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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e318299b7c6
Review Articles

Hereditary Syndromes With Associated Renal Neoplasia: A Practical Guide to Histologic Recognition in Renal Tumor Resection Specimens

Przybycin, Christopher G. MD; Magi-Galluzzi, Cristina MD, PhD; McKenney, Jesse K. MD

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Author Information

Department of Anatomic Pathology, Genitourinary Division, Robert J. Tomsich-Pathology and Laboratory Medicine Institute; and Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH

The authors have no funding or conflicts of interest to disclose.

Reprints: Jesse K. McKenney, MD, Department of Anatomic Pathology, Genitourinary Division, Robert Tomsich-Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Ave-L25, Cleveland, OH 44195 (e-mail: mckennj@ccf.org).All figures can be viewed online in color at http://www.anatomicpathology.com.

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Abstract

Many hereditary tumor syndromes are associated with neoplasms of the kidney. It is becoming increasingly well recognized that a given familial tumor syndrome may be very heterogenous in clinical appearance and that unrecognized patients may present initially for the treatment of a renal mass. It is therefore important for surgical pathologists to be aware of the specific gross and microscopic findings in the kidney that suggest a possible syndromic association. In this review, we detail the histologic features of syndromic-associated renal neoplasms, describe the presence of characteristic changes in the background renal parenchyma, and provide an update on associated extrarenal manifestations for each of the following syndromes: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma (RCC), hereditary leiomyomatosis-RCC, Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, germline succinate dehydrogenase mutation, hereditary nonpolyposis colorectal cancer syndrome, hyperparathyroidism-jaw tumor syndrome, PTEN hamartoma syndrome, constitutional chromosome 3 translocation, and familial nonsyndromic clear cell RCC. We also include a synopsis of renal medullary carcinoma because of its association with hereditary hemoglobinopathies.

Renal neoplasia is a common finding in patients with a genetic predisposition to cancer. As molecular diagnostic testing for these familial diseases has become more readily available, the heterogenous clinical appearance seen in many syndromes has become better recognized. Patients without overt clinical signs of their underlying syndrome may present initially for the treatment of a renal mass. Although many surgical specimens are received from patients who have a known syndrome diagnosis at the time of surgery, a pathologist may be the first physician to suggest the possibility of a syndromic association based on the presence of unique pathologic findings in a kidney resection specimen. In this review, we detail the pathologic features of renal neoplasms seen in a variety of hereditary/familial neoplasia syndromes. We specifically emphasize the gross and histologic features that are evaluated in routine renal tumor resection specimens that might suggest each individual syndrome. Although a detailed molecular genetic review is not presented, available confirmatory adjunctive studies of diagnostic importance are addressed. We also include a list of important extrarenal manifestations for each syndrome that might provide additional clues to a hereditary/familial neoplasia syndrome, and provide a final diagnostic commentary to highlight practical reporting or differential diagnostic issues that frequently arise when these diagnoses are considered.

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VON HIPPEL-LINDAU1–10 (Table 1)

Germline Genetic Alteration

Inactivating alterations in VHL tumor suppressor gene (3p25-26).2

TABLE 1
TABLE 1
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Background

The von Hippel-Lindau disease is an autosomal dominant heritable neoplasia syndrome that is characterized by multiple benign and malignant neoplasms that occur in a variety of organs including the kidney, eye, brain, spine, pancreas, and the adrenal gland. The constellation of neoplasms seen in von Hippel-Lindau disease was first described in the late 1800s, and multifocal renal cell carcinoma (RCC) is a hallmark feature seen in up to 65% of affected individuals.

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Renal Pathology

Grossly, the renal tumors associated with von Hippel-Lindau disease are bilateral, numerous, and often arise in a background of numerous renal cysts (Fig. 1A).4,7–9 These multiple renal tumors have histologic features that are typical of clear cell RCC (Fig. 1B), which is characterized by an alveolar arrangement of nested epithelial cells with clear cytoplasm surrounded by a delicate vascular network. Tubular or cystic areas may also be seen. The renal cysts are often lined by a flat layer of epithelial cells that have clear cytoplasm, but epithelial stratification, tufting, or early papillations may also line the cysts (Fig. 1C).4,8 In addition, small microscopic “tumorlets” of clear cell carcinoma are frequently present (Fig. 1D).

FIGURE 1
FIGURE 1
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Additional Diagnostic Comments

The renal cysts, particularly those with early papillations, may mimic clear cell-(tubulo)papillary RCC; however, the individual cysts in von Hippel-Lindau disease are separate and distinct, unlike the confluent multilocular masses typically seen with clear cell-(tubulo)papillary RCC. There is no consensus on diagnostic nomenclature for these individual cysts with epithelial hyperplasia or papillations, but we generally use a descriptive term such as “renal cyst with epithelial proliferation.” Others have used the term “renal epithelial cyst with atypia.” This diagnosis is followed by a comment describing the histologic features identified in the cyst and suggesting the possibility of early neoplastic transformation.

