REVIEW Kidney Tumors Associated With Hereditary Cancer Syndromes: An Emerging Opportunity and Responsibility in Surgical Pathology Mark Cameron Mochel, MD* and Steven Christopher Smith, MD, PhD*† Abstract: Recent years have seen a proliferation of new entities in renal neoplasia, especially renal cell carcinoma. In particular, several of these entities frequently present as part of hereditary cancer predisposition syndromes and have been variably classified based on associated syndromal names and features, eponyms, or based on the causative genetic or biochemical defect. Overall, we would argue that assisting in recognition of any hereditary cancer predisposition, however aggressive or however penetrant, is an opportunity for distinct and growing added value in contemporary pathology. In several cases, the kidney tumors or their associated syndromal stigmata are aggressive or may trigger ongoing surveillance or specific interventions for affected patients and family members. Prior experience with these tumors has led us to realize that we are frequently evaluating specimens with limited clinical context, let alone sufficient family history. The most subtle clues, whether from the gross room, the histomorphology, the laboratory information system, or the medical record, have proven essential in the recognition of these tumors. Highlighting close clinicopathologic correlation, as well as collaboration between subspecialty areas in surgical pathology, these contextual clues to several syndromal kidney tumors form the basis of a growing opportunity and responsibility in surgical pathology. Key Words: hereditary cancer syndromes, kidney tumors, surgical pathology (AJSP: Reviews & Reports 2017;22: 313–328) T umors of the kidney and renal pelvis remain a significant public health problem, with approximately 61,000 new cases and approximately 14,000 deaths estimated in the United States in 2015.1 While infrequent primary mesenchymal malignancies exist, the majority of these tumors are renal cell carcinoma (RCC) and urothelial carcinoma (UC). Earlier classifications of kidney tumors focused on cytologic features (clear cell versus granular, as delineated in the second series AFIP Fascicle,2 or based on cytology [and secondarily architecture]) with microanatomic correlation, such as in the Mainz Classification, with analogy to renal tubular cell of origin.3 However, contemporary classifications, beginning with the Heidelberg-Rochester Classifications,4,5 can be viewed as creating categories of tumors with characteristic histomorphologic features and distinct criteria that meaningfully correlate with immunophenotypic, molecular, and prognostic differences. Thus, a vital role for the surgical pathologist consists of From the *Department of Pathology and † Division of Urology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA. Reprints: Steven Christopher Smith, MD, PhD, Surgical Pathology, Virginia Commonwealth University School of Medicine, 1200 E Marshall St, Gateway 6-205, PO Box 980622, Richmond, VA 23298. E‐mail: firstname.lastname@example.org. The authors have no funding or conflicts to declare. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 2381-5949 DOI: 10.1097/PCR.0000000000000220 appropriate classification and grading of RCC based on contemporary consensus recommendations, thereby setting the stage for further prognostic and therapeutic refinement. The recent developments in the study and classification of syndromic RCC, arriving in tandem with molecular genetic technology around the turn of the millennium, offer a new dimension to the services to patients rendered by the surgical pathologist. Not only does identification of a kidney tumor characteristic, or even essentially pathognomonic, of an inherited cancer syndrome classify, stage, and prognosticate for the patient at issue, but also a potentially life-changing service can be rendered to family members by suspicion, workup, and recognition of a syndrome. Thus, introduced in the 2004 World Health Organization (WHO) Classification6 as a group of diseases termed “familial renal cell carcinoma” and emphasized significantly with multiple individual entities in the 2016 WHO Classification,7 a new group of distinctive RCCs characteristic to heritable cancer predisposition syndromes has been defined. These entities join RCCs of established morphologies that infrequently occur as part of multiorgan heritable syndromes (eg, clear cell RCC [CCRCC] and von Hippel-Lindau [VHL] syndrome). Hereditary RCCs have been defined classically by the incidence of a given tumor type (or characteristic spectrum of tumor types), usually in multiple close relatives, that is inheritable through germline mutation.8 As the authors of the 2004 WHO monograph observed, such cases often demonstrate onset of bilateral and/or multifocal tumors at a young age.6 However, this classic presentation represents an oversimplification and neglects increasingly appreciated aggressive types of hereditary RCC, for which questions of penetrance and bilaterality are more complex. Indeed, other distinguishing clinical features aside, a recent statistical model has yielded the recommendation that any patient 46 years or younger diagnosed as having RCC should be referred for genetic counseling.9 For comprehensive descriptions of the expanding spectrum of hereditary RCC, we recommend several recent, excellent reviews.10–12 Instead, herein, we provide a targeted review of cases, organizing them conceptually by types of distinctive features, whether evident by gross examination, studies from the clinical laboratory, distinctive histomorphology, or from careful review of the medical record, which provide the opportunity for their recognition. However, in terms of responsibility, we emphasize that generally genetic testing is the standard of care and criterion standard for diagnosis, such that syndromal labels should be rigorously avoided in clinical practice until diagnosis is secured unequivocally. Analogously to the diagnostic workup of Lynch syndrome in colorectal adenocarcinoma,13 our histologic and immunohistochemical findings should be regarded as a means for triage for definitive workup. Yet, contemporary technologies, ranging from increasingly pervasive contemporary high-throughput (“next-generation”) sequencing to the electronic laboratory information and medical record systems, coupled with state-of-the-art histopathology and immunohistochemistry (IHC), have put the AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 www.pathologycasereviews.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 313 AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Mochel and Smith surgical pathologist at the frontlines of recognition of these tumors. We note that ample evidence supports the contention that these syndromal cases also remain underrecognized by clinician colleagues.14 While many published series of these tumors weigh heavily on international collaborations and experience from expert consult series, recently available data document the relative prevalence of these tumors in consecutive series and even support the importance of the role of pathologic review. For example, Stratton et al15 have reported a consecutive series of 120 patients with kidney cancer referred for genetics at the Memorial Sloan Kettering Cancer Center. Of 95 patients who underwent testing, 28% were positive for a cancer syndrome (either an RCC-associated syndrome or Lynch syndrome associated with upper-tract UC). For RCC-associated syndromes, young age at diagnosis was significantly associated with syndromal diagnosis: fully 35% of cases diagnosed at younger than 40 years tested positive. Notably, for the RCC-associated syndromes, presence of (extrarenal) syndromic manifestations was not significantly associated with positive testing. In contrast to the RCC-associated syndromes, age at upper-tract UC diagnosis was not significantly associated with testing positive for Lynch syndrome. Also, again opposite the RCC-associated syndromes, for Lynch syndrome, syndromic manifestations and history of multiple cancers were both significantly associated with testing positive.15 These contrasting findings between RCC-associated syndromes and Lynch syndrome are salient, as our anecdotal experience has sometimes seen clinical colleagues emphasizing eliciting history of or assessment for rare syndromal