Table Of ContentBehnesetal.BMCUrology2013,13:3
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CASE REPORT Open Access
Hereditary papillary renal cell carcinoma primarily
diagnosed in a cervical lymph node: a case report
of a 30-year-old woman with multiple metastases
Carl Ludwig Behnes1*†, Christina Schlegel2†, Moneef Shoukier3, Isabella Magiera4, Frank Henschke5,
Alexander Schwarz6, Felix Bremmer1 and Hagen Loertzer2
Abstract
Background: Papillary renal cell carcinoma is a rare cancer. Some cases can be attributed to individuals with
hereditary renal cell carcinomas usually consisting oftheclear cell subtype. Inaddition, two syndromes with
hereditary papillary renal cell carcinoma have been described. One is the hereditary leiomyomatosis and renal cell
carcinoma, which is characterized bycutaneous and uterine leiomyomas and renal cell carcinoma mostly consisting
ofthe papillary renalcell carcinoma type IIwitha worse prognosis.
Case presentation: We describe a case of a 30-year-old woman withhereditaryleiomyomatosis and renalcell
carcinoma syndrome with extensively metastasized papillary renal cell carcinoma, primarily diagnosed in a cervical
lymph nodelacking leiomyomas at any site.
Conclusion: Papillary renal cell carcinoma in young patients should be further investigatedfor a hereditaryvariant
likethe hereditary leiomyomatosis and renal cell carcinoma even ifleiomyomas could not be detected. A detailed
histological examination and search for mutations is essential for the survival ofpatients and relatives.
Keywords: HLRCC, Fumaratehydratase (fh), Papillary renal cell cancer, Leiomyomatosis
Background mutations in the met proto-oncogene (MET) on chromo-
Renal cell carcinoma (RCC) is a rather rare cancer with some 7q32 are responsible for HPRC [7]. The other syn-
an incidence of about 71,000 newly diagnosed cases per drome compromises the hereditary leiomyomatosis and
year in Europe. Approximately 31,000 of these patients renal cell carcinoma (HLRCC; MIM# 150800), which is
die because of RCC [1]. Only a few cases represent characterized by papillary RCC typeIIwithaworseprog-
hereditaryRCCs[2],ofwhichtheVon-Hipple-Lindausyn- nosis as well as typically cutaneous and uterine leiomyo-
drome (VHL; MIM# 193300) is best known [3]. Further- mas [8]. The HLRCC is caused by heterozygous germline
more, Birt-Hogg-Dubé syndrome (BHD; MIM# 135150) mutations of the fumarate hydratase (FH) gene on
[4] and tuberous sclerosis (TS1; MIM# 191100 / TS2; chromosome 1q34 [9]. The intracellular hypoxia inducible
MIM# 613254) [5] have been reported to be associated factor (HIF) is stabilized due to an accumulation of FH
with hereditary RCC mostly of the clear cell or chromo- based on the mutations in this gene region and is
phobesubtype.Inadditiontwosyndromesassociatedwith responsibleforapseudohypoxicstatecausingthereleaseof
hereditary papillary RCC have been described. One is different tumor promoting factors like VEGF, PDGF, and
represented by the hereditary papillary renal carcinoma TGF-α[10].Untilnow,125mutationsintheFHgenehave
(HPRC; MIM# 605074) usually consisting of papillary been described in the Human Gene Mutation Database
RCC type I witha betterprognosis [6] showingactivating Professional (HGMD release 2011.4; http://www.biobase.
de/hgmd/pro/start.php).
*Correspondence:[email protected] Here we report on a 30-year-old woman suffering on
†Equalcontributors HLRCC initial by presenting with cervical lymph node
1DepartmentofPathology,UniversityofGöttingen,Robert-Koch-Str.40,
metastasis and lacking cutaneous or uterine leiomyomas.
37075,Göttingen,Germany
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Behnesetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
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ThiscasedemonstratesthediagnosticchallengeofHLRCC at the age of 47. Medical records of the mother were not
especiallyincaseofmissingcutaneousleiomyomas. available. No further cases of RCC have been reported in
thepatient'sfamily(Figure3).
Case presentation
Clinicalfindings Pathologicalandgeneticfindings
A 30-year-old woman was admitted to the hospital be- On macroscopical examination cross sections of cervical
causeofpainlesslymphadenopathyintheleft neck.Com- lymph node demonstrated a grossly white, partly cystic,
puted tomography of neck and chest revealed multiple andnecrotic mass.
lesions up to 9.5 cm in diameter in the left supraclavicular Microscopical examination of the cervical lymph nodes
regionaswellasinthemediastinum(Figure1A).Basedon revealedatumorconsistingofpapillaryformationscrossed
a supraclavicular lymph node biopsy the diagnosis of a pa- by fibrotic areas. The papillae showed a monolayer of
pillary adenocarcinoma was confirmed (Figure 1B and C). tumor cells with large nuclei and numerous nucleoli as
In the following abdominal sonography and contrast- well as atypical mitotic figures. The tumor cells displayed
enhanced abdominal computertomography identified a abundant eosinophilic cytoplasm (Figure 1B and C). The
4 cm in diameter inhomogeneous mass in the lower pole immunhistochemicalexaminationsconfirmedapartialex-
of the left kidney (Figure 2A) as well as numerous pression of cytokeratin 7- and RCC-antibodies. Vimentin,
enlarged paraaortal lymph nodes. Partial nephrectomy of especially expressed in clear cell RCC, could only be
the left kidneyrevealed a tumor of4 cmindiameterwith demonstrated in the papillary stroma but not in tumor
a tan to gray cut surface. Paraaortal lymph nodes showed cells. A potential metastasis of a thyroid carcinoma could
tumor infiltrations. Two weeks later a new hypodense be excluded by the lacking expression of TTF-1 and
lesion2.2cmindiameterwasdetectedintheliver.Aclin- thyreoglobulin. Based on the also lacking expression of
icalcheck-upafter2monthdemonstratedbythoracaland estrogen- and progesteron-receptor a metastasis of an
abdominal computertomography numerous suspicious ovarian cancer was assumed to be unlikely. The tumor
mediastinal and paraaortal lymph nodes (Figure 1A and demonstrates no further specific antibody reaction. Thus,
2A) and further suspect lesions in the liver. The patient the lymph node metastasis seemed to be most likely
confirmedthathermotherdiedfromrenalcellcarcinoma causedbypapillaryRCC.
