²,³³
VHL gene mutation or promoter hypermethylation via molecular testing²⁴,³⁴
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
Has a tendency to grow into veins and renal sinus tissue,⁸,¹⁰,¹¹,³⁹,⁴⁰,⁴¹,⁴² discussed more with renal cancer staging

The behavior of clear cell RCC is known to be deceptive. Although small tumors of stage pT1a often have favorable outcomes, it is also known that recurrences can occur many years after the original diagnosis, including metastases to unusual sites, such as the skin, pancreas (Figure 3.53), or gallbladder.²⁴,⁴³,⁴⁴ Interestingly, although it might intuitively suggest advanced disseminated disease, there is evidence that surgical resection of isolated pancreatic metastases of RCC is clinically warranted and may be associated with long-term survival.⁴⁴ In general, clear cell RCC is considered to be a less favorable histologic subtype when compared to chromophobe or papillary subtypes.⁴⁵,⁴⁶

PEARLS AND PITFALLS: Pathology of Metastatic Clear Cell RCC for Guiding Clinical Treatment

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

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.

Figure 3.38. Rare examples of clear cell renal cell carcinoma can transition to a poorly differentiated component that may mimic a nonrenal adenocarcinoma. Differential diagnosis for this pattern could include urothelial carcinoma or metastatic adenocarcinoma of another origin, if viewed in isolation.

Papillary Renal Cell Carcinoma With Clear Cell Change

Papillary RCC is the second most common subtype of adult renal cancer, after clear cell RCC. Its prototypical features are discussed in more detail under the section on the papillary pattern. However, in some cases, possibly as much as 39%, papillary RCC can contain cells with clear cytoplasm, mimicking clear cell RCC (Figures 3.56,3.57,3.58,3.59,3.60).³⁷,⁵⁴ Fortunately, awareness of a few clues can help distinguish these two entities.

PEARLS AND PITFALLS: Papillary Renal Cell Carcinoma With Clear Cell Change (Figures 3.55,3.56,3.57,3.58,3.59,3.60,3.61)

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
Cytokeratin 7 often diffusely positive, contrasting to true clear cell RCC (Figure 3.60)³⁷
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

Chromophobe Renal Cell Carcinoma, Classic Type

Chromophobe RCC is usually considered the third most common subtype of renal cancer, at approximately 5% or less of adult renal cancers.⁵⁶ Grossly, it typically forms a tan-colored mass, which may have a central scar (Figures 3.63 and 3.64), or for eosinophilic variant, the color may be red-brown, more similar to that of oncocytoma (Figure 3.65).

KEY FEATURES: Chromophobe Renal Cell Carcinoma

Often unencapsulated or incompletely encapsulated (Figure 3.66)⁵⁷
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 3.43. Degenerative changes or scar in clear cell renal cell carcinoma (RCC) can be deceptive if encountered in a biopsy sample. This field comes from the center of a clear cell RCC tumor and contains vasculature with inconspicuous tumor cells, mimicking lymphocytes or capillaries.

Figure 3.44. Other areas of the same tumor from Figure 3.43 show transition to typical clear cell renal cell carcinoma.

Figure 3.45. Cystic changes can be variably present in clear cell renal cell carcinoma (RCC), which some authors have associated with favorable behavior. This tumor is predominantly cystic but contains solid areas within the walls, consistent with cystic clear cell RCC.

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 3.48. Carbonic anhydrase IX staining can be decreased in high-grade, poorly differentiated, or sarcomatoid clear cell renal cell carcinoma (RCC) tumors. This example included spindle cell and rhabdoid components with markedly decreased carbonic anhydrase IX staining in those areas, compared to diffuse staining in typical clear cell RCC areas.

Figure 3.49. Cytokeratin 7 staining is usually minimal in clear cell renal cell carcinoma, if any.

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

Immunohistochemistry⁵⁸

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 3.52. Copy number analyses or fluorescence in situ hybridization (FISH) can be used to support a diagnosis of clear cell renal cell carcinoma in difficult cases. This example shows 3p25 deletion via FISH with two copies of the centromere (red) but only one copy of the 3p25 region (green).

