Low-Grade Oncocytic Tumor: Report of Two Cases of An Emerging Entity in the Spectrum of Oncocytic Renal Neoplasms
Divakar SHARMA1, Trupti PAI1, Gagan PRAKASH2, Sangeeta DESAI1, Santosh MENON1
1Departments of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, MUMBAI, INDIA
2Departments of Uro-Oncology, Tata Memorial Centre, Homi Bhabha National Institute, MUMBAI, INDIA
Keywords: Low-grade oncocytic tumor, Immunohistochemistry, Oncocytic renal tumors, Emerging renal tumors
Low-grade Oncocytic Tumor (LOT) of kidney is an emerging neoplasm that forms an important differential diagnosis in a spectrum of entities
with oncocytic morphology. It has overlapping features with renal oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma,
but with distinct clinical, histomorphological and immunohistochemical features. LOT exhibits characteristic low grade oncocytic morphology
with a CD117 negative/CK7 positive immunophenotype. Herein, we describe two cases of this emerging entity, LOT, with emphasis on the
diagnostic aspects, including the histomorphology, immunoprofile and discussion on the close differentials.
Renal neoplasms with oncocytic/eosinophilic morphology
are a growing list of entities and their diagnosis is sometimes
challenging. Renal oncocytoma (RO) and eosinophilic
variant of chromophobe renal cell carcinoma (eChRCC)
are the most common tumors in this category. However,
many cases do not fit into the gamut of existing classified
entities. Low-grade Oncocytic Tumor (LOT) of kidney
is a provisionally named emerging renal neoplasm that
is not as yet included in the WHO classification of Renal
. These are low grade tumors with oncocytic
features, albeit with absence of nuclear features of eChRCC
and a characteristic CK7 positive/CD117 negative
immunoprofile. Ultrastructural features of numerous
mitochondria are seen in the cytoplasm of LOT (hence
the designation ‘oncocytic’), similar to RO, as against
numerous microvesicles with mitochondria that are seen
in eChRCC 1,2
. Additionally, karyotypic profile of LOT
is also in variance with either RO or eChRCC.
LOT is an addition to the other recently described
acronymic entities that include eosinophilic solid and cystic
renal cell carcinoma (ESC RCC) and high-grade oncocytic
renal tumor (HOT), all having distinct morphological
and immunophenotypic profile 3. Recognition of these
entities and their distinction from already characterized
renal tumors is important. Herein, we present the
clinicopathological features of two cases of this recently
described entity of LOT.
A 65-year male without any comorbidities presented
with lower urinary tract symptoms like increased
urinary frequency without any abdominal or flank pain.
Ultrasonography revealed a left renal hyperechoic mass
measuring 3.1x2.5 cm. Abdominal contrast enhanced
computerized tomography (CECT) revealed a solitary,
2.7x1.7x1.4 cm exophytic lesion in the upper and mid-pole
of the left kidney. Metastatic workup was negative. Left
partial nephrectomy was performed.
Gross findings revealed a well-circumscribed tumor
measuring 2 cm in the greatest dimension (pT1a). The
tumor had a tan brown, gelatinous and firm cut surface. No
central scar, hemorrhage or necrosis was seen (Figure 1A).
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|Figure 1: Case 1: A) Grossly,
cut surface revealed a wellcircumscribed,
gelatinous and firm tumor.
the tumor had an irregular
interface with the adjacent
renal parenchyma with no
capsule (B; H&E; 200x).
Tubuloreticular growth (C;
H&E; 200x) with low grade
oncocytic features (D; H&E;
400x) were observed.
diffuse CK7 positivity was
seen (E; IHC; 200x), while
CD117 was negative (F; IHC;
200x). Mast cells as internal
control in the adjacent
renal parenchyma were
immunoreactive (F; arrows).
On microscopy, the tumor was unencapsulated and had
an irregular interface with compressed renal parenchyma
at the periphery. The tumor had a solid, tubulocystic and
focal cribriform pattern. Tumor cells were monomorphic,
cuboidal in shape with moderate amount of oncocytic
cytoplasm and round centrally placed nuclei and focal
distinct nucleoli (WHO/ISUP grade equivalent was ISUP
grade 2). There were no prominent cell membranes,
no nuclear membrane irregularities or raisinoid nuclei.
(Figure 1B-D). There was no appreciable mitotic activity
or coagulative necrosis. Perinephric fat and Gerota’s fascia
were free of tumor. TNM stage was pT1aNxMx.
On immunohistochemistry (IHC), the tumor cells were
strongly and diffusely positive for CK7, while being
negative for CD117 (Figure 1E,F), vimentin and Alphamethylacyl-
CoA racemase (AMACR). E-cadherin staining
showed a diffuse membranous pattern and EMA showed
focal apical staining.
Based on these features, a diagnosis of low-grade oncocytic
tumor of kidney was given. Patient did not receive any adjuvant treatment. With a follow-up of 12 months till
date, the patient is disease free and asymptomatic.
