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www.onco a ge .com Onco a ge , 2022, Vol. 13, pp: 387-392
Resea ch Pape
Me aneph ic adenoma: molecula s udy and e iew o he
li e a u e
En ique Rod íguez-Za co1, Jesús Machuca-Aguado1, Lau a Macías-Ga cía2, Ana
Vallejo-Bení ez3 and Juan José Ríos-Ma ín1
1Pa hology Depa men , Uni e si y Hospi al Vi gen Maca ena, Se ille, Spain
2School o Medicine, Uni e si y o Se ille, Se ille, Spain
3Pa hology Depa men , Regional Uni e si y Hospi al o Malaga, Malaga, Spain
Co espondence o: En ique Rod íguez-Za co, email: [email p o ec ed]
Keywo ds: me aneph ic adenoma; BRAF; enal neoplasms
Recei ed: No embe 24, 2021 Accep ed: Janua y 17, 2022 Published: Feb ua y 17, 2022
Copy igh : © 2022 Rod íguez-Za co e al. This is an open access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion
License (CC BY 3.0), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal au ho and sou ce
a e c edi ed.
ABSTRACT
In oduc ion: Me aneph ic adenoma (MA) is an uncommon benign umo
accoun ing o 0.2–0.7% o adul enal epi helial neoplasms. The clinical cou se
is o en indolen , bu diagnosis should no be delayed since clinical symp oms
(hema u ia, e e , palpable abdominal mass, and lank pain) may be non-speci ic
and o e lap wi h hose o a malign enal neoplasm. We epo on 4 cases o AM, o
which mo phological and mu a ional analysis we e pe o med.
Ma e ial and Me hods: Immunohis ochemical s aining was pe o med on sec ions
cu om pa a in blocks o assess exp ession o WT1, imen in, acemase, CK7, CD10
and RCC. Tes ing o he BRAF gene mu a ion V600 was ca ied ou using eal- ime
PCR (Cobas® 4800).
Resul s: In all ou cases, umo s we e isible as well-ci cumsc ibed, non-
encapsula ed masses loca ed in he enal co ex and ex ending owa ds he medulla.
A immunohis ochemical examina ion, umo cells s ained nega i e o CK7, CD10
and RCC and posi i e o bo h WT1 (nuclea , in ense) and imen in (cy oplasmic,
in ense, and di use). Molecula analysis e ealed he BRAF gene mu a ion V600E in
h ee cases and wild- ype BRAF in he ou h.
Conclusions: BRAF molecula mu a ion analysis may aid diagnosis in cases
wi h a ypical his ological ea u es, especially in small incisional biopsies when
eassessmen o su gical ea men may be conside ed.
INTRODUCTION
Me aneph ic adenoma (MA) is a a e benign umo
o he kidney, accoun ing o 0.2% o adul enal epi helial
neoplasms [1]. The umo , which is composed o p imi i e
me aneph ic cells [2], is o en asymp oma ic. Some
au ho s ha e sugges ed ha MA may de i e om ma u ing
neph oblas omas (Wilms umo ), since immunopheno ypic
indings o e lap closely wi h hose o di e en ia ed
neph oblas oma and neph ogenic es s [3]. Though i may
also occu in child en, i is de ec ed mainly in adul s aged
be ween 50 and 70 and is mo e common ( a io 2:1) in
women [2, 4, 5]. Radical neph ec omy, c yoabla ion and
adio equency ha e been used o ea his neoplasm [5].
While he clinical cou se is benign, his ological
indings o en o e lap wi h hose o malignan umo s
including Wilms umo and enal papilla y neoplasms,
hus p omp ing he need o di e en ial diagnosis [6].
A be e unde s anding o his benign umo would
undoub edly aid he de elopmen o less in asi e
s a egies. Al hough mos au ho s ule ou he possibili y
o MA becoming malignan , one case has been epo ed o
a me aneph ic adenoma in associa ion wi h a high-g ade
sa coma (me aneph ic adenosa coma) [5, 7].
Immunohis ochemical analysis is a use ul ool
o di e en ial diagnosis. The li e a u e con ains ew
epo s o in eg a ed diagnosis o MA using molecula
echniques [8].
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Mu a ion o he BRAF gene p omp s cons i u i e
ac i a ion o he ERK-media ed signaling pa hway,
a o ing cell p oli e a ion and di e en ia ion.
