Context.—

Eosinophilic cytoplasm is the most common finding of difficult-to-classify kidney tumors. Morphology, cytogenetics, and immunohistochemical stains are discriminatory. This review compares well-recognized tumors such as granular clear cell carcinoma, papillary variants, chromophobe renal cell carcinoma, and oncocytoma and introduces newly described entities of hybrid oncocytic tumors, carcinomas defined by translocations, and carcinomas with deficiencies in the tricarboxylic acid cycle. The focus is on immunostaining, clinical correlations, and differential diagnoses. Representative examples of some entities are presented with elaboration on their workup.

Objective.—

To provide a review of the differential diagnoses for renal neoplasms with eosinophilic cytoplasm and elaborate on methods that may assist with correct identification.

Data Sources.—

Review of current literature on kidney tumors with eosinophilic cytoplasm, as well as the authors' personal experience.

Conclusions.—

Eosinophilic cytoplasm is a feature shared by many kidney tumors. Understanding the morphologic differences and the role of ancillary studies is key when encountering such a tumor.

Eosinophilic cytoplasm is a well-established feature of oncocytoma and chromophobe carcinoma. However, this finding is shared by a host of other kidney tumors (Figure 1). This review covers incidences (Table 1) and diagnostic criteria and stains to help with newly described and rare entities.

During the last few decades, the discovery of new, molecularly defined cancer types and immunostains has decreased the necessity to diagnose “renal cell carcinoma (RCC), unspecified.” Consequently, the percentage of RCC with unspecified histology recorded in the National Cancer Database declined from 1998 to 2014 (among 295 483 RCCs diagnosed) to 28% in community hospitals (−21%) and 10% (−63%) at National Cancer Institute–designated cancer programs.1  Despite the decrease, applying a diagnosis of RCC, unspecified, may limit the consideration of RCC type when clinicians choose targeted therapies for their patients.

Eosinophilic cytoplasm was the most common finding in a series of “RCCs, unclassified” (113 of 136 cases; 83%).2  Most (94 of 136 cases; 69%) were International Society of Urological Pathology (ISUP) nucleolar grades 3 or 4. Seventy-three percent (99 of 136) of cases had a predominantly oncocytoma/chromophobe RCC-like phenotype, whereas 14% (19 of 136) were clear cell–like, and 13% (18 of 136) resembled papillary RCC, collecting duct sarcoma, or sarcomatoid carcinoma.3,4  Therefore, the overrepresentation of eosinophilic tumors among those that are problematic creates an incentive to understand their ISUP classification.4 

Clear cell RCC can present with areas of cells with abundant pink cytoplasm, which is known as the granular variant.4  While reviewing a resection specimen, it is usually possible to find a transition to a definite clear cell pattern. In biopsies, however, the amount of tissue is far less. In these cases, immunostaining can be helpful. Staining with cytokeratin (CK) 7 and α-methylacyl CoA racemase/P504s (AMACR) can rule out papillary carcinoma, and cluster of differentiation (CD) 117 can be useful in ruling out chromophobe RCC and oncocytoma.5 

If the growth pattern is papillary with macrophages in stromal cores, the oncocytic variant of papillary RCC may be considered.6,7  Histologically, there are 2 types of papillary RCC: type 1 and type 2. Type 1 has a single layer of cells with less cytoplasm lining the papillae. Type 2 papillary RCC and the oncocytic variant share abundant pink cytoplasm and pseudostratified cells. Oncocytic variant was included in the 2016 World Health Organization classification as a potential type 3 papillary RCC. The presence of foamy macrophages in the stroma, a constant feature of papillary carcinoma, is diagnostically valuable.7,8  Useful immunostains for papillary carcinoma include AMACR and CK7.6,7  The more useful of the 2 is AMACR, which stains 93% of both type 1 and type 2 papillary carcinomas. CK7, although staining most type 1 carcinomas, stains only 20% of type 2 carcinomas. Papillary RCC is also positive for CD10 and negative for CD117, which is helpful for ruling out oncocytoma.5,7  Morphologically, oncocytomas may have a papillary pattern, but lack stromal cores showing blood vessels, red blood cells, and macrophages. When considering collecting duct/medullary carcinoma, CK34βE12 is generally positive, but it is usually negative in papillary carcinoma.