Figure 3.53. Clear cell renal cell carcinoma has an unusual predilection to metastasize to the pancreas (left).

Figure 3.54. Nuclear staining for PAX8 is generally supportive of metastatic renal cell carcinoma in the appropriate context. This patient had metastatic disease involving bone with a suspicious renal lesion.

Positive for KIT (CD117, Figure 3.77)
Carbonic anhydrase IX negative or minimal, in contrast to clear cell RCC (Figure 3.78)

The behavior of chromophobe RCC is generally favorable⁴⁵,⁴⁶; however, aggressive behavior is possible, especially with sarcomatoid change (Figure 3.79), necrosis (Figure 3.80), or vascular invasion (Figure 3.81).⁵⁹,⁶⁰ Some prior studies have suggested that the rate of sarcomatoid change is higher in chromophobe RCC than other RCC types (despite the much lower prevalence of the tumor type overall)⁵⁹,⁶¹; however, this has been challenged by other large series finding low rates of sarcomatoid change.⁶⁰ Since the nuclei are inherently atypical in chromophobe RCC, grading using the typical system does not appear to have value and is not recommended.⁶²,⁶³,⁶⁴,⁶⁵ Some novel systems of grading have been proposed, the most well-known being the chromophobe tumor grade described by Paner et al.⁶⁶ This system divides tumors with the typical pattern of widely spaced nuclei (grade 1) from tumors with more overlapping and crowding of nuclei (grade 2) and those

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 3.58. This case of papillary renal cell carcinoma (RCC) with clear cell change could be easily mistaken for clear cell RCC if this area were encountered in isolation. Sampling additional areas of the tumor, or for a biopsy sample, immunohistochemistry, may be helpful to recognize the correct classification.

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 3.61. Carbonic anhydrase IX staining is negative in the papillary renal cell carcinoma (RCC) with clear cell change from Figures 3.59 and 3.60, contrasting to clear cell RCC.

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 3.68. Nuclei of chromophobe renal cell carcinoma often vary considerably in size.

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.

Genetically, chromophobe RCC most commonly has rearrangements of the TERT promoter, mutations of mitochondrial genes, and mutations of TP53 or PTEN.⁵⁸,⁶⁷ With respect to copy number pattern, chromophobe RCC tends to have copy losses of chromosomes Y, 1, 2, 6, 10, 13, 17, and 21 and lesser rates of loss for chromosomes 3, 5, 8, 9, 11, and 18.⁵⁶,⁵⁸ However, chromosomal gains have also been noted by some authors.⁶⁸ For difficult cases, particularly with respect to the eosinophilic variant, some form of copy number assessment may be helpful, such as conventional cytogenetic karyotyping, FISH, or copy number assays; however, this is less necessary for distinction between chromophobe and clear cell RCC, which can usually be resolved with morphology and immunohistochemistry (especially KIT, carbonic anhydrase IX, vimentin, and cytokeratin 7). Distinction of eosinophilic chromophobe from oncocytoma is discussed further under the oncocytic/eosinophilic pattern.

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).

Figure 3.80. Necrosis has also been associated with more aggressive behavior from chromophobe renal cell carcinoma in some studies. This example shows coagulative necrosis with calcification at bottom center.

Clear Cell Papillary Renal Cell Carcinoma

Clear cell papillary RCC is interesting in that it is a distinct entity in renal tumor classification⁶⁹,⁷⁰ that was only recognized as different from clear cell RCC in 2006.⁷¹ Now, with increased recognition, it is thought that this makes up as much as 3% to 4% of adult RCC, making it likely the fourth most common RCC subtype, approaching the incidence of chromophobe RCC.⁷²,⁷³ These tumors are almost always small (predominantly stage pT1a) and low grade (grade 1-2).⁷² Although they microscopically resemble clear cell RCC, they often do not grossly have its golden-yellow or orange color (Figures 3.82,3.83,3.84).

KEY FEATURES: Clear Cell Papillary Renal Cell Carcinoma

Composed of

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 3.82. Clear cell papillary renal cell carcinoma (RCC) may form solid or cystic tumors that are not necessarily golden-yellow like clear cell RCC. This mass forms a solid and cystic lesion with white areas that slightly bulges beyond the contour of the kidney.

