Advances in Anatomic Pathology:
Differential Diagnosis of Renal Tumors With Papillary Architecture
Tickoo, Satish K. MD*; Reuter, Victor E. MD*,†
*Department of Pathology, Memorial Sloan-Kettering Cancer Center
†Department of Pathology, Weill Medical College of Cornell University, New York, NY
Reprints: Satish K. Tickoo, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: firstname.lastname@example.org).
Papillary renal cell carcinoma is the second most common malignant renal epithelial tumor and constitutes approximately 15% of renal cell tumors. However, papillary architecture is neither unique to papillary renal cell carcinoma, nor do all papillary renal cell carcinomas show exclusive papillary histology. Many of the nonpapillary renal cell carcinomas with papillary architecture have been recognized only recently. Distinction of these from papillary renal cell carcinoma is essential, as biologic behavior and potential therapeutic options are distinct in many such tumors. Close attention to the cytologic and growth pattern characteristics will allow us to arrive at the proper diagnosis in most cases, although sometimes immunohistochemistry and rarely genetic evaluation may be needed.
Papillary renal cell carcinoma (PRCC) is the second-most common renal neoplasm after clear cell RCC.1–4 Although papillary architecture is a characteristic of PRCC, variable proportions of similar architecture are present in some other tumor types recognized in the 2004 World Health Organization (WHO) classification system.5 Over the past 2 decades, a number of other renal tumors have been described, many of which show variable, and occasionally prominent, papillary architecture. Most, if not all, of these tumors almost certainly would have been regarded as PRCC in the past. Recognition and proper diagnosis of these tumors is essential not only to maintain the purity of PRCC as a specific entity, but also because of the distinct clinicopathologic features of these tumor types. For example, these mimics include tumors with potentially benign or indolent behavior (eg, clear cell-PRCC and acquired cystic disease-associated RCC) and highly aggressive tumors such as hereditary leiomyomatosis RCC (HLRCC)-associated renal cancers, collecting duct carcinoma (CDC), and MiTF/TFE translocation-associated carcinomas. In this study, we will review the cytomorphologic features of PRCC and some of its mimics, highlighting the features that allow us to arrive at the appropriate diagnosis (Fig. 1).
PAPILLARY RENAL CELL CARCINOMA
PRCC constitute 10% to 15% of all renal cortical tumors.1–5 Like other common renal cell tumors, currently more than 50% of cases present as incidental masses, usually detected on radiologic investigation for unrelated conditions.1,4,6 Metastases at presentation are uncommon, unlike some of the other renal tumors with papillary architecture. Although the reported tumor size ranges from 1 to 18 cm (median, 6.4 cm), in modern times a downward size migration is being observed because of the incidental discovery on imaging.1,4,6 Majority of patients have unilateral tumors; however, in nonsyndromic settings PRCC is more often bilateral and multifocal compared with other common renal cell tumors.7,8
Grossly, PRCC is typically well circumscribed, often surrounded by a fibrous pseudocapsule (Fig. 2A).1,4,7,9 As a matter of fact, of all common renal cell tumor types, PRCC is most likely to be surrounded by a fibrous pseudocapsule. Most tumors exhibit variegated cut surface with appearances related to microscopic findings. Tumors with abundant foamy macrophages show yellow-to-tan cut surface, whereas those with intratumoral hemorrhage appear dark tan to brown. Grossly, visible areas of necrosis, hemorrhage, and cystic changes are common, being present in up to two-thirds of the tumors. Some tumors may be almost entirely necrotic. Among the usual renal cell tumors, PRCC is the most likely to show multifocality, with reported incidences of even greater than 45% of the cases. Although multifocality indeed is frequent in PRCC, this very high reported incidence may also be a result of including microscopic lesions many of that are considered papillary adenomas and not carcinomas now.
Conforming to the gross circumscription, a majority of PRCCs show well-defined fibrous pseudocapsule on light microscopic evaluation (Fig. 2B). Even when the capsule is incomplete, most tumors tend to be well circumscribed. Infiltration into surrounding renal parenchyma is rare, and at the most, focal. Extensive infiltrative and irregular tumor edges should always raise the differential diagnostic possibility of an alternative diagnosis. The tumor capsule is often lined by a single layer of epithelium that is morphologically similar to that lining the papillae (Fig. 2B).1,4,7 The capsule with the lining imparts the appearance of a tumor filling a large cystic space in many cases of PRCC.