Ac i a ion o RAF, in bo h i s homodime and
he e odime o ms, igge s he phospho yla ion o
MAPK kinase (MEK), which in u ns p omp s he
phospho yla ion o ex acellula signal- egula ed kinase
(ERK); ERK ac i a ion p omo es cell p oli e a ion and
signal ans o ma ion h ough in e ac ion wi h se e al
molecules c ucial o umo pa hogenesis [9, 10].
The speci ic BRAF gene mu a ion V600E has been
epo ed in o e hal o all cu aneous melanomas and
papilla y hy oid ca cinomas, as well as in a numbe o
blood cance s including hai y cell leukemia; i is also
p esen in indolen and benign umo s such as melanocy ic
ne us [11]. This speci ic mu a ion has also been s udied
in malignan neoplasms such as enal cell ca cinoma in
esponse o a ge ed he apies [12]. In benign neoplasms
like MA, se e al au ho s ha e no ed ha es ing o he
BRAF V600E mu a ion may be a aluable ool o he
diagnosis [1, 2, 11].
RESULTS
G oss examina ion e ealed well-ci cumsc ibed,
non-encapsula ed umo s measu ing be ween 1.5
and 6 cm (mean 3.7 cm), wi h ocal a eas o blood-
con aining cys s and solid, in some cases p esen ing
calci ica ions. His ologically, MAs we e composed
o small, monomo phic epi helial cells displaying no
signi ican a ypia o mi o ic igu es, showing papilla y
o acina pa e ns, and edema ous o hyalinized s oma
wi h calci ica ion (psammoma bodies) (Figu e 1A).
Immunohis ochemical examina ion showed posi i e
s aining o WT1 and imen in, and nega i e s aining
o acemase, CK7, CD10, CD57 and RCC (Figu e 1B).
Mu a ion analysis by eal- ime PCR e ealed he BRAF
gene mu a ion V600E in h ee cases and wild- ype BRAF
in he ou h. Based on mo phological ea u es and he
indings o immunohis ochemical and molecula analysis,
all ou cases we e diagnosed as MA. Th ee o he pa ien s
a e ali e and well 12, 5 and 2 yea s a e su ge y, while
he ou h died 13 yea s a e he p ocedu e due o o he
causes.
DISCUSSION
MA is an uncommon, benign umo o he kidney
composed o spindle cells associa ed wi h epi helial cells.
In 1988, Mos o i e al. [13] desc ibed MA o he i s
ime as a dis inc nosologic en i y among enal neoplasms,
wi h ubula -like epi helial cells. This umo is cu en ly
classi ied among he me aneph ic neoplasms, which also
include me aneph ic adenoma and me aneph ic s omal
umou [4]. MA, which accoun s o 0.2–0.7% o adul
enal epi helial neoplasms, de i es om emnan s o
emb yonic enal issue [1, 3, 4].
A g oss examina ion, MA appea s as a well-
ci cumsc ibed neoplasm wi h a yellowish su ace, o en
displaying e idence o seconda y changes including
ocal nec osis, hemo hage and/o cys ic degene a ion.
Coa se calci ica ion may also be p esen . The umo
mass gene ally anges in size be ween 3 and 6 cm in
diame e , al hough umo s o up o 15 cm ha e been
epo ed [4]. His ologically, i comp ises an acina
a angemen o small cells. Di e en ial diagnosis o
MA includes Wilms umo , neph ogenic es s and enal
papilla y neoplasms [5]. MA ypically exp esses WT1
and CD57, bu s ains nega i e o CK7 and acemase.
Posi i e in ense s aining o WT1 was eco ded in he
ou cases epo ed he e, bu CD57 s aining was in mos
o hem weak; so, BRAF mu a ion helped us o con i m
he diagnosis o MA.
Oncogenic BRAF no mally egula es cell di ision
and di e en ia ion h ough he MAP kinase signaling
pa hway. BRAF mu a ions, iden i ied in se e al solid
umo s and blood cance s, p omp he cons i u i e
ac i a ion o he pa hway, which has been widely
documen ed in melanomas [9, 10, 14]. Mos BRAF
mu a ions in ol e a hymine-adenine ans e sion, leading
o he subs i u ion o aline by glu amic acid a codon
V600 (V600E) [14].
Mos epo ed MAs display a no mal geno ype,
lacking he simul aneous ch omosomes 7 and 17 gain and
Y ch omosome loss cha ac e is ic o papilla y enal cell
ca cinoma and common in neu oblas oma.