stigmata as a trigger for genetic assessment for hereditary RCC syndromes on the one hand, yet being nonplussed by presence or history of (more common) Lynch syndrome– associated malignancies on the other. At tumor boards and other interdisciplinary conferences, we now emphasize that published data actually support the opposite approach. Helpful with regard to the goals of this review are very recently reported observations on hereditary leiomyomatosis RCC (HLRCC) syndrome. Again from the experience of Memorial Sloan Kettering Cancer Center, Kopp et al16 have recently reported a retrospective analysis of the utility of pathologic evaluation to inform clinical genetic testing for HLRCC, finding that, of 29 patients referred for genetic testing, 21 had suspicious histopathologic features identified and documented previously (whether renal tumors or leiomyomata). Importantly, positive mutation testing was significantly associated with suspicious histopathologic features, to our mind formally demonstrating the importance of prospective histopathologic recognition of these tumors. (They also reemphasize that lack of a family history or phenotypic features of this particular syndrome should not be deemed in any way dismissive of consideration of HLRCC.) Thus, predicated by data that pathologists may recognize suspicious tumors and so facilitate patient triage for genetic workup16 and positive genetic diagnosis of a substantial subset of those tested,15 we embark on this review. Selected syndromes and their associated neoplasms are presented in ways that they may be encountered by the surgical pathologist, in several cases in the exact manner where we have encountered them. Our goal is to facilitate additional progress in the pathologic recognition of syndromal kidney tumors, including both RCC and UC, so that a greater proportion of affected kindred may be tested, treated, and surveilled. Our intention is to make the argument that through careful integration of clinical data, laboratory studies, and gross and microscopic pathology, the surgical pathologist can become the essential diagnostic nexus for unrecognized but affected patients. 314 www.pathologycasereviews.com CLUES FROM GROSS EXAMINATION Hereditary Papillary RCC Hereditary papillary RCC (HPRCC) is an autosomal dominant syndrome RCC predisposition syndrome that demonstrates a phenotype of development of numerous, bilateral, multifocal papillary RCCs with classic low-grade (so-called “type 1”) papillary morphology.17,18 In contrast to the other syndromes discussed here, this particular type of hereditary renal cell carcinoma is not associated with any extrarenal manifestations. Remarkably, this disease is caused by germline mutation of the MET proto-oncogene, with mutations detected characteristically in the kinase domain of this receptor tyrosine kinase,19,20 with additional nonrandom duplication of chromosome 7 harboring the mutant allele.21 Hereditary papillary RCC is exceptionally rare, perhaps the rarest of the syndromes discussed in this review; review of published literature references less than 50 well-characterized families.10,22 In well-characterized kindred, the tumors seem to arise in individuals in late middle age.17,19,20 A subset of these cases may present earlier,22 as seen in the case presented in Figure 1. Aggressive clinical behavior has been noted for the tumors arising in HPRCC, and nephron-sparing surgery is proposed for when tumors exceed 3 cm. Hereditary papillary RCC is reviewed here as a syndrome that might be encountered or considered upon examination in the “gross room,” based on the remarkable appearance of nephrectomy specimens from affected kidneys. Prior studies of the microscopic papillary lesions in grossly unaffected renal parenchyma in HPRCC have estimated such neoplasms, which would be regarded as papillary adenomas in the sporadic setting, as in the range of more than 1000 to more than 3500. Grossly, affected kidneys have been described as harboring dozens to hundreds of tumors bilaterally,12,17,18,20 which presents a remarkable gross appearance, with the renal parenchyma substantially replaced with numerous tumors showing a classic white, tan, solid morphology of papillary RCC (Fig. 1). Similarly, the histomorphology of these tumors has been described as indistinguishable from sporadic papillary RCC, often encapsulated, and tending to show low International Society of Urological Pathology nucleolar grade23 features. Cytologically, tumor cells have predominantly granular, often amphophilic to basophilic, cytoplasm, with a widely variable proportion of cells with clear cell cytology.24 This clear cell cytology, thought to represent glycation or lipidization, is seen in the context of the classic tubular and papillary, sometimes solid, architecture of conventional papillary RCC; the sinusoidal vascular pattern of CCRCC is not observed. Other conventional papillary RCC features, including foamy macrophages involving fibrovascular cores and psammoma bodies, have been described as quite frequent, whereas hemorrhage and necrosis are variable.22,24 Formation of glomeruloid structures has also been described.24 A very recent report describes 2 members of an HPRCC family demonstrating tumors with the classic morphology of biphasic squamoid alveolar papillary RCC.25 Biphasic squamoid alveolar papillary RCC is an emerging entity, seeming to be closely related to and likely a subtype of papillary RCC (it is reviewed elsewhere in this issue by Hes et al). One additional observation we would make from HPRCC cases that we have reviewed is that, although even extensively multifocal papillary RCC can be quite common in the sporadic setting, in the background of end-stage kidney disease26 (see also a review in this issue by Williamson), in HPRCC there is often the appearance of innumerable papillary carcinomas and adenomas popping out of the background of an otherwise relatively pristine renal parenchyma (eg, Fig. 1B). © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Kidney Tumors and Hereditary Cancer Syndromes FIGURE 1. A, The gross pathology of kidneys affected by HPRCC may be quite distinctive; a total of 13 separate grossly identifiable nodules of papillary RCC were grossly identified (A, yellow arrows, those visible in this plane) in this nephrectomy specimen from an affected 32-year-old man (blue arrow, hematoma at site of prior partial nephrectomy for PRCC). The background renal parenchyma showed innumerable lesions with the morphology of unencapsulated papillary adenomas (B, arrows). Higher power (C) of a tumor nodule and an adjacent adenoma (right) show similar, classic low-grade papillary morphology. D. Many foci of HPRCC show at least focal areas of clear cell cytology and psammoma bodies. One reason why recognition of HPRCC is important is because the frequent bilaterality of renal involvement may engender difficult clinical choices from the standpoint of surgical management. However, the importance of surveillance for affected family members is increasingly recognized. Indeed, according to a recent expert consensus statement reported by the Kidney Cancer Research Network of Canada, there are now established protocols for surveillance imaging for affected individuals by abdominal computed tomography or magnetic resonance imaging, with recommended start at age 18 years. If normal imaging at baseline, these studies are to be repeated at age 30 years and then biennially subsequently.27 Lastly, it bears note that at least some of the mutated MET oncogenes present in HPRCC may be targetable by small molecular inhibitors28,29; in a phase 2 clinical trial, responses to a targeted MET inhibitor were strongly associated with patients having a germline MET mutation (including partial response or stable disease in 100% of the HPRCC subset of patients treated).30 CLUES FROM THE CLINICAL LABORATORY Renal Medullary Carcinoma Although seldom considered among hereditary forms of RCC, renal medullary carcinoma (RMC) represents an archetype of hereditary RCC, albeit one where the RCC phenotype is of very low penetrance. Renal medullary carcinoma is a distinctive, poorly differentiated adenocarcinoma that arises, characteristically, in the collecting system of the kidney in individuals with sickle cell trait or disease (Fig. 2). Davis et al31 characterized RMC in 1995 as an aggressive tumor with