There are reported cases of multifocal, bilateral renal tumors with histologic features resembling sporadic clear cell-(tubulo)papillary RCC, and we have encountered multiple examples of similar cases that resemble von Hippel-Lindau disease based on the clinical setting.11 Sporadic clear cell-(tubulo)papillary RCC is characterized by a multilocular growth with cysts that are lined by clear cells.11–16 Variable numbers of papillary excrescences are present on the cyst surface and are comprised of similar neoplastic cells with clear cytoplasm. The stroma between the cysts often contains small tubules formed by clear cells. Both the tubules and papillae may be lined by clear epithelial cells with luminal orientation of their nuclei (ie, reverse polarity or “piano key” appearance). More solid areas that closely resemble conventional clear cell carcinoma and more predominant papillary growth mimicking papillary RCC may also be seen.

Whether or not these cases represent von Hippel-Lindau disease (or another distinct hereditary syndrome) is somewhat controversial and represents a topic of current study by several groups. Sporadic clear cell-(tubulo)papillary RCCs are thought to be distinct from clear cell RCC and, to date, have lacked a chromosome 3 abnormality.15,17 More recently, Williamson et al18 studied tumors resembling clear cell-(tubulo)papillary RCC in patients with clinical features of von Hippel-Lindau syndrome and found chromosome 3p deletions in 82%. Additionally in these cases, the typical immunoprofile of sporadic clear cell-(tubulo)papillary RCC, such as diffuse cytokeratin 7 reactivity, was not present. Additional studies are needed to evaluate renal tumors with histologic features resembling clear cell-(tubulo)papillary RCC in this clinicopathologic setting to address their association with any germline alterations.

If the constellation of renal findings strongly suggests von Hippel-Lindau disease, then we search our digital medical records for potential syndromic associations and contact the urologist to discuss the possibility of a genetic syndrome. For reporting purposes, we diagnose the renal neoplasms and cysts with the same criteria and terminology used for sporadic clear cell RCC. We include a comment to document the possibility of the specific genetic association.

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HEREDITARY PAPILLARY RCC19–31 (Table 2)

Germline Genetic Alteration

Activating mutation in MET protooncogene (7q31).

TABLE 2
TABLE 2
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Background

A family with a predisposition to developing multiple, bilateral papillary RCCs was described in 1994 by Zbar et al.29 The same group subsequently described a series of 10 separate families,28 and later identified that mutations in the MET protooncogene were responsible for the disease.24,27 Hereditary papillary RCC is now well accepted as a specific class of inherited renal cancer with an autosomal dominant pattern of inheritance and incomplete penetrance.

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Renal Pathology

Affected patients typically have numerous bilateral macroscopic tumors that may number in the 100s. Histologically, the tumors are indistinguishable from otherwise typical sporadic type 1 papillary RCCs.22,32 They are characterized by a large cystic space that has a thick fibrous capsule with neoplastic cells lining the inner surface (Fig. 2A). The cystic space defined by the capsule may be completely filled by tumor papillae (Fig. 2B) or may have a loose papillary architecture with abundant empty space. Other papillary architectural patterns may include solid (Fig. 2C), glomeruloid, and trabecular. The cells lining the individual papillae typically have a low cuboidal epithelium and are nucleolar grade 1 and 2 (Fig. 2D). Associated intratumoral calcifications and foamy histiocytes are also frequently identified. The background kidney commonly contains innumerable microscopic foci of papillary renal neoplasia that individually are identical to sporadic renal papillary adenomas.19

FIGURE 2
FIGURE 2
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Additional Diagnostic Comments

Because these germline MET mutation-associated RCCs are histologically indistinguishable from sporadic type 1 papillary RCCs, the syndrome may only be suspected based on the presence of a large number of separate tumors and/or a known family history of renal neoplasia.

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HEREDITARY LEIOMYOMATOSIS-RENAL CELL CARCINOMA (HLRCC)33–44 (Table 3)

Germline Genetic Alteration

Activating mutation in FH gene, which encodes the enzyme fumarate hydratase.