The BRAF gene mu a ion V600E is epo ed in
oughly 90% o me aneph ic adenomas [2, 4, 11, 15],
wi h only 2 desc ibed cases o V600D mu a ion [2] and
1 o V600K [16]. Caliò [14] e al. iden i ied he V600E
mu a ion in 41 ou o 48 MA pa ien s (85%) wi h a
mean age o 54, while Chouei i e al. [11] epo ed i in
26/29 pa ien s (89%) also wi h a mean age o 54, and
Ding e al. [17] desc ibed 27 MA pa ien s wi h mean
age o 39 yea s and 22 (81%) wi h BRAF mu a ion.
O he au ho s ha e epo ed he V600E mu a ion in
smalle se ies [18–21]. In ou esea ch, as shown in
Table 1, he mu a ion was iden i ied in h ee o he ou
pa ien s s udied (75%), aged be ween 19 and 65 (mean
47.5).
Se e al au ho s ha e d awn a en ion o he
ela ionship be ween wild- ype BRAF and MA in
younge adul s (i.e., unde 25). O he 29 cases epo ed
by Choue i [11] e al., all h ee pa ien s ha bo ing wild-
ype BRAF we e well below he mean age. By con as ,
in he ou pedia ic cases o MA desc ibed by Chami
e al. [22], only one ha bo ed wild- ype BRAF. An
epidemiological analysis was ca ied ou o he published
cases o MA in which he BRAF mu a ion has been
s udied. In Table 2 i can be obse ed ha , al hough he
age ange o p esen a ion is simila in bo h g oups, he
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mean age is 19.6 yea s lowe in he wild- ype BRAF
pa ien s (31.1 s. 50.7). The p esen s udy de ec ed he
BRAF gene mu a ion V600E in pa ien s aged be ween
50 and 65, while he younges pa ien (aged 19) ha bo ed
wild- ype BRAF.
A ela ionship ha has no been p e iously
highligh ed is he highe incidence o wild- ype BRAF in
male pa ien s. As desc ibed abo e, me aneph ic adenoma
is mo e common in emale pa ien s in a 2: 1 a io, jus like
in mu a ed BRAF MA (Table 2). By con as , in wild- ype
BRAF MA, he incidence in men is highe han women
wi h a 1.45: 1 a io. A ema kable case is he se ies o
48 pa ien s by Calio e al. [14], whe e he F:M a io in
mu a ed BRAF is 2.7: 1, while in wild- ype BRAF i is
1: 6.
The e o e, mu a ed BRAF MA a e mo e equen
in elde ly pa ien s and women, which is consis en wi h
s udies in o he pa hologies. E en wi h hese esul s, i is
necessa y o ca y ou s udies wi h a g ea e numbe o
cases in o de o ensu e i .
MATERIALS AND METHODS
This pape epo s on MA in h ee men and one
woman, aged be ween 19 and 65 (mean age 47.5);
pa ien da a a e p o ided in Table 3. The diagnosis
Figu e 1: (A) Monomo phic epi helial p oli e a ion, displaying no signi ican a ypia o mi o ic igu es, wi hin an edema ous s oma
con aining psammoma bodies (Pano amic iew. HE). (B) In ense posi i e nuclea s aining o WT1.
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was con i med and subsequen ly e iewed ollowing
WHO- ecommended c i e ia [4]. In all cases, MA
p esen ed as a single, asymp oma ic mass disco e ed
inciden ally du ing imaging p ocedu es; CT scan
con i med he p esence o a soli a y, space-occupying,
solid enal umo . A neph ec omy was pe o med in all
pa ien s.
