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© 2019 College of American Pathologists

 Review Article
Eosinophilic Kidney Tumors
Old and New
Kenneth A. Iczkowski, MD; Rebecca C. Czaja, MD
 Context.—Eosinophilic cytoplasm is the most common
finding of difficult-to-classify kidney tumors. Morphology,
cytogenetics, and immunohistochemical stains are discrim-
inatory. 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 carci-
nomas 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.
E osinophilic cytoplasm is a well-established feature of
oncocytoma and chromophobe carcinoma. However,
this finding is shared by a host of other of 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 predom-
inantly oncocytoma/chromophobe RCC-like phenotype,
whereas 14% (19 of 136) were clear cell–like, and 13% (18
Accepted for publication May 22, 2019.
From the Department of Pathology, Medical College of Wisconsin,
Milwaukee.
The authors have no relevant financial interest in the products or
companies described in this article.
Dr Iczkowski is the president-elect of the International Society of
Urologic Pathology.
Corresponding author: Kenneth A. Iczkowski, MD, Department of
Pathology, Medical College of Wisconsin, 9200 W Wisconsin Ave,
Milwaukee, WI 53226 (email: kaiczkowski@mcw.edu).
Arch Pathol Lab Med
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 author’s
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.
(Arch Pathol Lab Med. doi: 10.5858/arpa.2019-0203-RA)
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 AND PAPILLARY-LIKE RCCS
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 a-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 immuno-
stains for papillary carcinoma include AMACR and CK7.6,7
The more useful of the two 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
Eosinophilic Kidney Tumors—Iczkowski & Czaja 1
Figure 1. Differential diagnosis of eosinophilic kidney tumors. Abbreviations: FH, fumarate hydratase; SDH, succinate dehydrogenase.

papillary pattern, but lack stromal cores showing blood negative for CD117. The tumors showed loss of 1p36 gene
vessels, red blood cells, and macrophages. When consider- loci, loss of chromosome Y, rearrangement of the CCND1
ing collecting duct/medullary carcinoma, CK34bE12 is gene, and copy number changes of chromosome 14. In
generally positive, but it is usually negative in papillary contrast to expected findings of papillary RCC, they did not
carcinoma. have trisomy of chromosomes 7 or 17 or gain of
Michalova et al8 described 10 cases with papillary RCC chromosome Y.
morphology and immunostaining, but with chromosomal A related entity is shown in an example of a 5-cm tumor
abnormalities resembling oncocytoma. The tumor cells in from a middle-aged woman. This was a grossly yellow
these specimens were mostly in a single layer, with tumor (Figure 2, A), microscopically consisting of thyroidlike
abundant eosinophilic cytoplasm and foamy macrophages. follicles with inspissated colloidlike secretions surrounded
Like papillary RCC, all of the cases were reactive for by abundant spindle cell stroma (Figure 2, B and C). This
AMACR, 7 of 10 were reactive for CK7, and all were example is thyroidlike follicular carcinoma, which is
considered a relative of papillary carcinoma.9,10 This tumor
displayed CK7 positivity, whereas AMACR was negative,
Table 1. Incidence of Renal Neoplasms With consistent with the literature. Staining with thyroid tran-
Prominent Eosinophilic Cytoplasm scription factor 1 (TTF-1) and thyroglobulin was negative;
Incidence Among Renal this ruled out a metastasis from the thyroid. CD10 stained
Entity Neoplasms the stromal component, but not the epithelium (Figure 2,
Papillary renal cell carcinoma, 5% (18% among all papillary D). Stromal cells were CK negative, as well as negative for
type 2 types) desmin and anti–muscle actin antibody (HHF35). The
Thyroidlike follicular 40 cases differential diagnosis in such a tumor includes a look-alike
carcinoma category called atrophic-like kidney lesion.11 According to
Xp11 translocation renal cell 3% recent research, the leiomyoma-like stroma in RCCs is
carcinoma polyclonal, and not part of the neoplastic process.12 This
FH deficient 20 cases previously called specimen came to be judged likewise. The clinical signifi-
unclassified19; others cance of this diagnosis was that the tumor was not a
SDH deficient 0.1% sarcomatoid carcinoma; the nucleolar grade was then 2 of 4,
Chromophobe 7% so the patient did not need to receive radiation.
Oncocytoma 7%
Hybrid oncocytic tumor 1% TRANSLOCATION CARCINOMAS
Liposarcoma Few A papillary pattern also characterizes Xp11 translocation
Epithelioid angiomyolipoma ,1%; 120 cases RCC.13 Grossly, the tumor is centered on the medulla, with
Xanthogranulomatous ,1% infiltration of perihilar fat (Figure 3, A). The growth pattern
pyelonephritis is predominantly nested alveolar or papillary (Figure 3, B).
Abbreviations: FH, fumarate hydratase; SDH, succinate dehydrogenase. Psammoma bodies (calcium apatite) are a frequent histo-
2 Arch Pathol Lab Med Eosinophilic Kidney Tumors—Iczkowski & Czaja
Figure 2. Thyroidlike follicular carcinoma. A, Gross. B, Circumscription stain. C, Stroma on left, follicle structures on right. D, CD10 stromal staining
(hematoxylin-eosin, original magnifications 34 [B] and 320 [C]; original magnification 340 [D]).