TABLE 3
TABLE 3
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Background

In 2001, an autosomal dominant syndrome that was characterized by cutaneous and uterine leiomyomas was reported to have an association with RCC.40 The multiple cutaneous (and later uterine) leiomyoma syndrome had been well described since the 1950s, but this report described the novel association with renal neoplasia and mapped the affected gene to chromosome 1q42.3-q43. It was subsequently discovered that the predisposing gene coded for the enzyme fumarate hydratase.41

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Renal Pathology

Most hereditary syndromes with neoplastic manifestations in the kidney are associated with multiple renal neoplasms. In contrast, HLRCC syndrome has a much lower penetrance of RCC (20% to 30%) and, when RCC is present, it is typically unilateral and solitary. These tumors frequently present at high stage with perinephric and/or venous invasion. The individual RCCs most commonly have a histologic appearance that, at least focally, resembles type 2 papillary RCC due to tall neoplastic cells containing abundant eosinophilic cytoplasm lining the papillae. The main low-power architectural patterns include papillary, tubulopapillary, tubular, and solid (Figs. 3A, B). Cysts, focal clear cell areas, and cribriforming may also be present (Figs. 3C, D). The combination of these different architectural patterns in any given case could also elicit a differential diagnosis that includes collecting duct carcinoma or tubulocystic carcinoma.

FIGURE 3
FIGURE 3
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The most important histologic finding that is distinctive and may provide the first clue to diagnosing the syndrome is a cytologic feature: enlarged nuclei, each with a very prominent orangeophilic or eosinophilic nucleolus surrounded by a clear halo, which imparts a “viropathic-like” appearance to the neoplastic cells (Figs. 3E, F). Cysts lined by similar-appearing eosinophilic epithelial cells are described in the background kidney and may potentially represent the precursor lesion.43

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Additional Diagnostic Comments

When the cytologic features of a RCC suggest the possibility of HLRCC, we search our digital medical records for potential syndromic associations and contact the urologist to discuss the possibility of a genetic syndrome. For routine reporting purposes, such tumors are generally subtyped as either as type 2 papillary or unclassified based on the presence or absence of well-developed papillary features. We include a comment to document the possibility of the specific genetic association. The exact specificity of these unusual cytologic changes for the HLRCC syndrome is not entirely known; however, we have anecdotally identified HLRCC cases based on the histologic features alone that were not suspected clinically. The Memorial Sloan-Kettering group has recently reported their experience with 8 patients who were clinically unsuspected of having any syndromic association at the time of surgery, but were subsequently diagnosed with HLRCC following a pathologic evaluation of an RCC that suggested the diagnosis.42

Recently, it has been suggested that utilization of immunohistochemistry for the detection of covalent modification of cysteine residues to S-(2-succinyl) cysteine (2SC) could potentially serve as a surrogate for the fumarate hydratase mutation.33 Bardella and colleagues reported that loss of fumarate hydratase function leads to high levels of protein succination within the cytoplasm of affected cells, which could be detected by immunohistochemistry using a previously described anti-2SC antibody.33,45 In a prospective evaluation of cases referred for genetic testing for HLRCC, the presence of 2SC-modified proteins (2SCP) by immunohistochemistry correctly predicted genetic alterations in FH in all cases tested. As recently reported in abstract form, the utility of this antibody has been validated by another group using the uterine smooth muscle tumors of HLRCC.46 In cases that are histologically suspicious for HLRCC, more routine utilization of the anti-2SC antibody as a screening test for fumarate hydratase mutation may increase with publication of additional validation studies.

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BIRT-HOGG-DUBÉ47–55 (Table 4)

Germline Genetic Alteration

Mutation in BHD gene, which encodes for folliculin.

TABLE 4
TABLE 4
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Background

In 1977, Birt, Hogg, and Dubé described a kindred with familial occurrence of multiple skin lesions comprised of fibrofolliculoma, trichodiscoma, and acrochordons; in addition, a few family members also had medullary thyroid carcinoma.47 More families with this genetic syndrome were subsequently described and other associations, such as spontaneous pneumothorax and intestinal polyposis, were noted. In 1993, Roth and colleagues first described the association with renal neoplasia, and other groups have confirmed this association.48,52 In 2001, the Birt-Hogg-Dubé gene locus was mapped to 17p11.2,51 and subsequently the gene product, folliculin, was identified.50

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Renal Pathology

Patients with Birt-Hogg-Dubé syndrome often have multiple bilateral renal tumors. Multiple subtypes of renal neoplasia have been reported in these patients as described in detail by Pavlovich et al.49 Most of these tumors are in the low-risk oncocytic renal neoplasia spectrum that includes chromophobe RCC, oncocytoma, and hybrid oncocytic tumors; however, clear cell and papillary RCCs are also reported. These patients also commonly have renal oncocytosis in the background renal parenchyma. Renal oncocytosis is characterized by a spectrum of oncocytic changes that diffusely involve the kidney and may include a dominant oncocytic neoplasm, smaller oncocytic nodules, infiltrative appearing oncocytic cells, cortical cysts lined by oncocytic cells, and oncocytic change in non-neoplastic tubules. Some other histologic features have been noted that seem to be unique to this syndrome, but their true specificity is not entirely known. The most common feature, which is seen within the spectrum of low-grade oncocytic renal neoplasms (typically described as “hybrid renal oncocytic tumor”), is the presence of individual tumor cells with cytoplasmic clearing but no prominent nuclear membrane irregularity (Fig. 4A). Although not well described, we have also anecdotally seen nodules of similar clear cells arising within hybrid oncocytic neoplasms in patients with Birt-Hogg-Dubé syndrome (Figs. 4B, C).