characteristic morphology that was strongly associated with the concomitant finding of drepanocytes in tissue sections. Essentially all of these tumors arose in individuals of African descent, with a strong male predominance and a © 2017 Wolters Kluwer Health, Inc. All rights reserved. tendency to present in the first 2 decades of life. Subsequent experience with these tumors has confirmed that they frequently occur in the young with an average age in the 20s, strong male predominance (>2:1), strong preference for arising in the right kidney (>2:1), high stage at presentation, and exceptionally poor prognosis.32–35 The issue of sickle cell trait, disease, or related hemoglobinopathy (a case arising in the setting of hemoglobin sickle cell disease was reported in the original series of Davis et al31) deserves particular mention, as the feature that frames the “hereditary” aspect of this tumor. Notably, while sickle cell trait is usually a clinically silent carrier state, extrarenal manifestations related to sickle cell disease are multisystem and quite variable, having been reviewed in detail recently.36 With regard to RMC, which occurs in the setting of either sickle cell trait or sickle cell disease, we note that while classifications have sometimes considered RMC a variant of collecting duct carcinoma4,5 or an independent entity,37 none of these classifications have definitively addressed the question of whether sickle cell trait is definitional. For instance, the 2012 Vancouver Classification describes this tumor as occurring “almost exclusively in children and young adults with sickle cell trait,” without further definition.37 We have recently encountered a case at the very crux of this diagnostic conundrum, one arising in the left kidney of a young female in her 20s definitively proven not to have sickle cell trait. Based on consultation with a panel of international experts, we proposed a terminology of RCC, unclassified, with medullary phenotype, as a provisional diagnostic term.38 We39 and others40–43 have observed additional such cases, a phenomenon that deserves further investigation prospectively to delineate its relationship, or lack thereof, to bona fide RMC. We have recently reported a cohort of 5 such tumors, with clinical, histopathologic, immunophenotypic, and prognostic features closely aligned with RMC.44 www.pathologycasereviews.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 315 AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Mochel and Smith kidney, including the fumarate hydratase (FH)–deficient RCCs of HLRCC syndrome (detailed below) or collecting duct carcinomas35 in the differential diagnoses, as history, positive electrophoresis or high-performance liquid chromatography studies, or histologic identification of sickled erythrocytes is present in essentially all cases.32–35,45,46 Morphologically, these tumors are striking, with a poorly differentiated adenocarcinoma morphology, with tubular, solid, and papillary infiltrative patterns. Most distinctive is a reticular and cribriform appearance that has been likened to that of a yolk sac tumor. High nuclear grade is characteristic, as is extensively infiltrative growth, including around native renal tubules and glomeruli, often inducing stromal desmoplasia with admixed inflammatory infiltrate. A significant subset of cases shows rhabdoid cytomorphology.34,35,46 A substantial body of work now relates RMCs to loss of function of the nuclear transcriptional regulator, SMARCB1 (BAF47, INI1), encoded on chromosome 22,46–49 with some studies finding loss of heterozygosity,46 hemizygous deletions,49 or loss of chromosome 22.32 Most recently, the intriguing finding of coincident hemizygous deletions of SMARCB1 with balanced translocations of SMARCB1 fusing the gene to one of multiple other loci (resulting invariably in complete loss of functional protein expression) has been reported in 4 RMCs.40 Regardless of the mechanism, SMARCB1 alterations have been associated with the useful diagnostic feature of loss of SMARCB1 immunohistochemical expression in RMCs.47–49 Although loss of SMARCB1, often associated with rhabdoid cytomorphology, is being increasingly reported in at the high-grade/undifferentiated end of the histologic spectrum of tumors of several different sites,50 including the kidney,51 we posit that these emerging findings underscore even more the importance of integration of immunohistochemical studies into an appropriate clinical and morphologic context. CLUES FROM HISTOMORPHOLOGY Succinate Dehydrogenase–Deficient RCC FIGURE 2. Renal medullary carcinoma represents an underappreciated example of a hereditary kidney cancer, one of low penetrance in the setting of sickle cell trait or disease. These tumors generally arise as a diffusely infiltrative mass, originating in the area of the collecting system, but often involving much of the organ (A), with high stage and metastasis at presentation. Morphologically, these tumors are characterized by a poorly differentiated carcinoma, with variable infiltrative morphologies, including prominence of solid and tubulopapillary patterns. Most classic and distinctive are reticular and cribriform (B) patterns, where sieve-like nests are seen infiltrating through a desmoplastic, inflamed stroma with variable myxoid change. Helpfully, SMARCB1 (INI1) expression is lost by IHC in all cases. In our opinion, however, testing to document hemoglobin trait or disease, whether by hemoglobin electrophoresis or by high-performance liquid chromatography (C), is requisite to make this diagnosis. Chromatogram courtesy of Dr Lorin Bachmann and Greg Gin, Virginia Commonwealth University School of Medicine. For our part, regarding recognition of this rare tumor, we consider correlation with laboratory studies to be both invaluable and requisite for appropriate workup. Demonstration of sickle cell trait is exceptionally helpful to address the differential between RMC and other high-grade adenocarcinomas primary to the 316 www.pathologycasereviews.com Germline mutations in the genes encoding succinate dehydrogenase (SDH), including SDHA, SDHB, SDHC, and SDHD, have been associated with heritable susceptibility to developing paragangliomas and pheochromocytomas, gastrointestinal stromal tumors (GISTs), and RCCs52 (Fig. 3). The specific genotype of heritable SDH-deficient tumor syndrome correlates with the presentation and clinical course of the syndrome. Although morphologically quite typical, paragangliomas occurring in the setting of germline SDHB mutations are associated with more aggressive behavior, with approximately one third of affected individuals developing metastases to lung or bone.53,54 This experience has been borne out in bladder paragangliomas as well.55,56 Germline SDHB mutations also seem to be the most common setting for SDHdeficient RCC.11 Given the possibility of aggressive neoplasia in heritable SDH deficiency syndromes, recognition of the syndrome through clinicopathologic assessment can majorly impact patient surveillance and management. The surgical pathologist may have the opportunity to contribute to syndrome detection through the diagnosis of distinctive tumors of the gastric wall and kidney. In addition, the pathologist can screen for all of the SDH-associated syndromes through IHC for SDHB, the expression of which is absent, because of resultant multimeric complex instability, in tumors associated with mutations of any of SDHA, SDHB, SDHC, and SDHD subunits.57–59 Gastrointestinal stromal tumors developing secondary to mutation of an SDH subunit and subsequent SDH deficiency, rather than the more common activating mutations in KIT or PDGFRA, © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Kidney Tumors and Hereditary Cancer Syndromes FIGURE 3. Recent scholarship has identified SDH-deficient RCC as a distinctive carcinoma arising in setting of individuals harboring germline mutation of one of the subunits of the SDH complex. Affected kindred demonstrate familial paragangliomas and GISTs, among other features. The SDH-deficient paragangliomas (A) are not histologically distinctive, but show loss of cytoplasmic expression of SDHB (B, see internal control endothelial cells with retained expression). Succinate dehydrogenase–deficient GISTs arise most frequently in the stomach and show a plexiform and nodular growth pattern (C). Epithelioid cytology is