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 3.85. Some areas of clear cell papillary (RCC) may be difficult or impossible to distinguish from clear cell RCC based on morphology alone. This example shows solid nests resembling clear cell RCC. The stroma is slightly prominent, which may be a clue, although this alone is not specific.

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)

Immunohistochemistry⁷²,⁷⁴,⁷⁵,⁷⁶,⁷⁷,⁷⁸,⁷⁹
- 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
Genetics:
- Despite resemblance to clear cell RCC, almost all clear cell papillary RCCs have been found to lack chromosome 3p25 deletion or VHL mutations,⁸⁰,⁸¹,⁸²,⁸³,⁸⁴,⁸⁵ with rare exceptions of uncertain significance⁸⁶

The importance of clear cell papillary RCC is that it has exceedingly favorable behavior.⁸⁷,⁸⁸ To date, no definite examples with well-characterized pathology from multiple series have been proven to metastasize, and the overwhelming majority have been pT1a. However, a recent case report documented a metastatic lesion with features in keeping with clear cell papillary RCC, including absence of VHL mutation/chromosome 3p25 loss. For this case, the corresponding primary tumor was never resected.⁸⁹ However, this does raise the question of whether rare metastasis from clear cell papillary RCC is possible, or if primary tumors left untreated can progress to a more aggressive carcinoma. For as yet not understood reasons, clear cell papillary RCC does have a tendency to be multiple and/or bilateral, even in the absence of end-stage renal disease.⁷² In general, thinking is that this entity may be a candidate for reclassification as a benign or low malignant potential tumor in future schemes, although additional data are needed.

PEARLS AND PITFALLS: Clear Cell Papillary-Like Tumors With Imperfect Features

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

Figure 3.89. This clear cell papillary renal cell carcinoma shows a branched glandular configuration. At left, the cells have less cytoplasm, and at right the cells have more cytoplasm. Especially prominent at right is alignment of the nuclei at the same height in the cytoplasm.

Figure 3.90. Nuclear alignment is a clue to the diagnosis of clear cell papillary renal cell carcinoma. This has been compared to the subnuclear vacuoles of early secretory phase endometrium. The cells resemble piano keys (where the nuclei are the black keys and the cytoplasm makes up the white keys).

Comment: Clear cell papillary RCC is a recently recognized renal tumor that morphologically resembles clear cell RCC but using immunohistochemistry and molecular analysis

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 3.92. Many clear cell papillary renal cell carcinoma tumors are cystic. This example shows predominantly cystic architecture with some small papillae protruding into the cysts. There is a central solid nodule, which would preclude a diagnosis of multilocular cystic neoplasm of low malignant potential.

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.

Figure 3.104. This renal neoplasm shows prominent branched glandular configuration morphologically, raising consideration of clear cell papillary renal cell carcinoma (RCC). However, several atypical features were present, including a size of 9 cm with renal sinus and vein branch invasion, and patchy AMACR and CD10 staining (not pictured). Our approach is to classify such cases as clear cell RCC, since clear cell papillary RCC would indicate a highly favorable histology with minimal or no known aggressive behavior.

Figure 3.105. This tumor closely resembles clear cell papillary renal cell carcinoma (RCC), occurring in a young man in his 20s. Although immunohistochemistry showed diffuse carbonic anhydrase IX staining and substantial cytokeratin 7 staining, other markers showed imperfect results, including strong AMACR staining, substantial CD10 staining, and negative GATA3 and high molecular weight cytokeratin. This constellation of features, including the young age, is suspicious for VHL disease, in which tumors can mimic clear cell papillary RCC.

Figure 3.106. Some translocation renal cell carcinomas (RCCs), such as RCC with NONO-TFE3 fusion in this case, can show nuclear alignment mimicking clear cell papillary RCC. Psammoma bodies or higher nuclear grade (grade 3 or higher) would be unusual for clear cell papillary RCC.

References:

Williamson SR, Eble JN, Cheng L, et al. Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile. Mod Pathol. 2013;26:697-708.

Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006;30:141-153.

Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol. 2013;37:1469-1489.