FIGURE 4
FIGURE 4
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Additional Diagnostic Comments

When the conglomerate of renal findings is suggestive of Birt-Hogg-Dubé syndrome, we again search our digital medical records for potential syndromic associations and contact the urologist to discuss the possibility of Birt-Hogg-Dubé. It should be noted that a subset of patients with germline mutations in the BHD gene do not have the typical skin findings (approximately 10%).54,55 For routine reporting purposes, we diagnose the tumors using criteria for sporadic RCC and include a comment to document the possibility of a specific genetic association. These tumors are typically diagnosed as chromophobe RCC, oncocytic renal neoplasm of low malignant potential, hybrid oncocytic tumor, or oncocytoma with or without oncocytosis based on the histologic features present in a given case.

The possibility of a hereditary renal oncocytoma syndrome that is not related to Birt-Hogg-Dubé has been suggested,56 but there are little data available at present.

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TUBEROUS SCLEROSIS COMPLEX57–73 (Table 5)

Germline Genetic Alteration

Inactivating mutations in the tumor suppressor genes TSC1 or TSC2, which encode the proteins hamartin and tuberin, respectively.

TABLE 5
TABLE 5
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Background

The description of tuberous sclerosis complex as a combination of symptoms/findings that most commonly includes epilepsy, intellectual disability, and behavioral problems in association with numerous varied tumor-like lesions has gradually evolved through numerous case reports and series since the time of the first recognized depiction in 1835.57–59 The penetrance of tuberous sclerosis is high, but the spectrum of clinical and pathologic findings is extremely variable.60 The brain, kidneys, skin, lungs, and the heart frequently have tumor-like lesions, but almost any organ may occasionally be involved. The associated intellectual disabilities are also extremely variable as up to half of patients have a normal intellectual capacity. Interestingly, although tuberous sclerosis is inherited as an autosomal dominant trait, 60% to 70% of cases are sporadic (ie, a new germline mutation).61,62 Therefore, an absence of family history does not exclude a diagnosis of the disease. The 2 tumor suppressor genes that are responsible for the syndrome complex have been identified at 9q34 (TSC1)63 and 16p13.3 (TSC2).64 These genes encode the proteins hamartin and tuberin, respectively.

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Renal Pathology

Patients with tuberous sclerosis may have 3 types of bilateral renal lesions: multiple angiomyolipomas, numerous renal cysts, and, less frequently, RCC. Most patients have multiple bilateral renal angiomyolipomas. These angiomyolipomas may have any of the variant histologies that are described (Figs. 5A–F): classic/“triphasic,” lipid rich/lipoma-like, sclerosing,74 monophasic/smooth muscle-like, associated with epithelial cysts,75,76 and epithelioid features with and without atypia.77–81 It has been suggested that the combination of angiomyolipomas with epithelioid features, associated epithelial cysts, and microscopic “tumorlets” (Fig. 5I) strongly suggest the diagnosis of tuberous sclerosis.77

FIGURE 5
FIGURE 5
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Multiple, bilateral renal cysts are also common and are lined by large atypical epithelial cells with prominent eosinophilic cytoplasm (Figs. 5G, H). RCC is less common than angiomyolipomas and cysts, but it is also reported in association with tuberous sclerosis.66–70,82–84 The overall incidence of RCC reportedly approximates that of the general population, but it occurs at a much younger age (average: 28 y).73 Data on tuberous sclerosis–associated RCC are relatively limited. Most information is based on case reports without detailed histologic descriptions or images. Moreover, the literature is complicated by reports of RCC in which the provided images show histologic features that strongly suggest the diagnosis of epithelioid angiomyolipoma. The true RCCs may be multiple and are most commonly reported as clear cell subtype (Fig. 5J). Merino and colleagues have suggested that smooth muscle proliferation associated with clear cell RCC, which has been reported under various diagnostic terms,85–88 may be a marker of tuberous sclerosis.89 Other renal tumors that have been documented include papillary RCC, chromophobe RCC (Fig. 5K), and renal oncocytoma. Cystic eosinophilic renal neoplasms with pleomorphic nuclei and variable architectural growth patterns were recently reported and seem similar to some other descriptions of tuberous sclerosis–associated RCC in the literature.67 Schreiner et al suggest that this morphologic pattern may represent a distinctive subtype of RCC in tuberous sclerosis, and we have encountered several similar examples of these cystic and eosinophilic RCCs in patients with tuberous sclerosis (Figs. 5L–O).