characteristic (D), as is loss of expression of SDHB (inset). Succinate dehydrogenase–deficient RCCs appear well circumscribed and often show a red/brown gross appearance (E and inset). At higher power, these tumors show oncocytic cytology, low-grade nuclear features, and prominent flocculent to vacuolated cytoplasm (F). Paraganglioma and GIST micrographs courtesy of Dr Sean Williamson, Henry Ford Health System. have several distinct clinicopathologic features.60–62 Succinate dehydrogenase–deficient GISTs tend to occur specifically in the stomach.62 Young age is a strong predictor of SDH deficiency in GISTs; in 1 large study, nearly all gastric GISTs in those younger than 20 years were SDH deficient, whereas SDH-deficient GISTs were rare in those older than 40 years.61 Succinate dehydrogenase– deficient GISTs tend to occur as multinodular masses with intervening bands of native gastric wall smooth muscle.62 The lesional cells usually have epithelioid cytology with eosinophilic cytoplasm. A small number of SDH-deficient GISTs show lymphovascular invasion and lymph node involvement, an infrequent but unique feature of SDH-deficient GISTs.62 Immunohistochemistry for SDHB loss can serve as a screening test for SDH deficiency, while, in addition, immunohistochemical loss of SDHA correlates strongly with germline SDHA mutation.63,64 The International Society of Urological Pathology 2013 Vancouver Classification of Renal Tumors included “succinate © 2017 Wolters Kluwer Health, Inc. All rights reserved. dehydrogenase B mutation–associated RCC” as an emerging/ provisional entity,37 now formalized in the 2016 WHO Classification7 as “SDH-deficient RCC,” reflective of distinctive clinical and morphologic features.59,65,66 Increasing collaborative experience of ours and others67,68 documents that these tumors tend to lack encapsulation, despite overall circumscription, and tend to show solid and nested growth with occasional entrapment of peripheral native renal tubules. Most helpful in our experience— and meriting consideration as a tumor recognizable by distinctive histomorphology—is the oncocytic cytology. The tumor cells are round to polygonal and typically possess flocculent to vacuolated cytoplasm, at least focally containing pale pink cytoplasmic inclusions, which may represent giant disrupted mitochondria.65 We have noted that tumor nuclei often show finely stippled chromatin, reminiscent of that seen in neuroendocrine tumors, and that often stromal mast cells are prominent.67 Of particular interest, as a relatively specific feature, these tumors tend to be scant in www.pathologycasereviews.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 317 AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Mochel and Smith their expression of broad-spectrum keratins and are often negative for expression of c-kit/CD117, a marker typically used to support diagnosis of a renal oncocytic neoplasm. Kidney-specific cadherin, another oncocytic RCC marker,69 in contrast, is often positive. A renal tumor with these features in a patient with a familial history of RCC, paraganglioma, or GIST should raise high suspicion for germline SDH subunit mutation. However, dependency on historical clues may limit syndrome detection, as only subsets of the larger reported cohorts show personal or family history of syndromal stigmata.67,68 Although we recommend immunohistochemical testing for SDHB to support the diagnosis in oncocytic tumors of compatible morphology,67,70 we emphasize that referral for germline genetic testing provides definitive assessment. These tumors remain quite rare, and the limited experience has not settled whether they occur with any frequency in the sporadic setting, by somatic mutation. Detection of SDH-deficient RCC has at least 2 vital clinical implications: the potential for aggressive paragangliomas and GISTs associated with germline SDH mutation and also the aggressive nature of the renal tumors themselves. Metastases have been documented in one third of the cases in a large series of SDH-deficient RCCs,68 which is relatively more than would be anticipated to occur from other, morphologically similar lowgrade oncocytic RCCs such as chromophobe RCC. Also, late metastases, occurring several years after resection, may occur.67,68 As a final note, while germline SDHB mutation seems to be the most common setting for syndromic SDH-deficient RCC, germline SDHC and SDHD mutations have been rarely associated with RCCs. However, RCCs with mutations of other SDH subunits have thus far generally lacked the aforementioned characteristic morphology associated with SDHB mutation.12,71–73 Hereditary Leiomyomatosis RCC Syndrome Hereditary leiomyomatosis RCC syndrome manifests as cutaneous and uterine leiomyomas and RCC with distinctive morphology (Fig. 4). The syndrome is inherited in an autosomal dominant fashion and is caused by mutations in the gene encoding FH.74–76 The surgical pathologist may encounter tumors of the skin, uterus, and kidney that prompt the consideration of this syndrome. While FH-deficient smooth muscle tumors may lack distinctive morphologic features, the FH-deficient RCCs show a variable, albeit striking constellation of morphologic findings enabling their prospective recognition.77 The presentation of multiple cutaneous leiomyomas, particularly in patients in the second, third, and fourth decades of life, is highly suggestive of HLRCC.78 The histopathology is that of a leiomyoma of the arrector pili muscles, termed piloleiomyoma, with intersecting fascicles of eosinophilic spindle cells in the dermis. The histomorphologic appearance of cutaneous leiomyomas in HLRCC is typically indistinct, although rare cases have eosinophilic cytoplasmic inclusions and perinucleolar halos around prominent nucleoli, reminiscent of changes seen in uterine leiomyomas of HLRCC.79 A detailed morphologic comparison between syndromic and nonsyndromic cutaneous leiomyomas found no significant differences.80 Immunohistochemical loss of FH in cutaneous leiomyomas has high specificity (97%) and moderate sensitivity (70%) for detecting HLRCC.80 Immunohistochemical positivity for 2-succinocysteine (2-SC) may correlate with FH mutation to a greater degree than immunohistochemical loss of FH.79 Patients with HLRCC present with uterine leiomyomas at a median age of 28 years, a decade before conventional uterine leiomyomas, and are more likely to undergo treatment for this condition, including hysterectomy.81 On histopathologic examination, the uterine leiomyomas of HLRCC often have high cellularity 318 www.pathologycasereviews.com and zones of nuclear atypia. A prevalent feature, apparent at least focally, is presence of large nuclei with macronucleoli and perinucleolar halos.82 Screening for these features with subsequent IHC for loss of FH or positivity for 2-SC may serve as helpful screening tests for FH mutation in the tumor,83 even HLRCC.84 However, one study showed lower correlation between immunohistochemical status of FH and 2-SC and mutational status of FH.85 In addition, while IHC may identify FH deficiency in uterine leiomyomas, this deficiency may occur more frequently in the sporadic setting of somatic FH mutation in the leiomyoma itself than in the syndromic setting of germline FH mutation.86 Therefore, testing must be considered in the appropriate clinicopathologic context, and these nuances must be contemplated when reporting the significance of such findings. Overall, our assessment is that greater experience with these stains in studies of leiomyomata with available constitutional FH mutation status will be necessary to determine the utility of the stain in this setting. Hereditary leiomyomatosis RCC–associated RCC is an aggressive malignancy that generally presents as a solitary renal mass.12,37 Therefore, rather than bilaterality or multifocality of the tumor itself, the recognition of the syndromic nature of the lesion apparently rests on any available clinical clues (uterocutaneous leiomyomatosis) and the histomorphologic features of the renal tumor. Given that the stigmata are often absent,16 we emphasize the power of careful morphologic inspection to identify these cases. These carcinomas demonstrate a range of histopathologic growth patterns, often within the same tumor, including frequently high-grade papillary and tubulopapillary architecture and less commonly tubular and