Michalova et al8  described 10 cases with papillary RCC morphology and immunostaining, but with chromosomal abnormalities resembling oncocytoma. The tumor cells in these specimens were mostly in a single layer, with abundant eosinophilic cytoplasm and foamy macrophages. Like papillary RCC, all of the cases were reactive for AMACR, 7 of 10 were reactive for CK7, and all were negative for CD117. The tumors showed loss of 1p36 gene loci, loss of chromosome Y, rearrangement of the CCND1 gene, and copy number changes of chromosome 14. In contrast to expected findings of papillary RCC, they did not have trisomy of chromosomes 7 or 17 or gain of chromosome Y.

A related entity is shown in an example of a 5-cm tumor from a middle-aged woman. This was a grossly yellow tumor (Figure 2, A), microscopically consisting of thyroidlike follicles with inspissated colloidlike secretions surrounded by abundant spindle cell stroma (Figure 2, B and C). This example is thyroidlike follicular carcinoma, which is considered a relative of papillary carcinoma.9,10  This tumor displayed CK7 positivity, whereas AMACR was negative, consistent with the literature. Staining with thyroid transcription factor 1 (TTF-1) and thyroglobulin was negative; this ruled out a metastasis from the thyroid. CD10 stained the stromal component, but not the epithelium (Figure 2, D). Stromal cells were CK negative, as well as negative for desmin and anti–muscle actin antibody (HHF35). The differential diagnosis in such a tumor includes a look-alike category called atrophic-like kidney lesion.11  According to recent research, the leiomyoma-like stroma in RCCs is polyclonal, and not part of the neoplastic process.12  This specimen came to be judged likewise. The clinical significance of this diagnosis was that the tumor was not a sarcomatoid carcinoma; the nucleolar grade was then 2 of 4, so the patient did not need to receive radiation.

A papillary pattern also characterizes Xp11 translocation RCC.13  Grossly, the tumor is centered on the medulla, with infiltration of perihilar fat (Figure 3, A). The growth pattern is predominantly nested alveolar or papillary (Figure 3, B). Psammoma bodies (calcium apatite) are a frequent histologic hallmark (Figure 3, C). Xp11 translocation cancers are more common in children and young adults, with a mean age of 31 and a female predilection of 57%.1315  The microphthalmia transcription factor (MiT) family gene undergoes translocation and is fused to a family of transcription factors, including TFE3 and TFEB, which has multiple gene partners.14  The nuclear reactivity for TFE is detectable with fluorescence in situ hybridization break-apart probes or immunostaining. Many variants have an abundant eosinophilic cytoplasm. A study of 47 cases (incidence 3% of all RCCs) displays rapid growth and progression of such tumors.16  Treatment is simple resection, although the mechanistic target of rapamycin (mTOR) and tyrosine kinase inhibitors may be beneficial.17  Notably, ISUP nucleolar grading was found to be noncontributory to predicting outcome in Xp11.2 translocation RCC, and is discouraged.16  The most common subtypes of this tumor are t(X;17) involving ASPSCR1-TFE and t(X;1) involving PRCC-TFE3.14 

Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are enzymes for consecutive steps in the tricarboxylic acid cycle, of which deficiencies give rise to distinct tumors. Fumarate hydratase–deficient tumors have a buildup of a byproduct, S-(2-succino)-cysteine (2SC), which also happens to accumulate in obesity and diabetes.18  Staining for 2SC is diagnostically useful because FH protein is rarely expressed, despite the presence of an FH mutation.19,20  FH-deficient carcinoma grossly exhibits a bubble-wrap appearance similar to that of tubulocystic carcinoma (Figure 4, A). It arises from the medulla (distal nephron), similarly to medullary and collecting duct carcinomas. Like medullary and collecting duct carcinomas, FH-deficient carcinoma characteristically presents at an advanced pathologic stage. Inclusion-like nucleoli (resembling cytomegalovirus) are a histologic hallmark of these tumors, and they display a variety of patterns (Figure 4, B). Most commonly, FH-deficient carcinomas will mimic the pattern of papillary RCC type 2 (74% of cases), and cribriform growth may also be seen (41% of cases).19 