Immunohis ochemical s aining was pe o med on
H&E- s ained sec ions cu om pa a in blocks o assess
exp ession o WT1, imen in, acemase, CK7, CD10 and
RCC. Tes ing o he BRAF gene mu a ion V600 was
ca ied ou by eal- ime PCR (Cobas® 4800) using he
DNA Sample P epa a ion Ki and he BRAF Mu a ion Tes
(Roche), which de ec s he BRAF gene mu a ions V600E,
Table 1: BRAF mu a ions in me aneph ic adenomas: li e a u e e iew
Resea ch and yea Numbe
o cases
Mean age
(yea , ange) Gende Tumo size
(cm, ange)
BRAF
mu a ion
Type o
mu a ion
P e ious epo s in
Caliò e al., 2016 99 52 (5–84) 71F 28M 3.4 (1.1–8) 87 (88%) V600E (97)
V600D (2)
Ding e al., 2018 27 39 (12–80) 9F 18M 3.1 (2–7) 22 (81%) V600E
Wobke e al., 2019 10 42 (10–62) 6F 4M 2.7 (1.3–3.5) 8 (80%) V600E
Ca ic e al., 2020 28 52 (9–73) 17F 10M 3 (0.5–12) 15 (53%) V600E
Chan e al., 2020 12 54 (38–76) 11F 1M 2.9 (1–6) 12 (100%) V600E
Lenci e al., 2021 1 73 F 3.2 1 (100%) V600K
Cu en s udy 4 54 (19–65) 1F 3M 3,7 (1.5–6) 3 (75%) V600E
Table adap ed om Caliò e al. [14].
Table 3: Epidemiological da a and BRAF s a us
Case Gende Age (yea s) BRAF s a us (V600E)
1 M 19 WT
2 F 50 Mu
3 M 56 Mu
4 M 65 Mu
Abb e ia ions: M: male; F: emale; WT: wild ype; Mu : mu a ed.
Table 2: Compa ison o age and gende incidence in mu a ed BRAF and wild ype BRAF
me aneph ic adenomas: li e a u e e iew
Resea ch and yea
Numbe o
MUTATED/WT
cases
Mean age
MUTATED/WT
(yea s, ange)
Gende
MUTATED BRAF WT BRAF
Male Female Male Female
Chouei i e al., 2012 26/3 54.7 (36−78)/32 (25−38) 3 (12%) 23 (88%) −3 (100%)
Dadone e al., 2013 1/0 61/− − 1 (100%) −
Pin o e al., 2015 6/0 52/− − 6 (100%) −
Udage e al., 2015 10/1 51.2 (16−84)/32 4 (40%) 6 (60%) 1 (100%) −
Chami e al., 2015 3/1 5.6 (4−9)/10 2 (67%) 1 (33%) 1 (100%) −
Caliò A e al., 2016 41/7 57 (5−84)/33 (10−74) 11 (27%) 30 (73%) 6 (86%) 1 (14%)
Ding e al., 2018 22/5 40 (25−73)/29 (12−47) 17 (77%) 5 (23%) 4 (80%) 1 (20%)
Wobke e al., 2019 8/2 46 (19−62)/26.5 (10−43) 3 (37%) 5 (63%) 1 (50%) 1 (50%)
Ca ic e al., 2020 15/9 47 (5−75)/36 (9−71) 7 (46%) 8 (54%) 3 (37%) 5 (63%)
Chan e al., 2020 12/0 54 (38−76)/− 1 (8%) 11 (92%) −
Lenci e al., 2021 1/0 73/− − 1 (100%) −
Cu en s udy 3/1 57 (50−65)/19 2 (67%) 1 (33%) 1 (100%) −
148 (84%)/29 (16%) 50.7 (4−84)/31.1 (9−74) 50 (34%) 98 (66%) 17 (58%) 12 (42%)
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V600K and V600D in o malin- ixed, pa a in-embedded
issue.
CONCLUSIONS
These esul s bea ou he indings o p e ious
s udies o BRAF gene mu a ions in MA, showing ha
molecula mu a ion analysis may aid diagnosis in cases
wi h a ypical his ological ea u es, especially in small
biopsies when non-su gical ea men is planned.
A highly accu a e de ini i e diagnosis o MA
was achie ed by combining immunohis ochemical and
molecula analysis; mu a ed BRAF MA a e mo e equen
in elde ly pa ien s and women. Accu a e ea ly diagnosis
may help o a oid unnecessa y agg essi e ea men s such
as adical neph ec omy.
Au ho con ibu ions
ERZ: concep ualiza ion, me hodology and
w i ing-o iginal d a ; JMA: w i ing-o iginal d a and
in es iga ion; LMG: concep ualiza ion and in es iga ion;
AVB: me hodology and w i ing- e iew & edi ing; JJRM:
w i ing- e iew & edi ing and supe ision.
CONFLICTS OF INTEREST
Au ho s ha e no con lic s o in e es o decla e.
FUNDING
This esea ch did no ecei e any speci ic g an om
any unding agency in he public, comme cial, o no - o
-p o i sec o .
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