PRCCs exhibit broad architectural spectrum, including papillary, tubular, solid, and solid-glomeruloid.1,4,7,9–11 The papillae in occasional cases may be closely packed, sometimes masking their true papillary growth pattern. Areas containing papillary architecture are observed in most cases (Figs. 2B, C). However, many tumors show variable, sometimes predominant or even exclusive, solid, tubular, and/or glomeruloid growth patterns (Figs. 2D, E).4,6,11 Glomeruloid pattern is composed of tubular structures with intraluminal tufting of tumor cells. Cells lining tubules are cuboidal with scant-to-moderate amphophilic cytoplasm, whereas the cells tufting into lumen often show abundant eosinophilic cytoplasm and usually higher-grade nuclei (Fig. 2E). Rarely, sarcomatoid differentiation may be observed; even more uncommon is the presence of heterologous elements such as malignant osteoid. Sarcomatoid differentiation is a sign of aggressive disease, as in other types of renal tumors.
Cores of the papillae usually consist of loose fibrous tissue with prominent vasculature, and contain variable number of foamy macrophages in most cases.1,4,7,9,10 Psammoma bodies, hemosiderin-laden macrophages, and hemosiderin deposition within tumor cells are also often seen. However, in some cases, the cores may have scant or no macrophages (particularly in tumors with eosinophilic cytoplasm), or may show marked hyalinization or variable degrees of edema. In some tumors, marked edema results in fluid-filled, grape-like polypoid structures. In some other cases, the papillae contain no distinct cores, and may have micropapillary features.
Cytologic features are also variable. The cytoplasm may be scant to moderate and amphophilic, or abundant and eosinophilic.7,9 The cells in some tumors with eosinophilic cytoplasm resemble those observed in renal oncocytoma; such tumors have been called “oncocytic PRCC” (Fig. 2F).12 Occasional PRCCs contain variable, or sometimes prominent, “clear cell” areas. These clear-appearing cells, unlike the optically transparent cells in clear cell RCC, have fine cytoplasmic reticulations and granularity (Fig. 2G).4,6 The granularity is often associated with finely granular hemosiderin in the cytoplasm.
WHO divides PRCC into 2 types: type 1 with papillae covered by smaller cells with scant-to-moderate amphophilic cytoplasm (Fig. 2B), and type 2 with larger tumor cells, often with higher nuclear grade, eosinophilic cytoplasm, and nuclear pseudostratification (Fig. 2C).5,9 However, there are some tumors that show a combination of type 1 and 2 features. WHO system does not address the issue of classification of such PRCCs with mixture of morphologies. There are many tumors that may show prominent papillary architecture, but in fact are not PRCC. Many of these are often mistakenly regarded as type-2 PRCC (Fig. 1).