solid growth. Traditionally, these tumors were described as having “type 2 papillary” or collecting duct carcinoma–like morphology.76 Contemporary scholarship, led by a key series based at the US National Institutes of Health by Merino et al,77 has characterized a much broader spectrum of high-grade papillary, tubulopapillary, cribriform, solid, cystic, and unclassified patterns.87–89 Our own experience emphasizes that the morphologic pattern of tubulocystic carcinoma with areas of poorly differentiated growth often represents FH-deficient carcinoma such that when encountered morphologically additional testing, whether by IHC and/or genetics, is indicated.90,91 In the setting of diverse architectural patterns, the most unique feature of these neoplasms is cytologic and specifically nuclear; as described by Merino et al,77 the lesional cells possess large nuclei with eosinophilic, viral inclusion–like macronucleoli with perinucleolar halos. These remarkable nuclear features tend to be seen in the context of dense eosinophilic cytoplasm with a syncytial appearance. In 1 study, histomorphologic recognition of these features in 9 seemingly sporadic renal tumors prompted the identification of syndromic HLRCC.89 This series also noted the frequent presence of foci resembling collecting duct carcinoma, with infiltrative aggregates, tubules, and single cells within desmoplastic stroma.89 Immunohistochemistry for FH deficiency, as defined by FH negativity and 2-SC positivity, seems to strongly correlate with the presence HLRCC and FH mutation.88 Beyond these markers and pervasive expression of PAX8 and retained expression of SMARCB1 (our unpublished observations), the immunohistochemical spectrum of these tumors has not been studied comprehensively. (With some concern not to confuse the main morphologic theme for HLRCC-associated RCCs, we are compelled to note that we have very recently described a subset of immunohistochemically FH-deficient tumors with a much lower-grade oncocytic morphology, actually quite similar to SDHdeficient RCC, predominantly in patients with convincing features of HLRCC.70 These unusual tumors, which we have conjectured might be related to the overlapping metabolic consequences of FH and SDH deficiency, serve as a reminder of the © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Kidney Tumors and Hereditary Cancer Syndromes FIGURE 4. Hereditary leiomyomatosis RCC syndrome is characterized by leiomyomas, usually multiple, of the cutaneous arrector pili muscles (A, inset) showing classic fusiform eosinophilic cells with cigar-shaped nuclei. Fumarate hydratase stain in these tumors is characteristically negative (B, note internal control retained FH expression in endothelial cells). Uterine leiomyomatosis (C) in HLRCC is usually florid and morbid, often necessitating hysterectomy. At higher power, nuclear atypia, often with at least focal prominent nucleoli with perinuclear clearing (D) as seen in the characteristic renal tumors, again with FH loss by immunostain (inset). The high-grade RCCs show highly variable morphology, including cystic, tubulocystic, nested, and solid patterns (E); most distinctive are prominent, viral inclusion-like eosinophilic nucleoli with perinucleolar halos (inset). These tumors were first described as showing a papillary morphology, as is apparent here (F); hyalinization of the fibrovascular cores is a helpful feature in recognizing HLRCC-RCC tumors. Uterine leiomyoma micrographs courtesy of Dr Michelle Hirsch, Brigham and Women's Hospital. utmost importance of clarifying the nature of any syndromal association for an individual case.) For a high-grade RCC suggestive of clinical, morphologic, or molecular reasons to be an HLRCC-associated RCC, we encourage the diagnostic term of “FH-deficient RCC.” Based on encountering a significant number of cases of immunohistochemically FH-deficient RCC not harboring any evidence or history of syndromal stigmata, we proposed this term at the 2015 United States and Canadian Academy of Pathology meeting.91 Our intention was to provide a tractable and defensible provisional term, emulating that used for SDH-deficient RCC, to describe a morphologically and immunohistochemically appropriate tumor where syndromal status was not known and where “HLRCC-associated RCC” could thus not be used forthrightly. It is also a term adaptable to the scenario, which we have already seen anecdotally, © 2017 Wolters Kluwer Health, Inc. All rights reserved. where FH mutations are detected in an otherwise unclassified RCC by high-throughput somatic mutation profiling of tumors in assays ordered to try to identify targetable mutations. Overall, the expectation is that this term be used with a recommendation for referral for genetic counseling, again with hopes that growing experience will answer the outstanding question in this field of whether sporadic FH-deficient RCCs occur with any frequency by somatic mutation (similar to the aforementioned uterine leiomyomata). The presence of at least a few cases from The Cancer Genome Atlas papillary RCC series introduces the possibility of FH-deficient RCC due to somatic FH mutation,92 and applying a syndromal and genetic label to such a case would be inappropriate. Either way, we note recent, promising preclinical data suggesting that FH-deficient tumors may show sensitivity to therapeutic targeting of ABL1 kinase.93 www.pathologycasereviews.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 319 AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Mochel and Smith CLUES FROM THE LABORATORY INFORMATION SYSTEM Upper-Tract UC in the Setting of Lynch Syndrome Upper-tract UC represents an example of a kidney tumor—in this case, one based in the pelvicalyceal system or ureter—where hereditary Lynch syndrome–associated tumors represent a small albeit meaningful subset (Fig. 5). Across all organ sites and tumor types, Lynch syndrome is thought to be the most common of inherited cancer syndromes, an autosomal dominant predisposition to carcinomas of multiple organs.94 Lynch syndrome manifests with colorectal, endometrial, gastric, small bowel, hepatobiliary, ovarian, and central nervous system (CNS) tumors, with the rare occurrence of prostatic and testicular germ cell neoplasms.95 Patients with Lynch syndrome may also present with cutaneous sebaceous neoplasms in a syndromal variant known as Muir-Torre syndrome.96 As a syndrome first postulated by a pathologist (the University of Michigan's Aldred Scott Warthin in the 1890s) based on observations in the medical record of clustered cancers in affected families, Lynch syndrome represents a prototypical example of syndrome recognition through correlation with prior diagnostic data from the medical record for related tumors.94 Lynch syndrome also represents the current best “use case” for the utility of surgical pathology to identify unselected cancer resection specimens for further appropriate genetic testing.13,97 This remarkable development is facilitated by more reliable, contemporary IHC for mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, which have entered routine clinical use as relatively sensitive and specific markers for identification of individuals at significant risk of harboring germline mutations in the corresponding genes (or in EPCAM, which flanks MSH2 locus and results in its inactivation).13,97 Biochemically, these proteins form heterodimers to function in MMR (MLH1 with PMS2 forming the MutLα complex; MSH2 and MSH6 forming the MutSα complex), such that frequent patterns of loss result in loss of the expression of the entire complex (ie, both proteins in the dimer) by IHC. In colorectal carcinoma, the relative sensitivity and specificity of different patterns of loss of MMR protein expression to germline mutation, as opposed to somatic loss, and the resultant probability of Lynch syndrome have been carefully delineated.98 In upper-tract UC, these parameters have not been as systematically assessed, and genetic counseling should be recommended if abnormalities are detected. Overall, in Lynch syndrome, the relative prevalence of germline mutations, by gene, is MLH1 (~40%), MSH2 (~50%), and MSH6 (~10%), whereas PMS2 mutations are thought to be quite rare.98,99 Physiologically, MMR functions to detect and repair DNA bases inserted erroneously during replication; loss of function results in a so-called “mutator” phenotype associated with increased somatic point mutations and instability in the length of microsatellite repeat sequences throughout the genome, the latter resulting in mutational effects by several mechanisms.100 While colorectal and endometrioid adenocarcinomas are the most common Lynch syndrome–associated cancers, UC of the upper tract is the third most common malignancy, occurring in approximately 5% of Lynch syndrome patients,95,101 with highest risk among Lynch syndrome patients harboring MSH2 mutations.99,102,103 Prior studies have suggested that upper-tract UC patients with Lynch syndrome are more often female and younger than in sporadic cases.15,95,99,104 In terms of the histomorphology of the UC, prior studies have associated inverted growth pattern and low stage with microsatellite instability,105–107 the latter a molecular surrogate strongly associated with Lynch syndrome. A very recent, large, consecutive series of unselected uppertract UCs from the Cleveland Clinic, reported by Harper et al,108 provides useful data regarding the prevalence of MMR protein loss among upper-tract urothelial tumors and the features of such tumors. Their findings differ somewhat from the aforementioned clinical and histologic parameters thought to be characteristic of FIGURE 5. A pelvicalyceal-based high-grade UC in a nephroureterectomy specimen from a 62-year-old woman with history of a cecal adenocarcinoma and strong family cancer history is seen, with a dense peritumoral lymphocytic infiltrate (A); at higher power, infiltrative invasion around ducts and glomeruli is apparent (B), staged as pT3. By MMR protein IHC, loss of expression of MLH1 (C) and PMS2 (D) was noted, with retained MSH2 (E) and MSH6 (F). Genetic workup revealed a MLH1 germline mutation. 320 www.pathologycasereviews.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 these cases. Of more than 200 cases studied, 7% overall demonstrated loss of MMR proteins. Of cases with personal history of a Lynch syndrome–associated neoplasm, 30% showed loss of MMR protein expression. Twelve of 14 cases with MMR protein loss by IHC demonstrated loss of MSH2 and MSH6, whereas 2 showed loss of only MSH6 (none in the series showed MLH1 and/or PMS2 loss, although such cases have certainly been reported109). Of the 14 tumors with MMR protein loss reported by Harper et al,108 8 involved the ureter, 4 involved the renal pelvis, and 2 involved both sites. Nine tumors arose in males, and 5 in females; all were high grade without variant histology, none with marked anaplasia. An equal breakdown of 7 cases each was noted between cases that were “low stage” at pTa/pT1 versus “high stage” at pT2/pT3. Importantly, although increased intratumoral lymphocytes (as seen in other Lynch syndrome–associated tumors), inverted growth, pushing tumor-stroma interface, and lack of nuclear pleomorphism were all seen more frequently in the MMR protein–deficient tumors, the only histologic features statistically significantly associated were intratumoral lymphocytes and pushing borders. They concluded that none of the histologic features were sufficiently sensitive or specific to use for screening, and they note that MSH2 and MSH6 immunostains might have a role in a targeted or even universal screening.108 Beyond the value to potential affected family members, the identification of Lynch syndrome may aid in prevention of secondary/additional malignancies, a phenomenon well documented for Lynch syndrome patients in the (much more common) post– colorectal carcinoma setting.110 Intriguingly, also, there are suggestions in the literature that upper-tract UCs related to Lynch syndrome may benefit more from adjuvant cisplatin-based chemotherapy after nephroureterectomy than sporadic patients,111 a phenomenon reminiscent of differences in prognosis and chemotherapeutic response in Lynch syndrome–associated colorectal cancers. Birt-Hogg-Dubé Syndrome The unique constellation of cutaneous follicular hamartomas, renal tumors, and pulmonary cysts associated with Birt-HoggDubé syndrome (BHDS) may prompt the pathologist to consider the syndrome, especially if any prior diagnostic context of characteristic skin, kidney, or lung lesions is available from the laboratory information system (Fig. 6). Birt-Hogg-Dubé syndrome is secondary to an inherited or sporadic germline mutation in FLCN, which encodes the protein folliculin.112,113 While the heritability of the syndrome and the infrequency of the classic cutaneous lesions of BHDS, discussed below, may provide the first clinical clues, the presence of multiple renal tumors and pneumothorax also raise suspicion for the syndrome.114,115 Patients with BHDS classically present with numerous small papules involving the face, neck, and upper trunk.116,117 On histopathologic examination, these papules appear as either fibrofolliculomas or trichodiscomas, two entities that are thought to be closely related, or possibly the same lesion examined at different planes of section.118 Fibrofolliculomas are composed of elongated and interconnected strands of follicular epithelium, associated with a distinct fibrovascular stroma composed of thin collagen fibers and abundant capillaries. Trichodiscomas appear as circumscribed lobules of identical fibrovascular stroma with a minor component of follicular epithelium at the periphery. While the clinical scenario of numerous facial papules may raise a differential diagnosis of several syndromes, including Cowden syndrome, Brooke-Spiegler syndrome, and tuberous sclerosis (TS) (see below), the diagnosis of a fibrofolliculoma or trichodiscoma may assist the clinician in classification of the disorder.118 In the absence of stated clinical suspicion for BHDS, the infrequency of these hamartomas still © 2017 Wolters Kluwer Health, Inc. All rights reserved. Kidney Tumors and Hereditary Cancer Syndromes should prompt a surgical pathologist to at least reflect on the possibility of the syndrome. The renal neoplasia of BHDS also demonstrates characteristic histopathologic features.119,120 Patients with BHDS tend to develop multiple, often bilateral, neoplasms of the kidney. While a minority of the renal tumors in BHDS are CCRCCs, the majority of renal tumors are either chromophobe RCCs or hybrid oncocytic neoplasms with features of both chromophobe RCC and oncocytoma. These hybrid oncocytoma/chromophobe tumors (HOCTs) tend to show a solid growth pattern with a variably arranged admixture of large oncocytic cells with dense cytoplasm and round nuclei, reminiscent of classic renal oncocytoma, with contrasting areas of cells with well-defined cell borders, flocculent pink cytoplasm, and crinkled nuclei with halos, reminiscent of chromophobe RCC.119,120 Scattered single cells or aggregates of cells with cytoplasmic clearing within an oncocytic neoplasm are a common feature of the HOCTs occurring in BHDS.12 As noted in the largest series of these lesions, these HOCTs tend to be quite solid, lacking supportive architectural features of classic oncocytoma, such as the foci of edematous connective tissue or the presence of a central scar.119 In addition, the grossly unremarkable renal parenchyma is typically involved by oncocytosis.119 This oncocytosis can take the form of oncocytic changes in renal tubules, to small aggregates of oncocytes, to cysts lined by oncocytes, to oncocytomas.12 The surgical pathologist who encounters multiple chromophobe RCCs, multiple oncocytomas, hybrid oncocytic neoplasms, or oncocytosis in a nephrectomy specimen should investigate the possibility of BHDS.12 Of note, hybrid oncocytic neoplasms of the kidney, similar to those seen in BHDS, have been described outside BHDS121–123 and within the spectrum of renal tumors associated with TS.124 In addition, renal oncocytosis with bilateral and multifocal renal oncocytomas remains a differential diagnostic consideration on nephrectomy evaluation. Recent study has identified disruptive mutations of mitochondrial DNA in cases of bilateral and multifocal renal oncocytomas but not in the renal tumors of BHDS.125 Finally, the surgical pathologist encountering a pulmonary cyst resection or pneumothorax surgical specimen may have the opportunity to prompt investigation for BHDS.120,126 As described by Furuya et al126 in a large series of pulmonary surgical pathology in BHDS, the pulmonary cysts of BHDS are typically multifocal, concentrated