Spectrum of preneoplastic and neoplastic cystic lesions of the kidney.
CYSTIC DISEASES COMMONLY ASSOCIATED WITH TUMORS
Acquired Cystic Disease of the Kidney
The incidence of developing RCCs in the native kidneys of patients with acquired cystic disease of the kidney (ACDK) is approximately 3% to 7%, which represents up to 100 times greater risk than that found in the general population. (2-5) Acquired cystic disease of the kidney is often, though not always, associated with a history of dialysis. The duration of dialysis in patients with end-stage renal disease (ESRD) often correlates with the incidence of ACDK and RCC. At the same time, cystic disease is not always required for the development of tumors in the ESRD setting. In a recent series (6) of 52 patients with ESRD and RCC, only 39 (75%) had associated ACDK, whereas 13 (25%) had noncystic ESRD. The tumor types seen in ESRD and ACDK encompass (1) the 3 common subtypes of RCC, including clear cell (conventional) RCC, papillary RCC, and chromophobe RCC, which are morphologically similar to those found in sporadic settings, with papillary RCC being reported as the most common subtype among the 3; (2) the 2 other subtypes of RCC that are either exclusively or predominantly seen in the setting of ESRD: acquired cystic disease (ACD)-associated RCC, a tumor only found in the kidneys of patients with end-stage ACDK, (6,7) and clear cell papillary RCC, a newly established entity initially reported among patients with ESRD of both the cystic and noncystic types, (6) but which later was also described in sporadic settings. (8,9)
ACD-Associated RCC.--The ACD-associated RCC is the most common subtype of RCC seen in ACDK, accounting for the dominant mass in 36% of end-stage kidneys overall and in 46% of end-stage ACDK. (6) Grossly, the tumors are usually multifocal and bilateral, and are identified by imaging or incidentally in nephrectomies performed on nonfunctional, small, or shrunken kidneys bearing numerous cysts (Figure 1, A). Most tumors are well circumscribed, often appearing to arise within cysts (Figure 1, B). Larger tumors may appear more solid, with thick, fibrous capsule and foci of necrosis and hemorrhage. Microscopically, they appear in a background of numerous cysts with intervening renal parenchyma showing other changes of end-stage kidney disease (Figure 1, C), and the tumors show various combinations of acinar, solid alveolar, solid sheetlike, microcystic or macrocystic, and papillary architectural patterns. Tumor cells usually have abundant granular, eosinophilic cytoplasm and large nuclei with prominent nucleoli. Intracytoplasmic and intercellular, microscopic lumina, imparting a cribriform or sievelike appearance, are characteristic and are present in most cases, irrespective of the predominant architectural pattern. Most cases (79%) also show intratumoral oxalate crystals, (6) a relatively specific feature that has been consistently observed only in ACD-associated RCC and not in other tumor types arising in the ACDK setting (Figure 1, D). The prominent papillary architecture in some cases might lead to misinterpretation of these tumors as type 2 papillary RCC. Additionally, some tumors contain variable, usually only focal, areas of clear or vacuolated cytoplasm, which requires a differential diagnostic determination with clear cell RCC. By immunohistochemistry, the tumor cells stain diffusely positive for AMACR ([alpha]-methylacyl-coenzyme A racemase) but are negative or at the most focally positive for CK7. Stains for CD10, RCC, and glutathione S-transferase a are also reported to be positive. (10) Genetically, ACD-associated RCC is different from papillary or clear cell RCC. Rather than trisomy of chromosomes 7/17 or loss of 3p, which is characteristic of papillary and clear cell RCC, respectively, a recent study (10) on 9 cases of ACD-associated RCC showed variable combined gains of chromosomes 3, 7, 16, 17, and Y using fluorescence in situ hybridization and comparative genomic hybridization. In the nonneoplastic renal parenchyma, there are often cysts lined by large eosinophilic cells that show an immunophenotype similar to that of ACD-associated RCC. The cysts may be discrete and widely dispersed, but they may also cluster (clustered microcystic lesions; Figure 1, E).