The issue of nuclear grading remains contentious in PRCC.1,5,9,13–17 Many believe that Fuhrman grading system is well suited for these tumors, whereas others disagree and do not use Fuhrman grading scheme in PRCC. One of the recently proposed grading schemes suggests assessment of nucleolar prominence in the most pleomorphic foci rather than Fuhrman grade as clinically more useful.16
By immunohistochemistry (Fig. 2H), most PRCCs show diffuse positivity for cytokeratin (CK)7; however, diffuse positivity is more often seen in type-1 than type-2 tumors. Alpha-methylacyl coenzyme A racemase (AMACR) shows diffuse cytoplasmic granular staining. CD10 is often positive, characteristically with luminal membranous staining, although focal diffuse membranous (box-like) may also be present. Carbonic anhydrase-IX (CA-IX) is either negative or at the most focally positive, and such positivity is usually limited to papillary tips or perinecrotic areas. Stains for RCC, Pax2, and Pax8 are also positive.1,5,6,9,10,12
Cytogenetic and molecular studies have revealed distinct findings in PRCC18–20 that distinguish them from other renal epithelial tumors. The majority of sporadic PRCC are characterized by trisomy of chromosomes 7 and 17 as well as loss of chromosome Y. Some investigators have suggested that tumors exhibiting trisomy 7/17 only are likely to be benign, whereas those tumors exhibiting additional genetic abnormalities will behave aggressively, a hypothesis that has not been substantiated in the literature. Gains involving chromosomes 7 and 17 are also more often reported in type-1 than type-2 PRCC.20,21 More recently, molecular evaluation has also suggested the need for modifying the classification of PRCC.22MET gene mutations, reported in up to 13% of sporadic tumors, are only present in type-1 PRCC.23
Overall, 5 and 10-year survivals in PRCC are better than in clear cell RCC, and very likely worse than chromophobe RCC.1,2,6,7,15,24,25 However, some studies show no significant prognostic differences between PRCC and chromophobe RCC. Type-2 tumors reportedly have worse prognosis compared with type-1 tumors.13,22,26
COLLECTING DUCT CARCINOMA
CDC is a rare, highly aggressive RCC, likely originating from cells of collecting ducts of renal medulla.27–33 The entire spectrum of diagnostic features of CDC is still evolving, but some characteristic, although not entirely specific, morphologic, and immunophenotypic features are well recognized.
The tumors are predominantly located in medulla, but larger tumors often involve the cortex secondarily. Classically, the cut surface is gray-white with invasive borders, and most often the tumor shows a multinodular growth pattern (Fig. 3A). Areas of necrosis, hemorrhage, and cystic change are frequent. Majority of tumors grossly invade renal sinus and perinephric fat. Some well-circumscribed tumors with purely cystic appearance, earlier considered low-grade CDC, have recently been regarded as a separate entity, “tubulocystic carcinoma.”34,35 However, some CDCs with otherwise typical aggressive features also show variable amount of tubulocystic areas. Therefore, whether pure tubulocystic carcinomas represent distinct tumor entities or variations in morphologic spectrum of CDC is not clear at present.
Histologically, CDC is primarily a high-grade adenocarcinoma. The tumors typically show a variety of architectural patterns, usually in various combinations, including tubular, solid tubular/acinar, papillary, solid sheet-like, cribriform, and (rarely) diffuse signet ring cell-like (Figs. 3B, C). Like other RCCs, CDCs may also show sarcomatoid features. Sarcomatoid features in CDC do not have as dramatic biologic significance as in other RCCs, as usual CDC by itself is a very aggressive tumor.36 CDC typically shows a multinodular growth pattern with markedly desmoplastic stroma and intratumoral inflammatory infiltrate, including lymphocytic, lymphoplasmacytic, or neutrophilic, occasionally with microabscess formation. Dysplastic cytologic features in the surrounding renal collecting ducts are often present, although such changes are not specific for this tumor. CDCs characteristically have high-grade cytology, often with marked nuclear pleomorphism and brisk mitotic activity. Sometimes cytoplasmic mucin may also be observed. Angiolymphatic invasion and metastases to regional nodes is frequent.
On immunohistochemical staining, CDC is generally, but not always, positive for high molecular weight cytokeratin (34βE12), epithelial membrane antigen (EMA)/mucin-1, cell surface associated (MUC1), CK7, c-kit, and carcino-embryonic antigen (CEA). Stains for lectins, Ulex europaeus agglutinin-1 (Fig. 3C), peanut agglutinin, and soybean agglutinin are also usually positive, but not in all cases.28,30,31,33,37 The tumors stain variably for CD10, AMACR, E-cadherin, and Pax-2, but are usually negative. In the few tumors tested, CDCs have consistently shown monosomies of chromosomes 1, 6, 14, 15, and 22. Loss of heterozygosity of multiple chromosomal arms, including 1q, 6p, 8p, 13q, and 21q were present in most of the tested cases, and minimal area of deletion located at 1q32.1-32.2 has also been identified. Amplification of HER2 is present in some cases. Importantly, trisomies of 7 and 17 (typical of PRCC) and chromosome 3 losses (typical of clear cell RCC) are not present in CDC.38–42
CDC frequently shows metastatic at presentation, commonly with multiple organ involvement, including lymph nodes (44%), various viscera (32%), with lungs being most common site (17%) followed by bones (16%).32 Bone metastases produce both osteolytic and osteoblastic lesions in CDC. Unlike what is usual in more common RCC subtypes, approximately two-third cases of CDC are symptomatic at presentation. Approximately half of patients are dead of disease within 2 years.1,32,43
As some CDCs show prominent or predominant papillary architecture, mistaken diagnosis of type-2 PRCC is not uncommon. However, extensive infiltrative architecture with stromal desmoplasia, multinodular growth pattern, combination of multiple architectural patterns, and extensive metastases at presentation are not typical of PRCC and should always raise the differential diagnostic possibility of CDC (Fig. 1). Immunohistochemical patterns will also help in this distinction in most, although not all, cases. In some difficult cases, cytogenetic analysis may be required.