Clinically, these tumors are usually associated with cognitive impairment and developmental delay. Some are associated with hereditary leiomyomatosis–RCC syndrome, involving uterine or skin leiomyomas, and patients may have a buildup of fumaric acid in their urine.19  FH-deficient carcinoma has no distinct chromosomal aberration pattern.20  The tumor will show total loss of FH by immunostaining; however, the sensitivity of this marker is reduced because missense mutations in the FH gene can yield retained staining. Thus, the best marker is the induction of 2-SC. The differential diagnosis for FH-deficient carcinoma includes medullary carcinoma, which can be ruled out with a negative INI1/SMARCB1, as this stain is retained in FH-deficient tumors.

SDH-deficient carcinomas have germline mutations in the SDH complex iron sulfur subunit B (SDHB) gene.18  The SDHB gene is composed of 4 subunits and is critical for the function of oxidative phosphorylation in mitochondria. As such, mutations in the SDHB gene serve as a marker for dysfunction in mitochondrial complex II. Patients with mutations in SDHB have also been associated with paragangliomas (30%) and pulmonary chondromas, and a small percentage with gastrointestinal stromal tumors. Such patients with concurrent gastrointestinal stromal tumors are resistant to treatment with imatinib. SDH-deficient RCC metastases occur in 33% of specimens, particularly those that are high grade.18  Grossly the tumor is cystic (Figure 4, C), and 26% are bilateral. The histologic hallmark is flocculent cytoplasmic vacuoles with a pale eosinophilic, wispy, or bubbly appearance with low-grade neuroendocrine-like nuclei (Figure 4, D). Like chromophobe carcinoma, this tumor is generally positive for CK7. There is loss of SDHB, unlike eosinophilic chromophobe carcinoma, which would retain positivity for SDHB. SDH-deficient carcinoma shares a differential diagnosis with chromophobe carcinoma and oncocytoma; criteria are shown in Table 2.

There are several points of comparison between renal oncocytoma and chromophobe RCC. Focally, chromophobe carcinoma displays islands of cells with abundant cytoplasm, separated by edematous stroma, with crisp plant cell–like cytoplasmic borders (cytoplasmic retraction effect). Chromophobe carcinoma features nuclear wrinkling and halos, and is composed of 3 cell types.21  Type 1 cells are small, with solid, slightly granular eosinophilic cytoplasm; type 2 cells display perinuclear halos or a translucent zone in a background of pale and flocculent, but not clear, cytoplasm; and type 3 cells are large, polygonal cells with hard cell borders and abundant cytoplasm with a reticular pattern.

Considering oncocytomas, grossly, they are well-defined, mahogany brown to tan-yellow tumors. Microscopically, they consist of solid nests of cells that can display nuclear enlargement due to degenerative atypia.22  Amin et al23  described a variety of morphologic patterns: archipelaginous (classic), tubulocystic, trabecular, and with scarring and haloes, prominent nucleoli (42%), degenerative pleomorphism (12%), oncoblasts (12%), and fat invasion (12%). Recently, retinoblastoma (Rb) was reported as a specific marker for oncocytoma that is negative in chromophobe carcinoma.23,24 

Chromophobe carcinoma has an eosinophilic variant that can be mistaken for oncocytoma. Certain immunostains may help to distinguish oncocytoma, hybrid oncocytic tumor, and an eosinophilic variant of chromophobe carcinoma (Table 3). Chromophobe carcinoma is usually a “vimentinphobe,” negative for vimentin.25  The most useful stain to diagnose chromophobe RCC is CK7, which stains diffusely positive.26  Comparably, oncocytomas present with single cell positivity and clear cell carcinomas will most commonly be CK7 negative, helping to narrow the differential diagnosis away from these diagnoses. Additionally, up to 90% of cells in oncocytoma and 70% of cells in chromophobe carcinoma have nuclear positivity for progesterone receptor, and both are negative for estrogen receptor.25  For ambiguous diagnoses, these tumors have distinct cytogenetic differences, with oncocytoma commonly having normal karyotype.27 