Clear Cell Papillary RCC.--Clear cell papillary RCC is believed to be the second most common subtype of RCC in ESRD. Most of the tumors are well-circumscribed and are often variably cystic with fibrous capsule (Figure 2, A). Occasional tumors show marked myoid metaplasia of the capsule, sometimes with extensions of smooth muscle into the tumor. Most tumors exhibit variable papillary and tubular/acinar architecture. In some cases, papillae appear tightly packed, appearing solid. Sometimes the papillary structures tuft from the walls of the cystic spaces (Figure 2, B). Some tumors show markedly crowded, small, "collapsed" acini containing scant cytoplasm, and giving the tumor a solid, sheetlike appearance. Its relationship to the recently described renal angiomyoadenomatous tumor is unclear, but we believe that such tumors fall within the morphologic spectrum of clear cell papillary RCC. Except in solid, collapsed acinar areas, the tumoral cells have predominantly clear cytoplasm with low-grade (equivalent to Fuhrman grade 1-2) nuclei. One of the most characteristic features of the tumor is the linear arrangement of the tumor nuclei away from the basal aspects of the cells, either in the middle of the cell or closer to the apex (Figure 2, C). Foamy macrophages, tumor necrosis, and vascular invasion are not features of these tumors. Most tumors are small and confined to the renal parenchyma, although rare cases extending into the renal sinus have been described. (8,9)
The immunoprofile of these tumors is characteristic: tumor cells express carbonic anhydrase IX (CAIX) in a diffuse, membranous distribution but staining is absent along the luminal borders of the tumor cells (cup-shaped distribution) (Figure 2, D). CK7 staining is diffusely positive, whereas racemase (AMACR) staining is negative. CD10 is also negative in most cases, although it is common to see patchy or even diffuse immunoreactivity for 34[beta]E12. Occasionally, conventional clear cell RCCs may also show focal, linear nuclear arrangement, mimicking clear cell papillary RCC; however, other areas in the tumors lack such linear arrangement and demonstrate the classic morphologic findings of clear cell RCC. In our experience, an immunohistochemical panel that includes CK7, CAIX, and CD10 is helpful in distinguishing the 2 entities in such cases.
The biologic behavior of RCCs in ESRD is reported to be less aggressive than that of the RCCs in sporadic or non-ESRD settings; the tumors, at presentation, are often smaller and at lower stage. (3,11) However, a few cases have behaved aggressively and metastasized. ACD-associated RCC may have a greater potential for aggressive behavior than do other types of tumors in ESRD. Rare cases with sarcomatoid features have been reported, and as would be expected, these cases show aggressive clinical behavior. (6,12) Although the overall small, low-stage RCCs in ESRD may reflect their inherent biologic features in this setting, more likely, the stage and size are related to their incidental early detection because of close clinical follow-up and radiologic evaluations of patients with ESRD.
The mechanisms underlying the increased incidence of RCC in ESRD and ACDK have not been elucidated. The presence of multiple subtypes of RCCs in this clinical setting, even in the same patient, suggests ESRD has a unique "acquired predisposition" for molecular alterations facilitating renal tumorigenesis. Papillary adenomas and dilated tubules or clustered microcystic lesions lined by the eosinophilic cells (Figure 1, E) have been suggested as putative precursors of the tumors in the kidneys of ESRD. However, the exact relationship between the coexisting cysts and RCCs requires further investigation.
von Hippel-Lindau Syndrome
von Hippel-Lindau (VHL) syndrome is an autosomaldominant, inherited familial cancer syndrome predisposing patients to a variety of malignant and benign neoplasms, with retinal, cerebellar, and spinal hemangioblastomas, RCC, pheochromocytoma, and pancreatic tumors most frequent. (13,14) Patients carry a germline mutation or deletion of the tumor suppressor gene VHL located on 3p25-26. When a second, inactivating event affects the remaining wild-type VHL allele, loss or alterations of the VHL protein causes activation of the HIF1 hypoxia signal pathway, which likely leads to tumor formation.