MITF Family Translocation RCC, Clear Cell Pattern

Translocation-associated RCC is best known for its occurrence in children and young adults, and indeed if a child or young adult develops RCC, the likelihood of an MITF family translocation tumor is higher. However, since RCC is rare in young patients, there are likely more MITF family translocation cancers in the typical age range for renal cancer (50 years and above).⁹²,⁹³ Most of these tumors have translocations of TFE3, located at Xp11.2. Hence, these tumors are sometimes referred to as Xp11 translocation carcinomas or similar names. Less frequently, translocations involve TFEB, located at 6p²¹,⁹²,⁹³ and very recently, rare translocations of the MITF gene itself have been reported.⁹⁴,⁹⁵ It is common for these tumors to have a prominent clear cell component, such that they could be confused with clear cell RCC.

PEARLS AND PITFALLS: MITF Family Translocation RCC

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)
- Pigment deposition
- Young age (suggestive but not necessary) (Figure 3.111)
- Stromal hyalinization (Figures 3.112 and 3.113)
Helpful immunohistochemistry:
- 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)
- Cathepsin K—frequently positive, but depends on the fusion⁹⁷,⁹⁸
- Keratin, EMA, or vimentin—may be negative or decreased (but not required, may be positive)⁹⁶
Molecular markers:
- 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

TFE3 RCC is best known; however, tumors with TFEB fusions, also known as t(6;11) RCC for the most common fusion between TFEB on chromosome 6 and MALAT1 on chromosome 11, also occur. These have been noted at their original description to have nests

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 3.115. Immunohistochemistry for the TFE3 or TFEB proteins can be technically challenging to optimize. However, a strong nuclear staining reaction can be supportive of the diagnosis of MITF family translocation renal cell carcinoma. This example shows strong nuclear TFE3 staining in a tumor with negative/minimal staining in adjacent normal tissue.

Figure 3.116. Break-apart fluorescence in situ hybridization in this example of TFEB rearrangement-associated renal cell carcinoma shows one copy of the TFEB gene with closely juxtaposed red and green signals (top). The other copy shows widely separated signals, supporting rearrangement.

Adrenal Cortical Lesions Involving the Kidney

A rare consideration for a renal tumor with a clear cell pattern is an adrenal cortical lesion. This can represent either a developmental rest or remnant, in which adrenal tissue is present within the kidney or fused to the renal capsule, or inadvertent sampling of adjacent adrenal tissue, such as in a core biopsy. If the differential diagnosis for a tumor within the adrenal gland itself includes metastatic RCC, the same principles also apply. Most adrenal cortical rests or remnants are small lesions (less than 2 cm) that are incidentally identified,¹⁰⁶ such as upon evaluation of a potential donor kidney (Figures 3.119 and 3.120) or at autopsy. However, rarely larger lesions can be encountered such as adrenal cortical adenoma that is fused with the kidney (Figure 3.121).

Figure 3.117. The prototypical pattern of TFEB rearrangement renal cell carcinoma shows large nests of cells with clear cytoplasm containing a rosette-like formation of smaller cells with hyaline globules, as shown here. However, this pattern is not entirely specific for TFEB rearrangement, having been occasionally observed in TFE3 tumors and not always present in TFEB tumors.

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 3.119. Adrenal cortical rests in renal specimens could lead to confusion with renal cell carcinoma (RCC). This biopsy of a possible transplant kidney contains a small amount of renal parenchymal tissue (arrow). The rest of the field is composed of adrenal cortical tissue, which could be misconstrued as RCC.

Figure 3.120. At higher magnification, adrenal rests are composed of cells with numerous cytoplasmic vacuoles rather than entirely clear cytoplasm.

Hemangioblastoma

Hemangioblastoma is a benign neoplasm of uncertain histogenesis that is overwhelmingly more common in the central nervous system; however, it has been recently recognized that it can occur at other soft tissue sites and rarely the kidney.¹⁰⁹,¹¹⁰,¹¹¹,¹¹²,¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷ In the kidney, this poses a tremendous diagnostic challenge, as it so closely mimics the morphology of clear cell RCC. In fact, it is well known that metastatic RCC versus hemangioblastoma is a diagnostic
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 3.121. This adrenal cortical adenoma is fused with the kidney and presented as a possible renal mass by diagnostic imaging. The surgeon recognized intraoperatively that it likely originated from the adrenal gland and resected the adrenal gland with a small rim of kidney tissue.