It has been known for a decade that the Fuhrman or ISUP nucleolar grading systems are not prognostically relevant for chromophobe carcinoma. The ISUP currently recommends against grading this entity entirely.28,29  The Paner grading system for chromophobe carcinoma,30  based on nuclear crowding and anaplasia, was devised as an alternative in 2010. This system was found to add no prognostic value after considering TNM stage and sarcomatoid differentiation,31  so the recommendation against grading remained unaltered.29 

A recent study considered variation in nuclear size when grading chromophobe carcinoma in a series of 32 primary chromophobe carcinomas.32  This series compared 12 chromophobe carcinomas with adverse pathology (stage pT3, recurrence, or metastasis), 15 controls (stage ≤pT2, no recurrence or metastasis after >3 years), and 8 metastases (3 were paired with primary adverse cases). Nuclei were measured by micrometer, and the mean variation in nuclear size between largest and smallest nuclei (excluding degenerative nuclei) was determined based on 5 of the “worst” high-power fields in each case. The variation in nuclear size was 3.7 ± 0.5 μm for primary tumors with adverse pathology and 3.4 ± 0.4 μm for metastatic sites, which differed significantly from 2.4 ± 0.4 μm for primary control tumors. An optimal variation in nuclear size cutoff of 2.5 μm was determined to discriminate adverse from indolent tumors. This study suggested that a grading system based on nuclear morphology would hold some relevance for prognosis.

An entity with overlapping features of oncocytoma and chromophobe carcinoma is hybrid oncocytic tumor. In this needle biopsy (Figure 5, A and B), perinuclear haloes are few, and occasional binucleate cells may be seen. The tumor is vimentin positive, and CK7 stains 70% of cells (Figure 5, C). Hale colloidal iron, however, is weak and stains only luminal borders, similar to oncocytoma (Figure 5, D). Hybrid oncocytic tumors behave intermediately between oncocytoma and chromophobe cell carcinoma.22,33  Table 3 compares hybrid oncocytic tumor with chromophobe carcinoma and oncocytoma. In a large series of oncocytic tumors by Delongchamps et al,34  hybrid oncocytic tumor represented 10% of tumors. Some hybrid oncocytic tumors are associated with renal oncocytosis or Birt-Hogg-Dubé syndrome (caused by an autosomal dominant mutation of the folliculin [FLCN] gene), which is itself associated with renal oncocytosis.21  Others are sporadic.34  Tumors are well demarcated and unencapsulated grossly, range from 2 to 11 cm, and may have a central scar.22  When findings are conflicting or limited (as in needle biopsies), 5 practical diagnostic choices apply: (1) oncocytoma; (2) oncocytic neoplasm, favor oncocytoma pending complete excision; (3) oncocytic neoplasm, see note (explaining overlapping findings); (4) oncocytic neoplasm, favor chromophobe carcinoma; and (5) chromophobe carcinoma.

As a further complication, a category of CD117-negative, CK7-positive tumors has also been described.35  These tumors do not completely fit into either eosinophilic chromophobe or oncocytoma categories. They uniformly show losses of 19p33.3 and/or 1p36.33, and display a solid, vaguely nested growth pattern.

Entities other than carcinoma can present with eosinophilic cytoplasm. As an example, a tumor from the left kidney of a middle-aged man was an 18-cm cystic and necrotic mass. On examination, there were areas of necrosis, and the tumor involved the inked resection margin as well as the colonic mesentery. Immunostaining for mouse double minute 2 (MDM2) showed focal nuclear positivity, but all other markers were negative, including CD31, erythroblast transformation-specific (ETS)–related gene (ERG), desmin, smooth muscle actin (SMA), CKAE1/3, CK34βE12, and CK18, AMACR, human melanoma black (HMB)–45, and CD117. Staining for CD99 displayed focal cytoplasmic positivity, but not membranous. Further testing provided positive MDM2 (cytogenetics), negative leukemia integration 1 transcription factor (FLI-1) (immunohistochemistry), and a lack of loss of integrase inhibitor 1 (INI1/BAF47) (immunohistochemistry). Additionally, Ewing sarcoma breakpoint region 1 (EWSR1) translocation testing by fluorescence in situ hybridization was negative. Altogether, a rhabdoid tumor, primitive neuroectodermal tumor, and Ewing sarcoma were ruled out. The diagnosis was dedifferentiated liposarcoma.