Renal lesions occur in 30% to 70% of patients with VHL, including renal cysts, cystic clear cell RCCs, and solid clear cell RCCs. (14,15) The cysts are usually multiple and bilateral, may be unilocular or multilocular, and are lined exclusively by clear cells (Figure 3, A). Traditionally, when the epithelial lining is only one cell thick, the cysts are designated as benign (Figure 3, B); when the lining becomes 2 or 3 cells thick with focal papillary tufting, the cysts are called atypical cysts (Figure 3, C). Almost all tumors in the VHL setting are clear cell RCCs of low nuclear grade (Fuhrman grade 1 or 2) and stage. (15) The RCCs are often multicentric and bilateral, arising both within cysts and de novo from noncystic renal parenchyma. In patients with VHL who carry the VHL germline mutation, deletion of the second VHL allele is associated with overexpression of CAIX in scattered renal tubular cells, clear cells of renal cysts, and clear cell RCC. In contrast, CAIX2 renal tubular cells show no VHL deletion. These observations suggest that the loss of VHL occurs diffusely in the clear cell cysts of patients with VHL. Whether histologically designated as benign or atypical, the cysts lined by clear cells, or even single renal tubular epithelial cells with the VHL gene deletion in this setting, likely represent precursor lesions for clear cell RCC. (16)
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Renal cell carcinomas are rare in patients with VHL younger than 20 years, but they occur with increasing frequency thereafter. (13,15) The mean age at onset is 44years, and about 69% of patients surviving to 60 years will develop RCC. (17) Depending on the absence or presence of pheochromocytomas in a patient with VHL, the disease has been classified as type 1 and type 2, respectively. (13) Certain genotype-phenotype correlations have been established. Loss of VHL protein through large deletions or nonsense mutations are associated with type 1 disease (with no associated pheochromocytomas), whereas germline VHL missense mutations confer a high risk for the development of pheochromocytomas. (18) The multiple, metachronous tumors in VHL patients have also been shown to be not clonal and develop independently. (19,20) At the same time, by copy number alteration and gene expression analyses, clear cell RCCs seen in VHL have been found to be more homogenous and harbor fewer copy number events compared with sporadic clear cell RCCs. (20)
Because RCCs continuously keep developing in the bilateral kidneys of patients with VHL, clinical management relies on a delicate balance between excising tumors to prevent metastasis and preserving enough renal tissue to maintain renal function. In general, small tumors are managed conservatively by watchful waiting, and larger tumors (>3 cm) are excised by partial nephrectomy. (21) Multiple, repeat partial nephrectomies on the same kidney, although technically demanding, have been shown to help patients avoid dialysis. (22)
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Tuberous Sclerosis Complex
Tuberous sclerosis complex (TSC) is an autosomaldominant, hereditary disease involving multiple organs, such as brain, skin, heart, lungs, and kidneys. (23) The underlying molecular alterations are inactivating mutations of TSCI or TSC2, tumor suppressor genes on chromosome arm 9q and 16p encoding hamartin and tuberin, respectively. Up to 50% of cases have no family history and represent either new mutations or variation in disease penetrance. Renal involvement is seen in about 50% of patients and is manifested in the form of renal cysts, angiomyolipomas (AMLs), and RCCs. (24)
Renal cysts occur in 30% to 40% of cases. They are usually small and scattered within otherwise unremarkable, intervening renal parenchyma or clustered within a segment to give a spongelike appearance. Typical cysts of TSC are lined by granular eosinophilic cells with large nuclei; some cysts show papillary tufting or intraluminal papillary excrescences filling the cyst (Figure 4, A). (24) Diffuse cystic formation, similar to autosomal-dominant polycystic kidney disease, develops in 5% of patients with TSC2 because of dual mutations in the 2 genes located contiguously on chromosome 16, TSC2 and PKDL (25,26)
Angiomyolipomas are very common in TSC, involving 50% to 100% of patients and are often bilateral and multifocal. Although the rare variant of angiomyolipoma (AML), epithelioid AML, has been reported more frequently in TSC than it has in patients without TSC, (27) whether TSC serves as a risk factor for epithelioid AML is still not clear. In contrast, RCCs occur in only 2% to 4% of patients with TSC. Clear cell RCC is reported to be the most frequent type. (28) Several other tumors, including renal oncocytomas, chromophobe RCC, or unclassified tumors composed of large cells with pink granular cytoplasm, similar to those lining the cysts, have also been described. (29-32) Recently, some TSC-associated renal cell tumors with distinctive morphology and not fitting the description of any of the usual RCC categories in the current World Health Organization classification system were described. (32) Similar to such RCCs, we have also encountered tumors with sheetlike, glandular, or papillary architecture, composed of high-grade, eosinophilic, granular cells (Figure 4, B) or cells with voluminous, clear cytoplasm, mimicking translocation-associated carcinomas (Figure 4, C) in cases of TSC. These tumors are immunohistochemically negative for TFE proteins. It is conceivable that some of the tumors described in the earlier literature might, in fact, represent RCCs with features described above.