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.

PEARLS AND PITFALLS: Renal hemangioblastoma Versus RCC¹⁰⁹,¹¹⁰,¹¹¹,¹¹²,¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷

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
Paradoxically, PAX8 may be positive in renal hemangioblastoma,¹⁰⁹,¹¹⁰,¹¹¹,¹¹²,¹¹³,¹¹⁴,¹¹⁵,¹¹⁶,¹¹⁷ contrasting to the brain, in which this is typically used to support metastatic RCC. Therefore, PAX8 should not be used in isolation to argue against renal hemangioblastoma

Figure 3.123. In some areas of the same case from Figures 3.121 and 3.122, adrenal cortical tissue intermingles with renal tubules.

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.

An unusual phenomenon that has been recently recognized is that rare RCCs can have overlapping features of hemangioblastoma, including positivity for inhibin.¹²³,¹²⁴ The significance of this is not well understood at present, but likely will be better characterized with the increasing awareness of renal hemangioblastoma and increasing use of immunohistochemistry.

Epithelioid Angiomyolipoma/Perivascular Epithelioid Cell Tumor (PEComa), Clear Cell Pattern

Angiomyolipoma is primarily discussed under the section on spindle cell pattern; however, a rare subset of tumors of the kidney within the angiomyolipoma/PEComa family of tumors are predominantly epithelioid and can closely resemble clear cell RCC (Figures 3.127 and 3.128).¹²⁵,¹²⁶,¹²⁷,¹²⁸,¹²⁹,¹³⁰,¹³¹ In contrast to conventional angiomyolipoma, which is well established as a benign neoplasm, epithelioid angiomyolipoma is considered to have malignant potential (Figure 3.129). However, the precise criteria for distinguishing epithelioid angiomyolipoma from conventional angiomyolipoma with focal epithelioid cells are not always well agreed upon.¹²⁸ Our approach is to reserve the diagnosis of epithelioid angiomyolipoma (which may have malignant potential) for tumors that are overwhelmingly epithelioid, to the point that they would be easily mistaken for RCC and that conventional angiomyolipoma would barely be a diagnostic consideration (Figures 3.127 and 3.128). Focal epithelioid features are not unusual in conventional angiomyolipoma (Figures 3.130 and 3.131) and need not be mentioned, as this might cause unnecessary concern for aggressive behavior from a benign neoplasm.

Precise criteria for malignancy are somewhat variable between studies. One series proposed that three or more of the following findings would be concerning for malignant behavior: 70% atypical epithelioid cells, two mitotic figures per 10 high-power fields, atypical mitotic figures, or necrosis.¹²⁵ Another series noted that associated tuberous sclerosis complex or concurrent angiomyolipoma, tumor size >7 cm, extrarenal extension or renal vein involvement, and carcinoma-like growth pattern were additional concerning features.¹³¹ Interestingly, a recent series found only 20 epithelioid angiomyolipomas (>80% epithelioid morphology) from a series of over 400 tumors from three institutions, with only one developing distant metastasis, suggesting that aggressive behavior may be rare in an unselected patient population.¹²⁷

KEY FEATURES: Recognizing Epithelioid Angiomyolipoma

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 3.126. At high magnification, this renal hemangioblastoma is composed of cells with clear to flocculent eosinophilic cytoplasm. There is a prominent vascular network, mimicking that of clear cell renal cell carcinoma (RCC). A low threshold to further investigate unusual RCC cases that are lacking obvious epithelial formations may be helpful in recognizing this benign neoplasm.

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).

Figure 3.130. Focal epithelioid features in a typical angiomyolipoma generally should not be referred to as epithelioid angiomyolipoma, to avoid implying potential malignant behavior. At high magnification, this example includes clear to eosinophilic epithelioid cells; however, focal fat is appreciable at lower left. The overall pattern of this tumor was readily recognizable as angiomyolipoma, arguing against epithelioid designation.