RENAL MEDULLARY CARCINOMA
Renal medullary carcinoma (RMC) is a distinctive clinicopathologic entity occurring almost exclusively in patients with sickle cell trait; occasional cases are reported in patients with hemoglobin sickle cell disease and very rarely in sickle cell disease.44,45 On account of the morphologic overlap (Fig. 3D), many consider it to be a particularly aggressive variant of CDC.1,4 As virtually all cases do have hemoglobin-S, some cause-effect relationship between hemoglobinopathy and this tumor has been suggested, although the exact mechanism still remains undetermined. The loss of immunohistochemical nuclear expression of INI1(hSNF5/BAF47) gene product, INI1 (SNF5) protein (which is immunohistochemically detected by Baf-47 antibody), similar to pediatric rhabdoid tumor of kidney, is a consistent finding in RMC (Fig. 3D).46 However, the molecular mechanism, that is, mutations/loss of gene or others, for this absent INI1 expression is not known yet.
RMC is a very uncommon tumor, mostly occurring in young patients (age range: 5 to 39 y), although occasional cases do occur in older patients. Most patients are of African-American ethnicity, with a few cases also reported in patients of Mediterranean ancestry.44,45 Cases in other races are very rare. Patients may present with hematuria or flank pain, but presentation with symptoms related to metastases is not uncommon.
Grossly, RMC typically is a medullary-based tumor, with gray-white cut surface, and infiltrative borders often with extension into perihilar fat. Satellite nodules in adjacent renal parenchyma are frequent, and these often represent tumor emboli in large vessels. At microscopy, most common architectural features of the tumor include reticular or cribriform glands. Other patterns include papillary (Fig. 3D), yolk sac-like, glandular, solid nests, tubules, undifferentiated sheet-like, and adenoid cystic-like; most tumors show a combination of architectural patterns. The stroma is almost always fibrotic or desmoplastic, and intratumoral inflammatory infiltrate, mostly neutrophils, is very frequent. Tumor margins are always infiltrative. Cytoplasmic mucin is also commonly observed. Cytology is mostly high grade, with moderate to marked nuclear atypia; occasional cases may show rhabdoid features. A characteristic feature is the presence of sickled red blood cells, both within the tumor and surrounding renal parenchymal vessels (Fig. 3D).