Epithelioid AMLs can closely mimic RCC; some of the tumors initially reported as RCC in patients with TSC have been shown to be examples of epithelioid AMLs. (33) Immunohistochemical stains for cytokeratin and HMB-45 may be helpful for this distinction. Epithelioid AMLs are [HMB-45.sup.+] and [cytokeratin.sup.-], whereas RCCs are [HMB-452.sup.-] and usually [cytokeratin.sup.+]. Distinct from clear cell RCCs in the VHL or sporadic setting, clear cell RCCs reported in patients with TSC do not harbor a loss of the chromosome arm 3p or a VHL gene mutation, suggesting that either they are not clear cell RCCs or mutations in the TSCI and TSC2 genes lead to clear cell or clear cell-like renal carcinogenesis via an alternate pathway. (34)
Autosomal-Dominant Polycystic Kidney Disease
Besides the aforementioned 3 types of renal cystic diseases with established associations to RCC, autosomaldominant polycystic kidney disease, the most common type of renal cystic diseases that accounts for 5% to 10% of all patients with ESRD on dialysis, has been postulated to be associated with an increased risk of RCC. However, there is no convincing evidence available supporting that association. (35-37) The reported potential precursor lesion, intracystic papillary tuftlike proliferation, is cytologically bland and is present in about 25% of the cases (Figure 5).
Other Cysts With or Without Associated Tumors
Simple cortical cysts constitute the most common renal cysts, with a reported incidence of more than 27% on radiologic evaluation in individuals older than 50 years. The number of these cysts and their incidence tends to increase with age. (38,39) Because most of these cysts have no important clinical significance, pathologists usually see them as incidental findings at autopsy or in kidneys removed for more-significant tumors or tumorlike conditions. The cysts are usually unilocular and oval to round with a smooth outline and lined by a single layer of flattened to cuboidal epithelium, often filled with transudate-like clear or straw-colored fluid. Infrequently, such cysts may be multilocular and demonstrate radiologic complexity, which may raise the possibility of a cystic neoplasm and lead to surgical resection.
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The lining epithelium in these unilocular or multilocular cysts occasionally shows more-complex architectural patterns (Figure 6). The lining in some cysts displays papillary proliferation of cuboidal or hobnail cells with either eosinophilic or basophilic cytoplasm; in some other cysts, the lining may be composed of clear cells in single or multiple layers but, in contrast to multilocular cystic RCC, without any mural clear cell clusters or nodules. Although displaying "atypical" features, these cysts essentially behave in a benign manner. (40) Knowing that even morecomplex multilocular lesions, with clusters of clear cells within the septa (multilocular cystic RCC), behave clinically in a benign manner (see later), we consider the cysts with clear cells to be benign and have used the designations such as multilocular clear cell-lined renal cysts. Ancillary studies we performed on a few cases have shown that the cysts with clear cells often demonstrate positivity for CK7 and CAIX and negative staining for CD10 and racemase, and the cysts with papillary proliferation, although exhibiting positive staining for CK7 and occasionally for racemase, are negative for trisomy of chromosomes 7/17 by fluorescence in situ hybridization. The significance of the staining patterns in these cysts, as well as their relationship to RCC, awaits further investigation.