in the lower lobes, incorporated with interlobular septae and visceral pleura, and lined by pneumocytes. In contrast, typical blebs and bullae are concentrated in the upper lobes and tend to lack a complete epithelial lining.127 These authors also describe structures resembling alveoli within the cysts and fibrotic cyst walls of BHDS pulmonary cysts.126 The pathologic differential diagnoses for cystic lung changes and pneumothorax are broad, and clinical and radiological correlations are frequently required for specific diagnosis.128 The presence of pulmonary cysts or pneumothorax, in concert with cutaneous or renal features of BHDS, should raise suspicion for the disorder. Although the renal neoplasms associated with BHDS show morphologic features that are in the spectrum of some of the less aggressive types of RCC, particularly those with oncocytomalike, chromophobe-like, or hybrid HOCT features, authors have emphasized that overall BHDS should not be deemed an indolent disease process.8,129,130 Coleman and Russo8 have emphasized that local overgrowth of even essentially benign tumors may be associated with loss of renal function and note that conservative nephron-sparing management of tumors of more than 3 cm has been recommended, similar to HPRCC. To us, these findings emphasize the importance of prospective recognition of potential BHDS tumors based on morphology and correlation with clinical www.pathologycasereviews.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 321 AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Mochel and Smith FIGURE 6. Biopsies of lesions from the face of a patient with BHDS revealed a proliferation of stroma with increased collagen and capillaries associated with a mantle of thinly stranded follicular epithelium (A, low power; B, intermediate power). A pulmonary cyst from the lung of a patient with documented BHDS is incorporated into pleura (C) and lined by pneumocytes (D). The histologic differential diagnosis includes emphysema, although cysts in the lower lobes such as this one are thought to be more characteristic of BHDS. The oncocytic tumors arising in the kidney in this syndrome have been described as showing hybrid features (E) between oncocytoma and chromophobe RCC, with solid growth and variable cytology with areas reminiscent of oncocytic (F, upper left) and chromophobic (F, lower right) morphology. and prior diagnostic findings on the one hand and inveigh in favor of strict criteria for oncocytoma diagnosis131 on the other. CLUES FROM THE ELECTRONIC MEDICAL RECORD Tuberous Sclerosis The pathologic lesions of TS span much of the specialty of surgical pathology (Fig. 7), including that of the lung (perivascular epithelioid cell tumors such as lymphangioleiomyomatosis and clear cell sugar tumor; pulmonary micronodular pneumocyte hyperplasia), heart (cardiac rhabdomyoma), and CNS (retinal hamartoma, cortical tuber, and subependymal giant cell astrocytoma). Characteristic cutaneous lesions of TS include facial angiofibromas (adenoma sebaceum), periungual fibromas (Koenen tumor), connective tissue nevi (shagreen patch), hypopigmented macules (ash leaf spots), and café-au-lait macules.117 The facial angiofibromas appear as small, often erythematous, papules with telangiectasias aggregating on the nasolabial folds, chin, and cheeks.118 Histologically, the angiofibromas appear as dome-shaped papules with increased 322 www.pathologycasereviews.com dermal collagen fibers, small and variably dilated blood vessels, and fibroblasts that may be spindled to epithelioid with occasional multinucleate forms. While multiple angiofibromas are characteristic of TS, they are not pathognomonic; multiple angiofibromas are also seen in most patients with multiple endocrine neoplasia 1 and were described in one patient with BHDS.132,133 Periungual fibroma consists of a stromal expansion of the dermis of acral skin in a manner that shares close resemblance to acquired digital fibrokeratoma. The renal pathology of TS includes bilateral angiomyolipomas, renal cysts, and RCCs.12 The full spectrum of histologic subtypes of angiomyolipoma have been characterized in TS, including the classic triphasic angiomyolipoma, lipid predominant, myoid predominant, and epithelioid.12 Angiomyolipomas in TS tend to be larger, more multifocal, associated with epithelial cysts, and more likely to have epithelioid morphology than those outside the TS complex; identification of numerous microscopic foci of angiomyolipoma has been strongly associated with TS.134 The renal epithelial cysts in TS are lined by flattened to hobnailed epithelial cells with eosinophilic cytoplasm with underlying cellular pericystic angiomyolipomatous stroma.134 © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Kidney Tumors and Hereditary Cancer Syndromes FIGURE 7. Facial skin biopsy in TS reveals multiple angiofibromas (A), with increased blood vessels and collagen fibers (B). This biopsy of a tumor from around the nail of a TS patient shows the appearance of a periungual fibroma (Koenen tumor), a protuberant and hyperkeratotic lesion (C). Patients with TS may also demonstrate lymphangioleiomyomatosis, a PEComa involving the lung parenchyma, which may present as diffuse cystic change (D); at pneumonectomy, the parenchyma shows diffuse cystic changes and a nodular, variably vascular myoid proliferation with overlying reactive cuboidal epithelium (E); HMB45 is positive (F). Renal lesions often include numerous macroscopic and microscopic angiomyolipomas (G, asterisks), often variably epithelioid (H); cysts with hobnailed lining are common (I). Eosinophilic solid and cystic RCCs (J) have recently been described both in the setting of TS and sporadically. These tumors show oncocytic morphology, solid and cystic growth, entrapped foamy macrophages, and multinucleate hobnailed cyst lining cells with cytoplasmic stippling (K). CK20 positivity is characteristic and distinctive (L). Lymphangioleiomyomatosis panels courtesy of Dr Scott Tomlins, University of Michigan. While the overall incidence of RCCs in patients with TS is controversial and may be only slightly higher than that in the general population, the renal epithelial neoplasia of TS occurs at a © 2017 Wolters Kluwer Health, Inc. All rights reserved. younger age and with multiple distinctive morphologies.124,135–138 In a contemporary series of 46 RCCs arising in 19 patients with TS, there were 3 groups of RCCs: TSC-associated papillary RCC, www.pathologycasereviews.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 323 AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 Mochel and Smith renal tumors resembling hybrid oncocytic/chromophobe tumors (HOCTs, such as discussed previously for BHDS), and renal epithelial neoplasms unclassifiable by WHO criteria.124 The TSCassociated papillary RCCs demonstrated complex papillary growth with the occasional appearance of other growth patterns (solid, acinar, nested, tubular, and alveolar). The tumor cells generally contained abundant clear cytoplasm with eosinophilic strands, which focally aggregated into globules. Nuclei were either International Society of Urological Pathology grade 2 or 3. These neoplasms possessed a unique immunophenotype: CK7 diffusely positive, carbonic anhydrase IX (CAIX) diffusely positive, CD10 positive, Alpha-methylacyl-CoA racemase (AMACR) negative, and TFE3 negative. The HOCT-like lesions associated with TS closely resembled those of occurring in BHDS and did not have a distinctive immunophenotype. A separate large series of 57 RCCs from 18 patients also classified lesions into 3 groups: RCCs with features similar to chromophobe RCC (chromophobelike), RCCs with features of the “renal angiomyoadenomatous tumor” (RAT-like RCC), and RCCs with granular eosinophilicmacrocystic morphology.137 The RAT-like RCCs demonstrated nested, elongated tubular, and focally papillary growth with admixed smooth muscle stroma, whereas the tumor cells of these lesions have the cytologic features of conventional CCRCC. The RCCs with granular eosinophilic-macrocystic morphology are composed of variably cystic, nested, and solid growth of tumor cells with typically abundant granular eosinophilic cytoplasm and round nuclei with prominent nucleoli.137 The cells lining cystic spaces were frequently hobnail in configuration, and multinucleated tumor cells were seen commonly. A morphologically