logic 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%.13–15 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
Arch Pathol Lab Med
discouraged.16 The most common subtypes of this tumor are
t(X;17) involving ASPSCR1-TFE and t(X;1) involving PRCC-
TFE3.14
TRICARBOXYLIC ACID CYCLE ENZYME–DEFICIENT
CARCINOMAS
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 hap-
pens 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 appear-
ance similar to that of tubulocystic carcinoma (Figure 4, A).
Eosinophilic Kidney Tumors—Iczkowski & Czaja 3

Figure 3. Xp11 translocation carcinoma, A, Gross, tumor in medulla.
B, Papillary-like morphology of an Xp11 translocation carcinoma. C,
Psammoma bodies are a histologic hallmark (hematoxylin-eosin,
original magnifications 34 [B] and 340 [C]) (courtesy Dr Ondrej Hes).
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
4 Arch Pathol Lab Med
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 pat-
tern.20 The tumor will show total loss of FH by immuno-
staining; 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 neuroendo-
crine-like nuclei (Figure 4, D). Like chromophobe carcino-
ma, 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.
RENAL ONCOCYTOMA AND CHROMOPHOBE
CARCINOMAS
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). Chro-
mophobe 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 pleomor-
phism (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
Eosinophilic Kidney Tumors—Iczkowski & Czaja
Figure 4. Tricarboxylic acid cycle–deficient carcinomas. A, Fumarate hydratase–deficient carcinoma, gross. B, Microscopic, prominent nucleoli
readily noted. C, Succinate-dehydrogenase deficient renal cell carcinoma, gross. D, Microscopic with frequent vacuoles. Courtesy of Dr Ondrej Hes
(hematoxylin-eosin, original magnifications 340 [B] and 310 [D]).

Table 2. Differential Diagnoses of Succinate Dehydrogenase (SDH)–Deficient Renal Cell Carcinoma

SDH-Deficient Renal Cell Chromophobe Renal Cell
Carcinoma Renal Oncocytoma Carcinoma
Immunohistochemistry
SDHB Negative Positive Positive
CK7 Negative Typically negative Commonly positive
CD117 Negative Negative Commonly positive
Morphology
Nuclei Neuroendocrine-like Round nuclei Raisinoid or koilocytic nuclei
Architecture Varied, rare hypocellular stroma Nests floating in hypocellular
stroma
Cytoplasmic vacuoles Present Absent Absent
Cytoplasm Flocculent eosinophilic Granular eosinophilic Crisp, plantlike edges
Degeneration May show dedifferentiation May show degenerative atypia
(enlarged nuclei with smudged
chromatin)
Entrapped nonneoplastic Common Rare Rare
tubules
Abbreviations: CD, cluster of differentiation; CK, cytokeratin; SDHB, succinate dehydrogenase complex iron sulfur subunit B.