PREDOMINANTLY CYSTIC RENAL TUMORS
Multilocular Cystic RCC
Multilocular cystic RCC, a renal cortical neoplasm with a distinct, multilocular gross appearance, is a variant of clear cell RCC. (41) Solid, grossly discernable mural nodules of the tumor are incompatible with the diagnosis. Microscopically, the tumor consists of numerous clear cell-lined cysts with small clusters of clear cells in the tumor septa (Figure 7). This entity accounts for approximately 4% of all clear cell RCCs and affects middle-aged adults with a male to female ratio of 1.2 to 2.1:1. Up to 90% of cases are discovered incidentally on radiologic evaluation for other causes. (42,43) The cystic tumor usually presents as a unilateral, solitary lesion with rare exceptions. In a recent study, VHL mutations were identified in 3 of 12 tumors (25%), and the tumor cells, in most cases, were strongly reactive to PAX2 and CAIX, similar to typical, low-grade clear cell RCC. (44) These findings are consistent with the concept of multilocular cystic RCC being a variant of clear cell RCCs. In line with the minimal tumor burden present in these tumors, prognosis is excellent; there was no recurrence or metastases on mean follow-up of more than 6.5 years in a more-recent study. (42) Based on the excellent outcomes, some have suggested redesignation of these lesions as multilocular cystic renal cell neoplasms of low malignant potential. (42) The differential diagnoses mainly include cystic nephroma, benign multilocular renal cortical cysts, and clear cell papillary carcinoma with predominant cystic configuration.
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Cystic Nephroma and Mixed Epithelial and Stromal Tumor
We, like some others, think cystic nephromas and mixed epithelial and stromal tumors represent a morphologic spectrum of the same entity. (45,46) Both tumors are typically located close to the renal hilum and pelvis. Cystic nephroma is entirely cystic, without any solid expansile growth or mural nodules. The mixed epithelial and stromal tumor is a multicystic or biphasic tumor with solid and cystic areas (Figure 8). In the adult population, both tumors show a marked female preponderance (F:M, 8:1). Steroid hormones have been suggested to play a role in the genesis and evolution of these tumors; women with these tumors often have a history of long-term estrogen replacement, whereas many men with the tumor have had long-term sex steroid exposure. Estrogen receptors and progesterone receptors are frequently expressed in the mesenchymal component. The stromal and epithelial components of both tumors show varied histologic features. The distinction between the cystic nephroma and the mixed epithelial and stromal tumor, in some cases, can be difficult to make and is more or less arbitrary. The presence of at least a 5-mm, solid component in the tumor has been considered by some (46) as sufficient for a designation of mixed epithelial and stromal tumor. In general, prominent ovarian-type stroma, smaller cysts, complex branching glands, phyllodes gland pattern, and stromal luteinization are more commonly seen in mixed epithelial and stromal tumors. The differential diagnosis mainly includes other cystic renal tumors discussed here. Solid mixed epithelial and stromal tumors also need to be distinguished from mesoblastic nephroma and metanephric adenofibroma. Cystic nephroma in the pediatric age group is an entity entirely distinct from the adult tumors and is considered a fully differentiated nephroblastoma (Wilms tumor).
Clear Cell Papillary RCC
Occurring in a sporadic setting, clear cell papillary RCC shows similar histologic features to the tumors seen in patients with ESRD; some tumors have a prominent cystic component (see above). Interestingly, multiple studies (8,9) have confirmed that these tumors do not show 3p25.3 losses, VHL gene mutation, trisomy of chromosome 7 or a loss of Y. Thus, the molecular alterations mediating the development of these tumors currently remain unknown.
Tubulocystic Carcinoma of the Kidney
Tubulocystic carcinoma of the kidney is a well-circumscribed tumor with pure tubular and cystic growth patterns, cysts and tubules lined by a single layer of atypical cells with abundant eosinophilic cytoplasm and a variable hobnail appearance, and stromal desmoplasia (Figure 9). Solid sheets or solid cell nests are not a feature of this tumor. Grossly, these tumors often have spongy cut surfaces with variably sized cysts. This entity is relatively uncommon and shows a strong male preponderance (M:F, 7:1). Clinically these tumors are less aggressive, with most presenting when small (pT1); approximately 10% of cases have shown local recurrence or distant metastasis. The relationship of these tumors to collecting duct carcinoma and papillary RCC remains controversial. (47-49) In our experience, areas sharing histologic features with tubulocystic carcinoma can occasionally be seen in otherwise typical collecting duct carcinoma.