Case 2 was a referral case and no clinical details were
available. We received an outside operated right radical
nephrectomy specimen of a 59-year male patient for
On gross examination, the tumor was well circumscribed,
at midpole, predominantly cortical based, with medullary
involvement. Tumor dimensions were 5.5x5x4 cm with
a grey white to tan brown, soft cut surface and focal
central areas of hemorrhage. No central scar or necrosis
was observed (Figure 2A). The tumor was confined to
the kidney; and the pelvicalyceal system, renal sinus,
perinephric fat, Gerota’s fascia and all cut margins (renal
artery, renal vein and ureter) were free.
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|Figure 2: Case 2: A) Grossly,
tumor cut surface was solid,
grey-white to tan, soft in
consistency with focal areas
of hemorrhage B,C,D)
Microscopically, a solid
growth pattern was observed
(B; H&E; 200x) with areas
of perivascular growth and
foci of hemorrhage (C; H&E;
200x). On high power, many
oncocytic cells showed
perinuclear halos with focal
infiltrate of lymphocytes (D;
diffuse CK7 positivity was
seen in the tumor cells (E;
IHC; 400x) while these were
negative for CD117 (F; IHC;
On microscopy, the tumor was sharply demarcated with
the adjacent renal parenchyma and had a predominantly
solid and nested growth pattern. The tumor cells had
uniform oncocytic cytoplasm with homogenous round
to oval nuclei (WHO/ISUP grade equivalent was ISUP
grade 1). Focal perinuclear halo were noted in many areas;
however, similar to case 1 there were no nuclear membrane
irregularities or raisinoid nuclei (Figure 2B-D). There was
no mitotic activity or coagulative tumor necrosis. Four hilar nodes identified were all negative for metastases.
TNM stage was pT1bN0Mx.
On IHC, the tumor cells were strongly and diffusely
positive for CK7, while being negative for CD117 (Figure
2E,F), CD10, AMACR, Synaptophysin and Chromogranin.
A diagnosis of low-grade oncocytic tumor of kidney was
given. No follow-up details were available for this case.
Oncocytic tumors with atypical or borderline morphology
and immunoprofile that do not fit the criteria of existing
defined entities are often reported descriptively as
‘Oncocytic renal neoplasm’ and comment is made regarding
their risk or malignant potential 4
. Trpkov et al. recently
published a series of 28 cases of renal oncocytic tumor
from 4 major institutions with characteristic low grade
morphology and typical CK7 positive/CD117 negative
immunoprofile, and designated such tumors as LOT
after detailed histomorphological and array comparative
genomic hybridization (aCGH) findings 1
In this series by Trpkov et al. the median age of the patients
was 66 years with a female preponderance. In our study,
both were male patients, one 65 years old (Case 1) and
the other 59 years old (Case 2). In concordance with the
literature, there was no syndromic association.
On gross examination, both tumors had circumscribed
borders; however, they were unencapsulated and had a
brownish, solid cut surface, without necrosis as is seen
in the previous studies. The majority of the cases (88%)
belonged to stage 1 with a median tumor size of 3 cm (1).
Similarly, both of our cases also were pT1, case 1 with 2 cm
tumor size, while in Case 2, tumor size was 5.5 cm. Both
were restricted to the kidney, without involvement of the
perinephric fat, renal sinus or Gerota’s fascia. Regional
nodes were negative for metastases (Case 2).
Microscopically, both the cases had a solid, compact
tubulocystic pattern. As reported previously 1, the
characteristic finding of loose reticular arrangement of
tumor cells within the edematous stroma was observed
in Case 1. This differentiates it histologically from
oncocytoma, which shows compact tumor island and nests
of tumor cells within the hypocellular stroma. Lymphocytic
aggregates described in the literature were not observed
in either of our cases 1. However, focal intercellular
sprinkling of lymphocytes was observed amidst tumor
cells in Case 2 (Figure 2D). Tumor cells had low grade
oncocytic morphology without any nuclear membrane
irregularities, multinucleation, or nuclear pleomorphism,
which differentiates the cases from eChRCC.
On IHC, both tumors had consistent findings of strong
diffuse CK7 positivity and CD117 negativity. The salient
features of LOT with its two main close differentials (RO
and eChRCC) are discussed in Table I. IHC workup with
CK7 and CD117 is commonly used to distinguish these
oncocytic entities. While RO and eChRCC are diffusely
positive for CD117, and negative or very focally positive
for CK7, LOT shows consistent CK7 positive/CD117
negative pattern as seen in both of our cases, while Hybrid
oncocytoma-chromophobe tumors (HOCT) are invariably
CD117 positive 5. Petersson et al. have comprehensively
described ‘sporadic’ HOCT in their case series of 14 cases
6. However, most of these tumors were positive for
CK7 and negative or focally marked with CD117. In all
probability, we believe these tumors were also cases of LOT
that have been designated as HOCT.
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|Table I: Salient features of LOT, Renal Oncocytoma and eosinophilic variant of ChRCC (1,2,9).