Arch Pathol Lab Med Eosinophilic Kidney Tumors—Iczkowski & Czaja 5

 Table 3. Immunostaining in Oncocytoma Versus Chromophobe Renal Cell Carcinoma
Renal Oncocytoma
Vimentin Positive (73% of cases)
CD10 Negative
Hale colloidal iron Apical/luminal positivity
CK7 Negative (except single cells)
CD117 or DOG1 Positive
PR Positive
RCC marker Negative
Abbreviations: CD, cluster of differentiation; CK, cytokeratin; DOG1, discovered on GIST 1; PR, progesterone receptor; RCC, renal cell carcinoma.
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 away from these diagnoses. Additionally, up to
90% of cells in oncocytoma and 70% of cells in chromo-
phobe carcinoma have nuclear positivity for progesterone
receptor, and both are negative for estrogen receptor.25 For
ambiguous diagnoses, these tumors have distinct cytoge-
netic 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 differentia-
tion,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 degen-
erative nuclei) was determined based on 5 of the ‘‘worst’’
high-power fields in each case. The variation in nuclear size
was 3.7 6 0.5 lm for primary tumors with adverse
pathology and 3.4 6 0.4 lm for metastatic sites, which
differed significantly from 2.4 6 0.4 lm for primary control
tumors. An optimal variation in nuclear size cutoff of 2.5 lm
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).
6 Arch Pathol Lab Med
Hybrid Oncocytic Tumor Chromophobe
Usually positive Negative
Negative Negative
Cytoplasmic
Positive or negative Positive
Positive Positive
Positive
Positive
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.
OTHER MASSES
Entities other than carcinoma can present with eosino-
philic 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,
CK34bE12, 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) (immunohisto-
chemistry), and a lack of loss of integrase inhibitor 1 (INI1/
BAF47) (immunohistochemistry). Additionally, Ewing sar-
coma 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 dediffer-
entiated liposarcoma.
Another example is of a middle-aged Caucasian 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
Eosinophilic Kidney Tumors—Iczkowski & Czaja
Figure 5. Hybrid oncocytic tumor. A, Needle biopsy shows an island of cells (top) in edematous stroma, like oncocytoma. B, However, possible
nuclear haloes and binucleation resemble chromophobe. C, Cytokeratin 7 stains 70% of cells, in the manner of chromophobe carcinoma. D,
However, Hale colloidal iron stain is weak and focal, concentrated on lumen borders (left) as expected with oncocytoma (hematoxylin-eosin, original
magnifications 310 [A] and 320 [B]; original magnifications 34 [C] and 320 [D]).

extended exophytically from the superior aspect without
vein invasion. Microscopically, the tumor displayed multi-
nucleated 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), ty-
rosinase, and Melan-A (by 2 different chromogens).
Electron microscopy confirmed premelanosome-like gran-
ules, making this the first reported epithelioid angiomyoli-
poma 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
Arch Pathol Lab Med
and cystic architecture (as the name suggests), and have a
predominant CK7-negative/CK20-positive phenotype.37–39
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 muta-
tions 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
Eosinophilic Kidney Tumors—Iczkowski & Czaja 7
Figure 6. Xanthomatous pyelonephritis. A, Lesion extends into fat. B, Some multinucleate cells are evident. C, KP-1 (CD68) immunostain. D,
Cytokeratin AE1/3 stain is negative (hematoxylin-eosin, original magnifications 32 [A] and 320 [B]; original magnification 320 [C and D]).
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 multi-
nucleate 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. Xan-
thogranulomatous 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.
SUMMARY
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 cyto-
plasm. Given the new literature that has surfaced, estab-
lishing the correct diagnosis is more attainable then in
8 Arch Pathol Lab Med
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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