Intrinsic Cystic Formation in Other Renal Cell Tumors of Various Subtypes
Besides the entities described above, intrinsic cyst formation or architectural pattern is also seen in many other RCC subtypes to a varying degree. Clear cell RCC may display areas of cystic architecture, especially in cases with low nuclear grades; papillary RCC, chromophobe RCC, collecting duct carcinoma, or even oncocytoma can all occasionally demonstrate focal to extensive cystic formation. A rare morphologic subtype of RCC, thyroidlike follicular carcinoma of the kidney, is characterized by a follicular, partially cystic, architectural pattern mimicking metastatic thyroid carcinoma.
RCC With Cystic Necrosis
Renal cell carcinoma with cystic necrosis is a relatively common phenomenon, often associated with clear cell RCC. Even extensively necrotic cystic RCCs (99% necrotic) have been shown to be capable of aggressive clinical behavior. (50) Extensive necrosis is not uncommon in papillary RCC. However, the extent of necrosis and cystic change in papillary RCC has no significant effect on the prognosis.
Epithelial Cysts in Mesenchymal Tumors Likely Developing From Entrapped Renal Tubules
Cysts lined by cuboidal to hobnail cells, with or without cytologic atypia, have been reported in primary renal synovial sarcoma and described in AML as AML with epithelial cysts. (51-53) These cysts have been hypothesized by some to represent entrapped, cystically dilated renal tubules in the corresponding mesenchymal tumors. Consistent with this hypothesis, primary synovial sarcomas of the kidney often harbor SYT-SSX2 gene fusion, the fusion type mostly associated with monophasic morphology. The cystic epithelium in AML with epithelial cysts is consistently negative for HMB-45 and estrogen receptor, suggesting an origin distinct from the
AML components. Diffuse labeling for PAX2/PAX8 has recently been demonstrated in the cysts of both entities, which is also consistent with the hypothesis that these cysts may develop from entrapped, dilated renal tubules. (54)
The presence of multiple renal cysts, both acquired and syndromic, may be associated with a variety of renal tumors. The morphology of the cysts and associated tumor types can help predict the genetic or acquired basis of the lesions, and such potential associations should be suggested in surgical pathology reports. Similar assumptions cannot be made in most predominantly cystic tumors that are not associated with cysts in the surrounding renal parenchyma.
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Ying-Bei Chen, MD, PhD; Satish K. Tickoo, MD
Accepted for publication October 17, 2011.
From the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Satish K. Tickoo, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 (e-mail: tickoos@ mskcc.org).
Renal Cystic Diseases Associated With Tumor Development Cystic Disease Disease Incidence Cancer Risk ESRD and ACD of the ESRD > 1:3000;ACDK Approximately kidney proportional to duration 3%-7% of dialysis (10 y, >90%) von Hippel-Lindau 1:30-50 000 45%-60% disease Tuberous sclerosis 1:10 000 2%-3% complex Autosomal-dominant 1:1000 Equivocal polycystic kidney disease Renal cysts with Age-related; >25% Likely extremely atypical epithelial at 50 y and older low or nil proliferation Potential Cystic Disease Tumor Types Preneoplastic Lesions ESRD and ACD of the ACD-associated RCC; Papillary adenoma; kidney clear cell papillary clustered RCC; usual types of microcystic RCC (papillary, lesions clear cell, chromophobe) von Hippel-Lindau Clear cell RCC Clear cell cyst disease (CAIX positive) Tuberous sclerosis Angiomyolipoma; clear Unknown; cysts complex cell RCC; lined by oncocytoma; RCC, eosinophilic unclassified/TSC- cells with atypia related Autosomal-dominant Clear cell RCC; Intracystic papillary polycystic kidney papillary RCC epithelial disease proliferation Renal cysts with Coincidentally Unknown atypical epithelial associated proliferation with RCCs Abbreviations: ACD, acquired cystic disease; ACDK, acquired cystic disease of the kidney; CAIX, carbonic anhydrase IX; ESRD, end-stage renal disease; RCC, renal cell carcinoma; TSC, tuberous sclerosis complex.
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|Author:||Chen, Ying-Bei; Tickoo, Satish K.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Apr 1, 2012|
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