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Additional Diagnostic Comments

In the setting of tuberous sclerosis, one must always consider angiomyolipoma as a leading differential diagnostic consideration to avoid misinterpretation as RCC.66,81 Epithelioid angiomyolipomas, particularly those with atypia, may very closely mimic an unclassified or clear cell RCC. At least a subset of the published cases of tuberous sclerosis–associated RCC in the literature represent monotypic epithelioid angiomyolipoma, which suggests that the real risk of RCC in tuberous sclerosis may be inflated.66 One should have a high index of suspicion for epithelioid angiomyolipoma when an unusual clear-to-eosinophilic renal neoplasm is encountered. The typical immunohistochemical markers used for all perivascular epithelioid cell family tumors (PEComas) such as angiomyolipoma (ie, actin, HMB45, MiTF, and melan-A) may show only focal and/or weak immunoreactivity in the neoplastic cells. In our experience, PAX-8 immunohistochemistry is very useful in this distinction as it typically shows diffuse nuclear immunoreactivity in RCC, but not in epithelioid angiomyolipoma. Lipid rich angiomyolipomas may closely mimic an adipocytic neoplasm. Careful attention to the intratumoral blood vessels typically reveals a preserved population of more typical, less lipid-rich neoplastic cells within the vessel wall (Fig. 5C). Smooth muscle tumors should be diagnosed with great caution in this setting, as a monophasic smooth muscle-like angiomyolipoma is a more likely diagnosis. Finally, in tuberous sclerosis patients, it is not uncommon to identify angiomyolipoma (lymphangioleiomyomatosis) within lymph nodes adjacent to the kidney (Figs. 5, 6), a finding which should not be regarded as evidence of malignancy.

FIGURE 6
FIGURE 6
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With regard to recognizing the possibility of tuberous sclerosis based on the renal findings, the presence of multiple angiomyolipomas should strongly suggest the diagnosis especially if epithelioid features, associated epithelial cysts, and microscopic “tumorlets” are present. More studies are needed to address the specificity of unusual histologic patterns of RCC for tuberous sclerosis complex (eg, the eosinophilic and cystic features).67 It should be emphasized that tuberous sclerosis is phenotypically heterogeneous and, as up to 70% of patients may have new germline mutations, the complex may be underrecognized clinically.

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GERMLINE SUCCINATE DEHYDROGENASE (SDH) MUTATION90–96 (Table 6)

Germline Genetic Alteration

Mutations in genes that encode the Krebs cycle enzymes: SDHB, SDHC, and SDHD.

TABLE 6
TABLE 6
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Background

Renal neoplasms have been reported in association with different SDH mutations. The most common mutation, SDHB, is also associated with hereditary paraganglioma-pheochromocytoma syndrome. Additional mutations in SDHB, SDHC, and SDHD have been associated with various combinations of RCC,92–94 a unique type of gastrointestinal stromal tumor (GIST) that has been reported as SDH mutant (or “pediatric-type”) GIST,91,97,98 and paraganglioma/pheochromocytoma.90,99

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Renal Pathology
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SDHB92

The majority of RCCs reported in association with SDH mutation have involved SDHB. These well-circumscribed tumors are typically arranged into solid nests or tubules, and cystic change is common (Fig. 6A). They are comprised of cuboidal neoplastic cells with granular eosinophilic cytoplasm, centrally placed nucleoli, and inconspicuous nucleoli (Fig. 6B). In at least focal areas, the cytoplasm of the neoplastic cells has a distinctive feature, either a pale eosinophilic cytoplasmic inclusion that resembles fluid (Figs. 6B, C) or bubbly intracytoplasmic vacuolization with only remnants of delicate, wispy eosinophilic material (Fig. 6D). Normal renal tubules are often found entrapped within the RCC. Rare cases may have higher grade histologic features that are not distinctive.

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SDHC

Renal neoplasms associated with a germline SDHC mutation appear to be extraordinarily rare. The reported cases, which are mostly from a single family, have been classified as clear cell RCC, and they typically are of low nuclear grade (nucleolar grades 1 and 2).94,95

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SDHD

SDHD-associated renal neoplasms are also very rare, and have been reported as clear cell RCC.94

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Additional Diagnostic Comments

When the histologic features of an RCC suggest the possibility of an SDH mutation, we search our digital medical records for potential syndromic associations and contact the urologist to discuss the possibility of a genetic syndrome. We also perform immunohistochemistry for SDHB, which should show loss of staining in a mutation-associated neoplasm (Fig. 6E).90,92 For routine reporting purposes, if the immunohistochemistry supports SDH alteration, we generally diagnose the tumors as “RCC with features suggesting SDHB mutation” and include a descriptive comment to document the unusual histologic features and immunohistochemistry.