Most cases show high pT and pN stages and satellite tumor nodules because of very frequent vascular spread. Most cases have metastases at presentation. Biologic behavior is very aggressive with mean survivals of approximately 4 months after diagnosis.44,45
MiTF-TFE/TFE FAMILY TRANSLOCATION-ASSOCIATED RENAL CARCINOMAS
Another group of tumors that because of their prominent papillary architecture in some cases might have been considered as PRCC in the past, is the MiTF/TFE family translocation-associated RCC. Although predominantly a tumor is of pediatric age group, it is now increasingly being recognized in adults. In children, these account for less than 5% of all renal neoplasms, but they constitute the most common type of RCC in this age group.47–60 Approximately 10% to 15% of cases in children have a history of prior exposure to chemotherapy.55 These tumors are defined by translocations involving MiTF/TFE family genes (TFE3 or TFEB). The TFE3 gene, localized to Xp11.2, may fuse with one of multiple chromosomal loci, the end result of which is the overexpression of the TFE3 protein.49,50,59,60 The TFEB gene is localized to 6p21 which fuses to alpha gene on 11q12.57 This fusion results in expression of the TFEB protein. Both TFE3 and TFEB expression may be detected by immunohistochemistry, a very useful and relatively specific diagnostic aid.52,53,57,58,60
Grossly, these tumors are generally well circumscribed but nonencapsulated. Size is variable with some examples measuring up to 21 cm. Some cases are associated with infiltrative borders and may show calcifications. The cut surface tends to be tan-yellow, often exhibiting hemorrhage and necrosis. Microscopically, significant overlap exists among different translocation groups. Carcinoma with high nuclear grade, prominent or occasionally predominant papillary and/or solid alveolar growth patterns, and composed of clear cells is most distinctive histopathologic appearance in Xp11 tumors (Figs. 4A, B). However, presence of cells with granular eosinophilic cytoplasm is not uncommon. Tumor cells are often discohesive which leads to alveolar and sometimes pseudopapillary architecture. Psammomatous calcifications are virtually always present and may be abundant as are cytoplasmic hyaline nodules. X;1 (PRCC-TFE3) carcinomas tend to have less cytoplasm, lower-grade nuclei, and fewer psammoma bodies. Papillary architecture is common, either merging with or sharply demarcated from solid/acinar areas. The 6;11 (Alpha-TFEB) tumors arecharacterized by tumor cells with clear cytoplasm, well-defined cell borders and round nuclei with prominent nucleoli. In addition, there may be a minor population of smaller tumor cells with minimal amounts of cytoplasm clustered around nodules of basement membrane-like type material (Fig. 4C). On account of the diverse morphologic spectrum seen in translocation-associated carcinomas, it is common for the diagnosis of type-2 PRCC, clear cell RCC, or RCC, unclassified to be entertained.
The diagnosis of translocation-associated carcinoma should always be entertained in a renal tumor that fails to stain for epithelial markers.1,4,6 Tumors associated with Xp11 translocations express TFE3 in a nuclear distribution whereas 6;11 tumors exhibit nuclear expression of TFEB (Fig. 4D). Up to 50% of the latter express melanocytic markers such as HMB-45 or A-103 whereas a small percentage of Xp11 tumors may also stain for these markers.59 One must keep in mind that both translocation-associated carcinomas and epithelioid angiomyolipomas may exhibit similar expression patterns for epithelial and melanocytic markers; the key in arriving at the proper diagnosis is in the differential expression of other markers in the panel. Unlike common RCCs, translocation-associated carcinomas are typically negative for all epithelial markers, although some may be focally or on rare occasions, even diffusely positive. Such positivity is most likely to occur for EMA. Vimentin is usually negative but may be weakly and focally positive. CD10, RCC antigen, AMACR, and E-cadherin are usually positive in TFE3 carcinomas. CD10 and RCC antigen are usually absent or only focally positive in TFEB tumors. Some tumors may show patchy to more diffuse membranous positivity for CA-IX.
TFE3 renal carcinomas among children, particularly ASPL-TFE3 carcinomas, usually present at advanced stage.56 But, despite high stage at presentation, including lymph node metastasis, clinical behavior in children is usually not aggressive, although long follow-ups are not available yet. Unlike their pediatric counterparts, the tumors in adults are reported to show a more aggressive clinical behavior.54
CLEAR CELL-PAPILLARY RENAL CELL CARCINOMA
Clear cell-PRCC is a recently recognized distinctive renal tumor, initially described in the setting of end-stage kidneys.61 It is amply clear now that they can also occur without evidence of impaired renal function.4,61–63 Although morphologically mimicking both the PRCC and clear cell RCC, published series as well as our experience reveals no evidence of 3p25.3 losses, VHL gene mutations, or promoter hypermethylations that are commonly observed in clear cell RCC.64 In addition, polysomy of chromosome 7 is also not seen, as would be expected in many PRCC. These molecular features support its distinctive nature. These tumors are usually unicentric, unilateral, and small; the largest described being 5 cm. However, in our experience, and as recently reported in literature, multifocality and bilaterality may be present in some cases.64
Grossly, they are well circumscribed and usually encapsulated. Areas of apparent hyalinization are common. Some cases with grossly thick capsules and apparent fibrotic cut surface show extensive myoid metaplasia of the capsule with extensions into tumor mass on microscopy. It is common for the tumor to be cystic, but some tumors are predominantly solid with very few cystic areas.