May contain multinucleated tumor giant cells (Figure 3.132)
May have a lesser spindle-shaped cell component, focal thick blood vessels or fat
Immunohistochemical reactivity:
- Melanocytic markers positive
- Cathepsin K positive¹³² (Figure 3.133)
- Often positive for smooth muscle markers, such as smooth muscle actin and less frequently desmin¹²⁷
- Cytokeratin negative
- Scant data available, but likely PAX8 and carbonic anhydrase IX negative
Molecular: subset has TFE3 rearrangements, like MITF family translocation RCC (distinguished from translocation RCC by lack of epithelial marker staining)¹³³,¹³⁴

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 3.133. Cathepsin K staining in angiomyolipoma and PEComas is typically diffuse and strong (shown here), in contrast to melanocytic marker labeling, which may be focal. This case showed negative staining for cytokeratin AE1/AE3 and EMA and was positive for TFE3 protein, supporting a TFE3 rearrangement PEComa.

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.

Although data are scant, discriminating epithelioid angiomyolipoma from RCC may have some potential implications for treatment purposes in the metastatic setting, as MTOR pathway inhibitors may be more likely considered than the typical VEGF pathway drugs or other tyrosine kinase inhibitors used for RCC.

Xanthogranulomatous Pyelonephritis

Xanthogranulomatous pyelonephritis is discussed in more detail under the inflammatory pattern and nonneoplastic pseudotumors. However, it is worth mentioning that this process may be confused for clear cell RCC when the foamy histiocyte component is predominant (Figure 3.134). Likewise, a spindle cell-like pattern may mimic sarcomatoid RCC (Figure 3.135). As long as this possibility is considered, immunohistochemical markers such as histiocytic markers (CD68 or CD163) and epithelial markers (keratin, PAX8) should resolve this distinction easily. Xanthogranulomatous pyelonephritis typically will have a more diffuse growth pattern, lacking the discrete nests of cells observed in clear cell RCC, and other inflammatory cell components are clues to the diagnosis (such as neutrophils, plasma cells, lymphocytes, or histiocytic giant cells).

PAPILLARY PATTERN

Papillary Adenoma

Papillary adenoma is, by definition, a small renal neoplasm with features resembling type 1 papillary RCC.¹³⁵ The 2016 World Health Organization (WHO) Classification increased the allowable size for this diagnosis from 5 mm (in the 2004 scheme) to 15 mm. Therefore, a papillary renal cell neoplasm may be classified as an adenoma, as long as it is 15 mm (1.5 cm) or smaller (Figure 3.136). Two limitations were given for this definition, that (1) the lesion must be unencapsulated (Figures 3.137 and 3.138) and (2) the nuclear grade must be 1 or 2 (not 3 or higher).¹³⁵ That said, we are not aware of any data indicating that papillary RCCs of this size (<15 mm) with nuclear grade 3 or encapsulation behave aggressively; however, these are reasonable working limits for the definition of papillary adenoma at present.

FAQ: Should I Change My Practice for Diagnosis of Papillary RCC in Renal Mass Biopsy in View of the Larger Allowable Size for Papillary Adenoma?

The larger allowable size for papillary adenoma does increase the potential that an adenoma may be sampled in a core biopsy specimen, in contrast to the historical 5 mm size, which would often be more difficult to visualize by imaging and biopsy. In most cases, masses will be larger than 15 mm based on clinical or imaging findings, so it is likely reasonable to continue to diagnose these as papillary RCC in the biopsy setting. If clinical findings indicate that the mass may be 15 mm or smaller, it would be reasonable to diagnose “papillary renal cell neoplasm” with a comment that distinction of adenoma from RCC would depend on size, grade, and encapsulation.

Papillary Renal Cell Carcinoma

Type 1

Papillary RCC, type 1, is the best characterized form of papillary RCC at present, composed of papillary or compact glandular structures, typically lined by cuboidal or columnar cells with an overall basophilic appearance at low magnification.¹³⁶

KEY FEATURES: Type 1 Papillary Renal Cell Carcinoma

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)
Cells cuboidal or low columnar (Figures 3.145 and 3.146)
Cytoplasm variable from pale eosinophilic to clear (vacuolated)³⁷,⁵⁴ or containing hemosiderin (Figure 3.147)
Architecture: papillary, glomeruloid structures, solid, or cystic
Immunohistochemistry¹⁹,⁴⁸,¹³⁷
- 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)
- Vimentin—often positive
- 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 3.150. AMACR staining is very strong in the tumor from Figures 3.148 and 3.149, supporting papillary renal cell carcinoma.