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LYNCH SYNDROME (LS) (Table 7)

Germline Genetic Alteration

Germline mutation in mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM).

TABLE 7
TABLE 7
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Background

LS, or hereditary nonpolyposis colorectal cancer, is an autosomal dominant cancer susceptibility syndrome that results from mutations in genes known to be associated with the DNA mismatch repair pathway, and is detectable as high-frequency microsatellite instability (MSI-H).100,101 The syndrome is most often associated with colonic or endometrial adenocarcinoma; however, tumors in other anatomic sites are described and more commonly include the skin, stomach, and the small bowel. More relevant to this review, there is also an association with urothelial carcinoma, particularly in the upper urinary tract (ie, renal pelvis and ureter).

Patients with LS-associated urothelial cancer often present 10 to 15 years younger than their sporadic counterparts, and generally lack typical risk factors. In patients with LS, the cumulative risk of upper tract urothelial carcinoma ranges up to 6% (22 times higher than the general population).102 This risk seems to be highest for MSH2 mutation carriers.103–105

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Renal (Pelvic) Pathology

Few studies have evaluated the morphologic features of MSI-H urothelial carcinomas of the upper urinary tract. Hartmann et al106 have reported that an inverted/endophytic histologic growth pattern (Fig. 7) in upper tract urothelial carcinomas predicted MSI-H with a sensitivity and specificity of 0.82. In a consecutive series of upper tract urothelial cancers, 31.3% had MSI-H, and these patients were more likely to have both a personal and family history of colorectal carcinoma, as compared to microsatellite stable carcinomas.107

FIGURE 7
FIGURE 7
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Additional Diagnostic Comments

Many carcinomas, such as colorectal and endometrial, are now routinely tested for mismatch repair function as an initial screen for LS. This is accomplished either by microsatellite instability analysis by polymerase chain reaction–based methods or mismatch repair protein expression by immunohistochemistry. Although it has not yet become standard practice, there is some evidence that assessing mismatch repair function may have utility in screening urothelial carcinomas of the ureter and renal pelvis. At present, testing is probably best reserved for upper tract urothelial carcinoma in young patients or those with a personal/family history of Lynch-related cancers; however, this practice could potentially evolve in the near future.

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HEREDITABLE SICKLE CELL HEMOGLOBINOPATHY AND MEDULLARY CARCINOMA OF THE KIDNEY108–119 (Table 8)

Germline Genetic Alteration

Germline point mutation, a single-nucleotide polymorphism, in the β-globin gene on chromosome 11 (most commonly resulting in HbAS, but HbSS and HbSC also reported).

TABLE 8
TABLE 8
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Background

Renal medullary carcinoma was described in 1995 by Davis and colleagues in a series of publications describing the pathologic, radiographic, and clinical features of the neoplasm.108,110,111 Since the time of the original description, several other series have confirmed the pathologic features of the tumor and its association with sickle cell hemoglobinopathy.108,109,112–119 Most reported cases are high stage at presentation and follow an aggressive clinical course with a mean survival of <6 months.

Renal medullary carcinoma has been termed the “7th sickle cell nephropathy,” as it is seen almost exclusively in young patients with sickle cell trait (most commonly of African descent, but rarely Mediterranean)111; however, rare cases have been associated with sickle cell disease (HbSS) or HbSC disease. The typical age range is between 5 and 39 years with presentation most commonly the third decade, but rare cases are identified in older adult patients. Hereditary sickle cell hemoglobinopathy is not necessarily a tumor predisposition syndrome and only a very rare subset of patients will develop this neoplasm; however, we include medullary carcinoma in this review because of its definitional association with the disease. It is hypothesized that the genetic mutation is not tumor inducing from a molecular genetic level, but rather because of red blood cell sickling and resultant ischemic damage in the renal medulla. It is our personal experience that an unrecognized hereditary hemoglobinopathy may be uncovered as a result of considering the diagnosis of medullary carcinoma.