On microscopy, most tumors have variable, and sometimes prominent, papillary architecture (Fig. 5A). In some cases, papillae are tightly packed giving rise to solid appearance. Sometimes these papillary structures are tufting into cystic spaces. Tubular/acinar features are also common, and some tumors have markedly crowded, very small “collapsed” acini, containing scant cytoplasm, and giving the tumor solid sheet-like appearance (Fig. 5B). Tumors with collapsed acini, variable tubular/acinar architecture, myoid metaplasia, and diffuse CK7 positivity have been considered to be separate tumor entities (renal angiomyoadenomatous tumor/RCC with diffuse CK7 immunoreactivity) by some authors.64–68 However, these morphologic features can be observed in otherwise typical clear cell-PRCC, and constitute features within the morphologic spectrum of clear cell-PRCC.4,64 Aydin et al64 have recently suggested the designation of “clear cell tubulopapillary RCC” for the morphologic spectrum of these tumors, although we do not see any specific advantages for this longer nomenclature (similar to PRCC with tubulopapillary features being designated as PRCC). Except in solid collapsed acinar areas, all tumoral cells have clear cytoplasm with low-grade (equivalent to Fuhrman grade 2) nuclei. One of the most characteristic features of the tumor is the arrangement of the tumor nuclei in a linear fashion, away from the basal aspect of the cell, either in the middle of the cell or more apically. Stromal hyalinization is frequently evident within the lesion. Foamy macrophages, tumor necrosis, and vascular invasion are not the features of these tumors. Most tumors are small and confined to the renal parenchyma, although rare cases extending into the renal sinus have been described. The number of cases in the literature with extended clinical follow-up information is small; however, our experience, and as recently reported by Aydin et al,64 suggests that these are tumors with indolent clinical behavior.
The immunohistochemical features of the tumor are quite characteristic (Fig. 5C). Tumor cells express CA-IX diffusely in a membranous distribution. However, it is common to see absence of staining along the luminal border of the tumor cells (cup-shaped distribution).4 There is diffuse staining with CK7, but racemase is negative. CD10 is negative in most cases, whereas it is common to see patchy to diffuse immunoreactivity for high molecular weight cytokeratin (34βE12).4
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER SYNDROME CARCINOMA
HLRCC syndrome is an autosomal-dominant syndrome, characterized by leiomyomas of skin and uterus, occasional leiomyosarcomas of uterus, and renal carcinomas. Genetic basis is germ-line inactivating mutations in fumarate hydratase (FH) gene located at 1q42.3-q43.4,69–72 The gene encodes for the enzyme fumarate hydratase, which is required to convert fumarate to malate in Krebs (tricarboxylic acid) cycle. Germ-line mutations in FH gene are accompanied by mutations or deletions of wild-type FH allele in the tumors. Loss of FH function results in increased levels of fumarate in cell which acts as competitive inhibitor of prolyl hydroxylase domain-containing proteins. These proteins are normally required for hydroxylation and subsequent degradation of hypoxia-inducible factor 1 (HIF-1) in association with the product of VHLgene. The consequent overexpression of HIF and transcription of multiple downstream products likely contributes to tumorigenesis, similar to that in clear cell RCC.
Renal tumors in HLRCC syndrome are clinically very aggressive carcinomas. On account of their frequently dominant papillary architecture, these were often regarded as type-2 PRCC in the past (Fig. 6A).4,6,73 The tumors are often solitary and unilateral, unlike most syndromic tumors, although multifocal tumors are being recognized more often now. Penetrance for RCC in the syndrome is lower than for cutaneous and uterine manifestations, with only 20% to 35% of patients developing RCC, whereas most patients develop cutaneous leiomyomas. In women, most develop uterine leiomyomas at relatively young age. The uterine leiomyomas are often cellular and with some atypical features.