Several unusual variants of type 1 papillary RCC have been described, ranging from those that resemble Warthin tumor with prominent inflammation¹³⁸ to predominantly solid tumors (Figures 3.152 and 3.153).¹³⁹ A recently described unusual pattern includes “squamoid” cells (Figure 3.154). Although this was initially proposed as an unusual RCC variant (biphasic alveolosquamoid RCC and similar terminology), recent work has shown that this is essentially an odd morphology of type 1 papillary RCC, with similar immunohistochemical findings. An unusual phenomenon in this variant is that cyclin D1 shows increased staining of the “squamoid” areas, for unknown reasons.¹⁴⁰,¹⁴¹,¹⁴² Other unusual morphologies include mucin in the papillary cores (Figure 3.155).¹⁴³

Genetically, type 1 papillary RCC often shows trisomy of chromosome 7 or 17 and loss of the Y chromosome, which are not entirely specific findings but have been used in some contexts to support the diagnosis, such as by karyotyping or FISH.³⁵ The hereditary papillary RCC syndrome, in which patients develop numerous multifocal type 1 papillary RCCs, is characterized by germline mutations of MET; however, the rate of MET mutations appears lower in sporadic papillary RCC than in the hereditary population,¹⁴⁴ contrasting to VHL, which is frequently mutated in both sporadic and hereditary clear cell RCC. For practical purposes, molecular testing is rarely necessary in diagnostic practice to distinguish papillary RCC from mimics, as the morphology and immunohistochemistry is usually sufficient to confirm the diagnosis. Most relevant differential diagnoses for type 1 papillary RCC are shown in Table 3.2.

Figure 3.151. Carbonic anhydrase IX staining is negative in the tumor from Figures 3.148,3.149,3.150, arguing against clear cell renal cell carcinoma.

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.

Figure 3.154. A recently recognized variant of papillary renal cell carcinoma (RCC) contains clusters of cells with more eosinophilic cytoplasm within tubular structures that resemble typical type 1 papillary RCC. When extreme, these structures can appear almost squamous, although they are negative for squamous markers. This has been termed “biphasic” papillary RCC.

Type 2 and Related Tumors

Papillary RCC was originally split into type 1 and type 2 based on the distinctive findings of eosinophilic cytoplasm and cells with prominent nucleoli and pseudostratified nuclei in the latter (Figure 3.156)¹⁴⁵; however, it is now increasingly recognized that type 2 tumors represent a heterogeneous category of neoplasms with differing genetics and potentially significant implications for treatment.¹⁴⁴ Most prominent among these are fumarate hydratase (FH)-deficient RCC/HLRCC syndrome-associated tumors, discussed in the next section. As such, we would consider type 2 papillary RCC to be almost a diagnosis of exclusion that should be used only after several considerations are argued against (Table 3.3).

Papillary Renal Cell Neoplasm With Reverse Polarity/Oncocytic Papillary RCC

In the past, oncocytic papillary RCC has been put forward as an additional possible subtype of papillary RCC, although it has not gained traction in classification schemes due to lack of agreement about its features.¹⁴⁶,¹⁴⁷,¹⁴⁸,¹⁴⁹ However, recent studies have suggested that there is a distinct subtype of neoplasm, characterized by oncocytic cells and papillary architecture with nuclei aligned toward the apex of the cells (Figures 3.157 and 3.158).¹⁵⁰,¹⁵¹,¹⁵²

TABLE 3.2: Differential Diagnosis of Type 1 Papillary Renal Cell Carcinoma (RCC)