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Renal Pathology

Medullary carcinomas have a destructive pattern of invasive growth that permeates normal renal structures and may be associated with a desmoplastic response or densely fibrotic stroma, which is unlike most other RCCs (except collecting duct carcinoma). The cytologic features are typically high grade and the cytoplasm is frequently densely eosinophilic. Separate satellite tumor nodules and extensive lymphovascular invasion are a frequent finding. The described architectural growth patterns are heterogeneous and include reticular/cribriforming, gland forming/tubules, cord-like growth, syncytial/solid, microcystic, and rhabdoid (Fig. 8). Other rare patterns include papillary and spindled. The presence of a predominant reticular pattern may mimic yolk sac tumor. Intracytoplasmic mucin is not uncommon. Intratumoral inflammatory infiltrates rich in neutrophils are also common, and microabscesses may be present. These carcinomas prototypically lose expression of nuclear SMARCB1/INI-1 protein by immunohistochemistry.109,120 The identification of sickled cells in adjacent blood vessels is reported as a corroborative finding for medullary carcinoma; however, red cell sickling may sometimes be difficult to assess confidently in routine formalin-processed, hematoxylin and eosin–stained tissue sections.

FIGURE 8
FIGURE 8
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Additional Diagnostic Comments

There may be substantial morphologic overlap between renal collecting duct carcinoma and renal medullary carcinoma. In fact, some authors regard medullary carcinoma as a subtype of collecting duct carcinoma. For practical purposes, the young patient age in medullary carcinoma (typically 10 to 30 y of age) and the presence of an associated sickle cell hemoglobinopathy are utilized in the distinction from collecting duct carcinoma. Loss of SMARCB1/INI-1 protein by immunohistochemistry has been reported in 15% of collecting duct carcinomas, so this may not be a useful distinguishing feature.121 The significant immunophenotypic overlap with collecting duct carcinoma with most markers tested is well recognized, so distinction based on the clinical setting is probably a more useful approach.

Malignant rhabdoid tumor of kidney may also cause a differential diagnostic challenge as it is also characterized by a loss of INI-1 expression and shows rhabdoid morphology.122,123 Patients with malignant rhabdoid tumor are typically much younger (mean: 11 mo vs. 15 to 30 y in medullary carcinoma); however, older patients may rarely be diagnosed with malignant rhabdoid tumor. Histologically, malignant rhabdoid tumor of kidney does not show the degree of morphologic heterogeneity with true glandular differentiation that is seen with medullary carcinoma; however, trabecular and pseudoglandular patterns are described.124,125 In our experience, PAX-8 expression would support medullary carcinoma; however, this is not fully evaluated and varying sensitivities with anti-PAX antibodies are reported among studies of medullary carcinoma.

The possibility of a metastatic or primary germ cell tumor such as embryonal carcinoma or yolk sac tumor might also be considered, which presents the potential for a major diagnostic error as renal medullary carcinoma commonly expresses the nuclear germ cell marker OCT3/4.126 PAX-8 is also expressed in a subset of yolk sac tumors, which presents another immunophenotypic pitfall.127 Other more recently described pan-germ cell markers, such as SALL4, have not been evaluated in renal medullary carcinoma. INI-1 expression should be retained in germ cell tumors.

Invasive urothelial carcinomas with either poorly differentiated features or glandular differentiation may also closely mimic medullary carcinoma. Again, the typical age range of medullary carcinoma is significantly younger than for urothelial carcinoma, which occurs in older adults. Immunophenotypically, urothelial carcinoma commonly expresses p63 and the urothelial marker GATA-3, but up to 25% of upper tract urothelial carcinomas may show nuclear PAX-8 expression. In older patients, the presence of a luminal component of papillary urothelial neoplasia or urothelial carcinoma in situ would support urothelial origin.

Another interesting development is the recognition of VCL-ALK translocations in a subset of renal neoplasms occurring in patients with sickle cell trait. There are 2 separate reports of VCL-ALK translocation-associated renal neoplasms with an identical morphology that differs somewhat from typical medullary carcinoma.128,129 They are characterized by a sheet-like growth of polygonal to spindled neoplastic cells with abundant vaguely granular eosinophilic cytoplasm. The nuclei are reported as vesicular with prominent small nucleoli, and distinct intracytoplasmic lumina are found. The associated inflammatory infiltrate is reported as lymphocytic. The available data are very limited at present, but several findings suggest the possibility that the VCL-ALK translocation renal neoplasms are a distinct entity representing a second hemoglobinopathy-related renal tumor: (1) the more histologically conventional renal medullary carcinomas tested have been negative for this translocation; (2) the tumors seem to have retained nuclear INI-1 expression by immunohistochemistry; (3) the morphologic findings are somewhat distinct including the absence of glandular differentiation; and (4) the limited follow-up data available suggest that the VCL-ALK tumors have a better clinical outcome than typical medullary carcinoma. Further study is needed to fully understand the relationship of VCL-ALK translocation-associated renal neoplasms to conventional medullary carcinoma.

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HYPERPARATHYROIDISM-JAW TUMOR SYNDROME130–148 (Table 9)

Germline Genetic Alteration

Germline mutation of HRPT2, which encodes parafibromin.