Renal carcinomas show variable, but often prominent, papillary architecture.73 Other common patterns in the tumor include, solid alveolar, tubular/glandular, and sheet like. Multiple growth patterns in the same tumor often coexist. Desmoplasia and multinodularity are also common, as are cystic features (Fig. 6A). Tumor cells are large and usually show abundant eosinophilic cytoplasm. Rarely, focal clear cell change may be observed. The most diagnostic and consistent feature of tumors is the presence of large nuclei with very prominent orangeophilic or eosinophilic nucleoli, surrounded by a clear halo, somewhat resembling cytomegalovirus inclusions (Fig. 6B).73 Possibility of HLRCC tumor should always be considered if these features are present in a kidney tumor in proper clinical and immunohistochemical setting.
Immunostain for CK7 is often negative, or only very focally positive. Stains for mucin and Ulex europaeus agglutinin-1 are negative. As a result of multinodularity and desmoplasia, many tumors resemble CDC. Immunostaining patterns, along with nucleolar features, should distinguish the tumor from CDC.4,73
MUCINOUS TUBULAR AND SPINDLE CELL CARCINOMA
Another relatively uncommon tumor that may be confused with PRCC is mucinous tubular and spindle cell carcinoma (MTSCC). Approximately 100 cases have been described in the literature.4,74–78 Although the average age at presentation is similar to that for other common renal tumors (range: 17 to 78 y; mean, 53 y), the tumor shows an unusual sex preference (male:female=1:4). Majority of the tumors are asymptomatic and discovered incidentally on radiologic evaluation for other conditions. The tumors mostly show indolent clinical behavior, with only rare reports of local lymph node metastasis and very occasional case reports of sarcomatoid differentiation.79
Grossly, the tumor is usually well circumscribed, occasionally encapsulated, and often, although not always, centered in medulla. Tumor cut surface is gray-white to tan or yellow, and often glistening. Hemorrhage or necrosis is unusual, except in the very rare sarcomatoid areas.74–79 On microscopy, the tumor shows a combination of tubules, some with papillations, and spindle cell areas in varying proportions (Fig. 7). Tubules usually have slit-like luminal spaces, and often show branching.74–77 Some tubules may be small and more rounded. Spindle cell areas show low-grade cytology with nuclei similar to those lining the tubules. Presence of variable amounts of basophilic extracellular mucin is very common. Cells lining the tubules are cuboidal to low-columnar usually with scant cytoplasm and relatively uniform nuclei having inconspicuous nucleoli. Some uncommon morphologic features that may be present include, predominant spindle cell or epithelial components, very scant mucin, focal clear cell or eosinophilic cytology, foamy macrophages, multifocal papillary areas, or sarcomatoid/high-grade epithelial areas (Fig. 7).78,79 Tumors often contain inflammatory infiltrate in the background.
Immunohistochemistry is not very useful in distinguishing these tumors from type-1 PRCCs, both being positive for CK7 and racemase.80 However, CD10 is usually negative, or at the most focally positive in MTSCC, whereas it is usually more diffusely positive in PRCC. Genetic analysis may be more useful in more difficult cases. MTSCC may show losses of chromosomes 1, 4q, 6, 8p, 11q, 13, 14, and 15, and gains of 11q, 16q, 17, and 20q. Trisomies 7 and 17 are not a feature of MTSCC, whereas these are quite frequent in PRCC.81–84
ACQUIRED CYSTIC DISEASE-ASSOCIATED RENAL CELL
Acquired cystic disease (ACD)-associated RCC, a recently recognized entity, is the most common subtype of RCC occurring in end-stage kidneys, specifically those with acquired cystic disease.4,61,62 As many of these show variable proportion of papillary architecture (Fig. 8A), misinterpretation as PRCC was not, and even today may not be, uncommon. Thus, it is not surprising that PRCC was earlier believed to be most common RCC subtype in end-stage kidneys. ACD-associated RCC accounts for the dominant mass in 36% of end-stage kidneys overall and in 46% of end-stage kidneys with acquired cystic disease.61 It also is the most common tumor type among other, often multiple, small tumor nodules dispersed within end-stage kidneys. ACD-associated RCC is seen exclusively in end-stage kidneys with acquired cystic disease. Most cases are diagnosed incidentally on radiologic follow-up in patients with chronic renal disease.