identical neoplasm, named eosinophilic, solid, and cystic RCC (ESC-RCC), was recently characterized in the sporadic setting in females.139 As indicated by its name, the histopathology of ESC-RCC demonstrates solid growth with cysts of various sizes. Similar to its syndromic counterpart, ESC-RCC is composed of cells with abundant eosinophilic cytoplasm with formation of amphophilic cytoplasmic granules/stippling and rounded nuclei with prominent nucleoli.139 Immunohistochemically, ESC-RCC is quite distinct, with positivity for CK20 and PAX8, focal positivity for AMACR, and negativity for CK7 and CD117. This immunophenotype is identical to that seen in TSC-associated granular eosinophilic-macrocystic RCC, although CK20 has been reported for only 2 cases.139 To summarize, TS involves susceptibility to neoplasms of multiple organ systems; the kidney is quite frequently involved with angiomyolipomas and cysts, the former often quite multifocal. The question of increased prevalence of RCC arising in the setting of TS remains controversial and is confounded by older studies that may have included epithelioid perivascular epithelioid cell tumors with clear cytology among “clear cell” RCCs. Synthesizing 2 recent series of well-characterized TS-associated RCCs,124,137 with our experience in this area, we find that most of the tumors show 1 of 3 patterns, either (1) papillary RCCs with predominantly clear cytology and prominent myomatous stroma (the so-called RAT-like pattern), (2) oncocytic carcinomas with variable oncocytoma and chromophobe RCC-like areas, and (3) tumors with the unique morphology described for the emerging entity of ESC-RCC. We suspect that increased scholarship in this area will continue to refine the spectrum and classification of RCCs seen in TS and determine the molecular basis for the relationship between TS-associated RCCs with the ESC-RCC pattern and sporadic ones. Von Hippel-Lindau Syndrome Von Hippel-Lindau syndrome is a tumor syndrome caused by mutations in VHL on chromosome 3. The syndrome manifests 324 www.pathologycasereviews.com with a variety of tumors, often with clear cells and rich vasculature, such as CCRCC and hemangioblastomas of the CNS. Correlations between phenotype and genotype have been characterized; deletions and truncations of the VHL gene (type 1 VHL) are associated with a low risk of pheochromocytoma and high risk of hemangioblastomas and RCC, whereas missense mutations of VHL (type 2 VHL) are associated with high risk of pheochromocytoma.11 Cutaneous lesions are limited to head and neck capillary malformations, seen in a small proportion of patients, and café-au-lait macules.117 While several of the syndromic tumors are uncommon and should raise the possibility of VHL by their diagnosis alone (hemangioblastomas, pancreatic serous cystadenomas, pancreatic neuroendocrine tumors with clear cell morphology, endolymphatic sac tumors, and papillary cystadenoma of the epididymis), several clues in the kidney, including multifocal CCRCC and distinctive renal cysts, may prompt diagnosis of the syndrome.12 In our experience, the substantial prevalence of the CNS lesions in VHL in particular leads to nephrectomy specimens coming “labeled” as from a patient with VHL or at least with prior documentation of the syndrome in the medical record, predicating our inclusion of this syndrome as one that may be recognized by careful review of the medical record. The gross pathology of the kidney in VHL is characteristic: bilateral, multifocal tumors with yellow to hemorrhagic cut surfaces with numerous cysts.11 The RCC of VHL has classic features of CCRCC, with nested clear cells arranged within a network of small capillaries. Whereas some VHL-associated RCCs show features reminiscent of clear cell papillary RCC (CCPRCC), these CCPRCC-like neoplasms of VHL lack the characteristic immunohistochemical staining pattern of CCPRCC (CK7 diffusely positive, CAIX positive, CD10 negative, AMACR negative) and further show frequent chromosome 3p deletion, as seen in CCRCC.140 Renal cysts, especially multifocal, lined by clear cells should prompt the pathologist to consider VHL. The cysts of VHL are lined by clear cells and may show proliferative features ranging from a thickened cyst lining to papillae formation to CCRCC— within a cyst wall formation.141,142 The presence of renal cysts lined by cells with clear cytoplasm, as opposed to the eosinophilic cuboidal cells lining typical renal cysts, has been shown to be distinctive for VHL.143 These cysts may be found in sections of grossly unremarkable kidney in patients with VHL, rendering close examination of nontumor sections (typically the last in the tray of slides) a source of potentially vital clues to detecting VHL. Furthermore, small, grossly undetected foci of CCRCC may be seen in these histologic sections from VHL-affected kidneys.143 In one study, the clear cells lining the renal cysts of VHL have been shown to have VHL deletions as well as CAIX positivity, supporting the hypothesis that these cysts represent an early phase of RCC tumorigenesis.144 CONCLUSIONS Throughout this review, we hope to have made the case that a modicum of suspicion, awareness, and clinical correlation may prompt the recognition of these syndromic tumors and thereby add real value for patients and their families. Our understanding of this role in integrated laboratory medicine continues to expand, and recent data support the pathologist's potential role in syndrome diagnosis.15,16 Particularly, as immunohistochemical reagents, ranging from MMR proteins to the Krebs cycle enzymes FH and SDHB, have gained widespread use, pathologic triage of suspicious cases, including recommending referral for genetic counseling and testing, is evolving from possibility to responsibility. In addition, we have already seen in anecdotal consultation cases that use of send-out high-throughput sequencing and other © 2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. AJSP: Reviews & Reports • Volume 22, Number 6, November/December 2017 multiplex molecular studies in the community, increasingly performed for advanced stage or unclassified tumors to try to identify a therapeutically targetable driver mutation, may “accidentally” identify a mutation associated with one of these syndromes. Key genes including FH, SDHB, and SDHA are tested in several popular AmpliSeq-based testing platforms, and soon this scenario will become increasingly pervasive. Certainly, caution is urged when these (at this time, mostly somatic) tumor-profiling studies are interpreted; it is our responsibility to note that a mutation seen in a tumor is just a mutation seen in a tumor, until with clinical correlation, genetic counseling, and testing for germline mutation, a syndromal diagnosis may be established. Given that several of these entities, especially SDH-deficient RCC and FH-deficient RCCs, are presently thought to arise predominantly in the setting of germline mutation, even if appearing to present sporadically, such findings cannot be ignored. With increasing experience and collaborative studies, it is our hope that we yet piece together the outstanding key questions of penetrance of tumor types per syndrome, the prevalence of sporadic forms of tumors closely associated with syndromes, and the morphologic, immunophenotypic, or molecular criteria to discriminate between them. One also suspects that, a number of years on into this era of whole-genome or whole-exome sequencing, the contemporary estimate that approximately 5% to 8%9 of kidney tumors are related to hereditary syndromes will be due for upward revision, as well. ACKNOWLEDGMENTS The authors thank the several colleagues who contributed photomicrographs as mentioned in the figure legends, as well as Drs Caleb King and Bryce Hatfield for critical reviews and editing. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. 2. Bennington JL, Beckwith JB. Tumors of the Kidney, Renal Pelvis, and Ureter. Washington, DC: Armed Forces Institute of Pathology Press; 1983. 3. Thoenes W, Storkel S, Rumpelt HJ. Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract 1986;181:125–143. 4. Storkel S, Eble JN, Adlakha K, et al. Classification of renal cell carcinoma: workgroup no. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80:987–989. 5. Kovacs G, Akhtar M, Beckwith BJ, et al. 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