Apart from describing clinicopathological and immunoprofiles,
Trpkov et al. had aCGH performed in 9 of their
cases 1. Frequent deletions in chromosomes 1q, 19p
and 19q were observed. These karyotypic abnormalities
are unique and different from those observed in eChRCC
wherein either multiple losses of chromosome 1, 2, 6, 10, 13
and 17 (as in classic ChRCC) or no copy number variation
(CNV) are seen 2.
HOCT with features mixed between RO and ChRCC is
considered as a variant of ChRCC in the current 2016 WHO
Classification 2. However, HOCT are usually diagnosed
in the setting of multiple and bilateral tumors, typically
in association with clinical scenarios of renal oncocytosis
and Birt Hogg Dube syndrome 7,8. Definite diagnostic
criteria for sporadic cases of HOCT are ambiguous and
variable use of the terminology has been observed 4.
Clinically, all cases of LOT described by Trpkov et al. had
indolent behavior with a favorable prognosis 1. However,
precise biological behavior of these tumors could not be
ascertained since the clinical follow up period was relatively
limited. More studies with larger cohorts and longer follow
up data are required to establish the indolent behavior of
these tumors. The present case (Case 1) is disease free and
is asymptomatic over a follow-up of 12 months, till date.
These two cases highlight that LOT can have different
morphological patterns and a better understanding of the
clinical, histomorphologic and immunoprofile of LOT
is important to differentiate it from its mimickers with
consequent development of management and surveillance
guidelines. Also, as more cases are recognized and
characterized, LOT would need to be formally incorporated
as a provisional entity in the next WHO classification of
renal tumors owing to its prognostic implications.
CONFLICT of INTEREST
None of the authors have any conflict of interest
As per our Institutional Ethics Committee policy for case
reports, consent is not required as long as the patient
information is anonymized and the submission does
not include images that may identify the person. In our
case report, no patient identifying information or clinical
images have been used. The authors state that the patient
confidentiality has been maintained and no patient
identifiers are used in this case report.
Concept: SM, Design: SM, DS, Data collection or
processing: DS, GP, Analysis or Interpretation: SM, TP, GP,
SD, Literature search: DS, Writing: DS, TP, SM, Approval:
SM, DS, TP, GP, SD.
1) Trpkov K, Williamson SR, Gao Y, Martinek P, Cheng L, Sangoi
AR, Yilmaz A, Wang C, San Miguel Fraile P, Perez Montiel DM,
Bulimbasić S, Rogala J, Hes O. Low-grade oncocytic tumour
of kidney (CD117-negative, cytokeratin 7-positive): A distinct
entity? Histopathology. 2019;75:174-84.
2) Paner G, Amin M, Moch H, Stokel S. Chromophobe renal cell
carcinoma. In: Moch H, Humphrey P, Ulbright TM, Reuter VE,
editors. WHO Classification of Tumours of the Urinary System
and Male Genital Organs. 4th ed. International Agency for
Research on Cancer: Lyon; 2016.27-28.
3) Siadat F, Trpkov K. ESC, ALK, HOT and LOT: Three letter
acronyms of emerging renal entities knocking on the door of the
WHO classification. Cancers (Basel). 2020;12:168.
4) Williamson SR, Gadde R, Trpkov K, Hirsch MS, Srigley JR,
Reuter VE, Cheng L, Kunju LP, Barod R, Rogers CG, Delahunt
B, Hes O, Eble JN, Zhou M, McKenney JK, Martignoni G,
Fleming S, Grignon DJ, Moch H, Gupta NS. Diagnostic criteria
for oncocytic renal neoplasms: A survey of urologic pathologists.
Hum Pathol. 2017;63:149-56.
5) Hes O, Petersson F, Kuroda N, Hora M, Michal M. Renal hybrid
oncocytic/chromophobe tumors - A review. Histol Histopathol.
6) Petersson F, Gatalica Z, Grossmann P, Perez Montiel MD,
Alvarado Cabrero I, Bulimbasic S, Swatek A, Straka L, Tichy
T, Hora M, Kuroda N, Legendre B, Michal M, Hes O. Sporadic
hybrid oncocytic/chromophobe tumor of the kidney: A
clinicopathologic, histomorphologic, immunohistochemical,
ultrastructural, and molecular cytogenetic study of 14 cases.
Virchows Arch. 2010;456:355-65.
7) Gobbo S, Eble JN, Delahunt B, Grignon DJ, Samaratunga H,
Martignoni G, Zhang S, Wang M, Brunelli M, Cossu-Rocca
P, Cheng L. Renal cell neoplasms of oncocytosis have distinct
morphologic, immunohistochemical, and cytogenetic profiles.
Am J Surg Pathol. 2010;34:620-6.
8) Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B,
Linehan WM, Merino MJ. Renal tumors in the Birt-Hogg-Dubé
syndrome. Am J Surg Pathol. 2002;26:1542-52.
9) Hes O, Moch H, Reuter VE. Oncocytoma. In: Moch H, Humphrey
P, Ulbright TM, Reuter VE, editors. WHO Classification of
Tumours of the Urinary System and Male Genital Organs. 4th
ed. International Agency for Research on Cancer: Lyon; 2016.43-44.