	Key Features	Pitfalls	Immunohistochemistry
Papillary RCC	Papillary architecture, usually at least focally conspicuous nucleoli May have foamy macrophages, psammoma bodies, vacuolated cells, intracytoplasmic hemosiderin	May have clear cells or solid growth	Positive: cytokeratin 7 (decreased if eosinophilic), strong AMACR, often vimentin Variable: high molecular weight cytokeratin Negative: WT1, CD57, carbonic anhydrase IX (or focal)
Metanephric adenoma	Very uniform bland nuclei	May have papillary component or calcifications	Positive: WT1, CD57 Negative: AMACR, cytokeratin 7 (or minimal)
Thyroid-like RCC	Colloid-like secretions		Positive: variable PAX8 (supporting primary renal cell lineage) Negative: TTF1 or thyroglobulin (to exclude metastatic thyroid cancer), AMACR usually negative or much less than that of papillary RCC
Clear cell RCC with papillary or pseudopapillary structures	Usually classic clear cell areas evident with thorough sampling		Positive: carbonic anhydrase IX (diffuse membrane) Variable: AMACR Negative: cytokeratin 7 (or focal)
MITF family translocation RCC	Mixed papillary and clear cell features, voluminous cytoplasm May have: psammoma bodies, pigment	Varied patterns	Positive: often melanocytic markers, TFE3 or TFEB protein, often cathepsin K Variable: AMACR, cytokeratin, EMA, vimentin Negative: usually cytokeratin 7
Clear cell papillary RCC	Branched glandular structures, clear cytoplasm, nuclei aligned above basement membrane	Can closely mimic clear cell RCC	Positive: cytokeratin 7 (diffuse), carbonic anhydrase IX (cup-shaped pattern), high molecular weight cytokeratin, GATA3 Negative: AMACR, CD10
Mucinous tubular and spindle cell carcinoma	Mixture of areas resembling type 1 papillary RCC with spindle cell component and mucinous material	Can be mistaken for sarcomatoid change in papillary RCC	Similar to papillary RCC

TABLE 3.3: Differential Diagnosis of Type 2 Papillary Renal Cell Carcinoma (RCC)

	Key Features	Pitfalls	Immunohistochemistry
Type 2 papillary RCC	Papillary architecture, eosinophilic cells, nuclear pseudostratification	Diagnosis of exclusion after the others are argued against	Positive: PAX8 (supporting renal origin), AMACR strong Negative: p63, GATA3
Fumarate hydratase (FH)-deficient RCC	Mixed architectural patterns: papillary, tubular, infiltrative Very prominent nucleoli with perinucleolar clearing	Morphology can be heterogeneous and not exclusively papillary	Positive: 2-succino-cysteine Negative: abnormal negative FH, usually negative cytokeratin 7
MITF family translocation RCC	Mixed papillary and clear cell features, voluminous cytoplasm May have psammoma bodies, pigment	Varied patterns	Positive: often melanocytic markers, TFE3 or TFEB protein, often cathepsin K Variable: AMACR, cytokeratin, EMA, vimentin Negative: usually cytokeratin 7
Medullary carcinoma	Infiltrative carcinoma, sometimes prominent inflammation, occurring in patient with sickle trait or other hemoglobinopathy	Rare cases recently described in patients without hemoglobinopathy, referred to as RCC, unclassified with medullary phenotype	Positive: OCT3/4 often Negative: abnormal negative SMARCB1 (INI1)
Urothelial carcinoma	Infiltrative growth pattern, invading around normal renal structures, usually more pleomorphism than RCC	PAX8 may be positive in upper tract urothelial carcinoma	Positive: GATA3, p63, high molecular weight cytokeratin Variable: PAX8
Metastatic carcinoma of another origin	Resembles carcinoma of organ of origin, lung cancer most common	Can mimic a primary tumor (solitary, unilateral, circumscribed)	Positive: organ-specific markers (TTF1, others)
Collecting duct carcinoma	Infiltrative carcinoma of renal origin not meeting criteria for any of the others		Positive: PAX8 Negative: p63, GATA3

In one classification scheme, this was referred to as oncocytic low-grade papillary RCC (type 4),150 and recently another group has proposed the name “papillary renal cell neoplasm with reverse polarity” for this entity.¹⁵¹,¹⁵² These have been found to be negative for vimentin, contrasting to usual papillary RCC, and negative for KIT, contrasting to oncocytoma and chromophobe RCC, with the unusual finding of GATA3 positivity that seems
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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