Grossly, the tumors are usually found in kidneys that are frequently small, shrunken, and granular, and bearing numerous cysts. The tumors are often multifocal and bilateral.61 Most tumors are well circumscribed, many appearing to arise within cysts. Larger tumors may appear more solid, with thick fibrous capsule, often with foci of calcification.
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Microscopically, the tumors show acinar, solid alveolar, solid sheet-like, microcystic or macrocystic, and papillary architecture in various combinations and proportions (Figs. 8A, B). Intracytoplasmic and intercytoplasmic microscopic lumina (“holes”), imparting cribriform/sieve-like appearance, are characteristic (Fig. 8B). Presence of intratumoral oxalate crystals in most tumors is another characteristic feature (Fig. 8B).1,4,33,61 As a matter of fact, ACD-associated RCC is the only tumor type in end-stage kidneys that consistently displays intratumoral oxalate crystals.61 Tumor cells usually show abundant eosinophilic cytoplasm and large nuclei with prominent nucleoli. In our experience, this usual tumor cytology in cases with prominent papillary architecture has been the main reason for misinterpretation of these tumors as type-2 PRCC. In some tumors, foci with clear cytoplasm may also be present. Rare cases with sarcomatoid features have been reported, and such sarcomatoid tumors, as expected, may show aggressive clinical behavior.61,85
The background renal parenchyma shows numerous cysts, some of which appear multiloculated, and some occurring clustered. Cyst lining often resembles the cells of the tumor, showing abundant granular, pink cytoplasm, and prominent nucleoli. The lining may show focal proliferation, sometimes with papillary architecture. Other cysts may have cuboidal to low-columnar lining, with amphophilic or clear cytoplasm and small nuclei occasionally with papillary infoldings. Cysts lined by large eosinophilic cells show immunophenotype similar to ACD-associated RCC, whereas those lined by cuboidal cells stain similar to typical PRCC.61
By immunohistochemistry, the tumor cells are diffusely positive for AMACR, but negative or at the most focally positive for CK7. Stains for CD10, RCC, and glutathione-S-transferase-α are also reported to be positive.4,61 ACD-associated RCC lacks trisomies 7 and 17, or 3p losses. Gains of chromosomes 1, 2, 6, and 10 are reported in some cases. Thus, genetically these tumors are quite different from PRCC or clear cell RCC.86–88 A recent larger study using fluorescent in-situ hybridization and comparative genomic hybridization showed combined gains of multiple chromosomes, including chromosomes 3, 7, 16, and Y.88
Most tumors have nonaggressive biologic behavior, likely because most are incidentally detected on follow up for renal failure and are diagnosed at small size with low pT stage. Very few reported cases have shown aggressive features, including pT3 stage or sarcomatoid differentiation. Very rare deaths because of tumor are reported, that too only in those with sarcomatoid features and metastatic disease.61
RENAL CELL CARCINOMA, UNCLASSIFIED, WITH PROMINENT PAPILLARY ARCHITECTURE
Occasionally, tumors may have prominent papillary or tubulopapillary architecture, but show other morphologic and/or immunophenotypical features that do not fit any of the above-described diagnostic categories. Such tumors are best regarded as RCC, unclassified. It is likely that they might represent multiple as-yet-not-recognized specific tumor entities. At the same time, not “pushing” them into and keeping them separate from the above-detailed specific entities is prudent. It prevents the dilution of clinicopathologic features of these specific entities, and provides us with a pool of tumors from which new specific entities may be derived as we gain more knowledge and experience about these tumors.1,4
Other tumors that occasionally need separation from PRCC include metanephric adenomas with prominent papillary architecture and epithelial-predominant Wilms tumor. However, their overall morphologic, and to a great extent immunophenotypic, features are distinct in these entities, and molecular evaluation, if needed, should help in the distinction.
In summary, a number of renal tumors other than PRCC may show prominent papillary architecture. Careful evaluation of all the gross and microscopic features should prevent their misdiagnosis as PRCC in most cases. Immunohistochemistry, and rarely molecular genetics, may be required in some cases for this distinction.
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