Another example is of a middle-aged white man with no history of tuberous sclerosis.36  He was found to have a 7.5-cm mass in the upper pole of a kidney. This mass extended exophytically from the superior aspect without vein invasion. Microscopically, the tumor displayed multinucleated giant cells, and was positive for calponin and SMA and negative for CKs. Additionally, the tumor lacked reactivity for the melanin-associated antigens HMB-45, microphthalmia-associated transcription factor (MITF), tyrosinase, and Melan-A (by 2 different chromogens). Electron microscopy confirmed premelanosome-like granules, making this the first reported epithelioid angiomyolipoma that was negative for premelanosome antigens. Epithelioid angiomyolipomas are a type of perivascular epithelioid cell tumor, similar to perivascular epithelioid cell tumors in locations such as liver and lungs.

Angiomyolipomas are often associated with tuberous sclerosis complex, and this is concurrent with 45% of epithelioid angiomyolipomas as well.36  Because of their varying appearances and pleomorphism, renal epithelioid angiomyolipomas can pose diagnostic difficulty, particularly if adipose cells are lacking.

Tuberous sclerosis complex (TSC) mutations are not exclusive to angiomyolipoma. A novel entity among kidney cancers is the eosinophilic solid and cystic RCC described by Trpkov et al.37  These occur mostly in women, have a solid and cystic architecture (as the name suggests), and have a predominant CK7-negative/CK20-positive phenotype.3739  Aggregates of histocytes and lymphocytes are commonly admixed with the tumor. Most eosinophilic solid and cystic RCCs have mutations in the TSC1 or TSC2 genes for tuberous sclerosis.40,41 

Another entity was recently described involving 7 cases that consisted of eosinophilic cells that differed from eosinophilic solid and cystic RCC by having prominent vacuolated cytoplasm.40  Unlike eosinophilic solid and cystic RCC, these cases were negative for CK7 and CK20, had a high nucleolar grade, and lacked an interspersed histiocyte and lymphocyte infiltrate. All of the tumors had previously been diagnosed in the unclassified renal cell category. Among 5 cases that were able to be tested with next-generation sequencing, 3 had somatic inactivating mutations of TSC2, and 2 had activating mutations of mTOR as well as the loss of chromosome 1. The end result was that all of the cases had hyperactive mTOR complex I signaling, as demonstrated by immunostaining.

Some renal masses with eosinophilic cytoplasm are benign. An example that exemplifies this was that of an elderly woman with focally cystic kidney masses, 6.5 and 4.0 cm. These masses extended into the perirenal adipose tissue and replaced the renal parenchyma (Figure 6, A). The differential diagnosis was narrowed by the lesion's multinucleate cells (Figure 6, B) and positivity for CD68 (Figure 6, C), but the lesion was negative for wide-spectrum CKs (Figure 6, D). Given the foamy histiocytes, the mass was diagnosed as xanthogranulomatous pyelonephritis. Xanthogranulomatous pyelonephritis is caused by chronic Escherichia coli or Proteus infection, and may contain fat.42  Differential diagnosis of this entity also includes renal replacement lipomatosis in which the clear to eosinophilic cells are fat cells, not xanthoma cells. This condition is characterized by varying degrees of renal parenchymal atrophy and perirenal fibrofatty proliferation secondary to chronic inflammation. In severe cases, imaging alone suggests a misdiagnosis of retroperitoneal liposarcoma.

Kidney tumors featuring eosinophilic cytoplasm can lead the examining pathologist down a difficult path to correctly diagnose the entity. Morphologically, many of these masses share multiple similarities other than eosinophilic cytoplasm. Given the new literature that has surfaced, establishing the correct diagnosis is more attainable then in previous decades. This includes better understanding of morphology as well as the emergence of ancillary studies that may be used to assist in diagnosis. Establishing the diagnosis is critical to the well-being of patients, and attention to distinguishing features and understanding the next step in the differentiation of these lesions will allow for more targeted therapy and ultimately better patient care.

Figure formatting done by Oleksandr Kravtsov, MD.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.

Competing Interests

Dr Iczkowski is the president-elect of the International Society of Urologic Pathology.