TABLE 9
TABLE 9
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Background

Hereditary hyperparathyroidism-jaw tumor syndrome is a recently described autosomal dominant disorder characterized by parathyroid neoplasms (adenoma or carcinoma) with associated hyperparathyroidism, fibroosseous lesions of the mandible and maxilla, renal cysts, and renal neoplasms.130 Patients typically present with hyperparathyroidism that often develops in adolescence, and hypercalcemic crisis may occur. There is reduced penetrance in females. The tumor suppressor gene responsible for the disorder, HRPT2, was localized to 11q21-q32145,147 and codes for the protein parafibromin.142

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Renal Pathology

Renal neoplasms and cysts have been reported in a subset of families with hereditary hyperparathyroidism-jaw tumor syndrome; however, the pathologic features of these renal lesions have not been comprehensively studied. Reportedly, cysts may be numerous and may produce a clinical appearance of “polycystic kidney disease.” Three different types of renal neoplasms have been reported in the literature. The most commonly reported neoplasm has histologic features of what would currently be classified as mixed epithelial and stromal tumor. Others have described adult Wilms tumor and papillary RCC. Additional studies are needed to further delineate the specific types of renal neoplasia associated with this syndrome.

The utility of immunostains for parafibromin in the identification of syndrome-associated parathyroid neoplasms has been reported136; however, to our knowledge, this has not been studied in the associated renal tumors.

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Additional Diagnostic Comments

This syndrome would likely be suspected only by the constellation of nonrenal manifestations.

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PTEN HAMARTOMA TUMOR SYNDROME149,150 (Table 10)

Germline Genetic Alteration

Germline mutations in the PTEN tumor suppressor gene at 10q23.

TABLE 10
TABLE 10
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Background

This syndrome has a broad clinical spectrum and includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome.150 Although the main cancer associations are breast and thyroid carcinoma, patients with germline mutations in PTEN have a 31-fold increased risk of developing RCC.149

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Renal Pathology

The renal tumors associated with this syndrome were not well characterized until recently. In 1 series of patients with PTEN Hamartoma Syndrome and renal neoplasia, most renal tumors were classified as papillary RCC (75%) including both type I and type II, but a subset of patients had chromophobe RCC (25%).149 There are no specific histologic features to aid in the identification of renal neoplasia associated with a PTEN mutation; however, PTEN protein is characteristically lost in the neoplastic cells by immunohistochemical evaluation.149

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Additional Diagnostic Comments

Germline PTEN mutation-associated RCC can only be recognized by the clinical constellation of findings. We do not routinely screen RCCs by PTEN immunohistochemistry.

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CONSTITUTIONAL CHROMOSOME 3 TRANSLOCATION151–160 (Table 11)

Germline Genetic Alteration

Balanced translocations involving chromosome 3 (with varying breakpoints and partners).

TABLE 11
TABLE 11
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Background

This rare syndrome was originally reported in 1979, but a number of families with this disorder have now been reported. The RCCs are often bilateral and multifocal, but the age of onset is older than in von Hippel-Lindau syndrome.

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Renal Pathology

The renal neoplasms have a clear cell morphology that is indistinguishable from sporadic clear cell RCC.

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Additional Diagnostic Comments

Constitutional chromosome 3 translocation is typically suspected only by the number of clear cell RCCs present and the family history.

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FAMILIAL NONSYNDROMIC CLEAR CELL RCC161 (Table 12)

Germline Genetic Alteration

Unknown.

TABLE 12
TABLE 12
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Background

By definition, the diagnosis of familial nonsyndromic clear cell RCC depends entirely on the exclusion of both von Hippel-Lindau disease and a constitutional chromosome 3 translocation. Whether or not these clear cell carcinomas are a heterogeneous group of unrelated causes or a single genetic cause remains to be shown.

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Renal Pathology

The renal neoplasms have a clear cell morphology that is indistinguishable from sporadic conventional clear cell RCC.

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Additional Diagnostic Comments

A clear cell RCC syndrome is typically suspected by the number of clear cell RCCs present and the family history. Exclusion of von Hippel-Lindau disease and a constitutional chromosome 3 translocation by molecular and cytogenetic testing is required.

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ACKNOWLEDGMENT

The authors are indebted to Dr. Anthony J. Gill (Department of Anatomical Pathology, Royal North Shore Hospital and University of Sydney) for allowing us to study and photograph several examples of SDHB mutation-associated renal cell carcinomas.

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Keywords:

renal cell carcinoma; hereditary; familial; von Hippel-Lindau; tuberous sclerosis; SDH; leiomyomatosis; Birt-Hogg-Dubé

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