A
B C
Figure1Coronalreformattedcomputedtomographyimageoftheinitialcontrastenhancedchestscanshowsrim-enhancingenlarged
lymphnodesleftsupraclavicularbetweenthesternocleidomastoidandthescalenemuscles(A,shortarrow)andfurthermore
conglomerate-liketumorsintherightuppermediastinum(A,longarrow).Histologicallythelymphnodeshowsinfiltrationsofapapillary
adenocarcinoma(B:H&E,x100/C:H&E,x400).
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A
B C
Figure2Coronalreformattedcomputedtomographyimageoftheinitialcontrastenhancedabdominalscanshowsarenalmass
locatedinthelowerpoleoftheleftkidney,appearinginhomogeneous,predominantlylessenhancingcomparedtothenormalrenal
parenchyma(A).Histologicallyandimmunohistochemicallyexaminationsofthepartialnephrectomyshowatumorsimilartothelymphnode
infiltrationwithanincreasedproliferation(B:H&E,x100/C:Ki67immunostaining,x100).
Macroscopical examination of the partial nephrectomy Microscopical examination of the partial nephrectomy
of the left kidney showed a tumor of 4 cm in diameter revealed a papillary RCC type II with the same morph-
with a gray-tan and hemorrhagic cut surface. The tumor ology as in the lymph node. Furthermore lymphangiosis
did not demonstrate a clear border to the surrounding and dissociated tumor islets could be detected. The
normalkidney. immunohistochemical results of the renal tumor tissue
were identical to the findings of the lymph node. In
addition the tumor showed a proliferation rate of 80%
byKi67staining(Figure 2B andC).
Molecular genetic analysis did not reveal any mutation
in the met-oncogene. The subsequent analysis of the FH
gene revealed a missense mutation (c.539A>G) leading
to amino acid substitution H180R at the protein level
(Figure 4). This sequence variant has been classified as a
pathologic mutation. Furthermore, this mutation could
be shown to be associated with a reduced activity of FH
byapproximately45%[11].
Conclusion
Figure3Thefamilypedigreewiththedescribedpatient The papillary RCC is a rare tumor entity normally
(denotedbyblackarrow)andhermother,whoalsodiedof
occuring beyond the age of 60 years being associated
renalcellcarcinoma.
with a better prognosis than the more often clear cell
Behnesetal.BMCUrology2013,13:3 Page4of5
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A
B
Figure4ChromatogramsofmutationanalysisinFHexon.A:Heterozygousmutation(blackarrow)c.539A>G(CAT→CGT),p.His180Argin
exon4oftheFH-gene.B:Wildtypesequence.
RCC[12].Especiallyappearingduringearlylifespan pap- metastases of a papillary RCC in cervical lymph nodes.
illary RCC should be tested for an hereditary variant. In the literature one case of an 18-year-old woman from
One of these variants is the HLRCC syndrome asso- a Dutch family with HLRCC presenting metastases of a
ciated with different mutations in the FH gene [13], RCC in cervical lymph nodes can be found [23]. Because
which functions as a tumor suppressor gene. Up to now of the here described patient young age the diagnosis
about 180 families with HLRCC have been found world- was suspicious for a hereditary syndrome such as HPRC
wide. Some of these mutations are sporadic [14]. In a or HLRCC. The genetic examination showed a mutation
North American series of male and female patients pap- intheFHgenetypicalforHLRCC.
illary RCC in HLRCC occurred at a median age of 42 To our best knowledge, a case of HLRCC with a com-
years of patents, in which the youngest patient was 11 parable lymph node and distant dissemination without
years old [15,16].The HLRCC syndrome is characterized any leiomyomas has not been described before. This
by leiomyomas especially of the skin and papillary RCC case shows the importance of a complete pathological
[8]. In HLRCC patients, leiomyomas of the skin can be examination including subtyping of papillary RCC and
observed by the age of 35 years in all affected men and genetic examination also in the absence of cutaneous or
in about 55% of affected woman [17,18]; leiomyomas of uterine leiomyomas.
the uterus occur in approximately 85% of females [19].
In addition FH mutations have also been described in Consent
caseofuterinefibroids[20].ThepapillaryRCCinHLRCC Written informed consent wasobtained from thepatient
shows a penetrance of about 20-25% and mostly consists forpublicationofthiscasereportandanyaccompanying
of a papillary RCC type II with a worse prognosis [12]; images. A copy of the written consent is available for
mostpatientsdiewithinfiveyears[21].BecauseRCCeven review bytheEditor-in-Chief ofthis journal.
inHLRCCtypicallyariseunilateral,animmediatelyneph-
rectomyisthemostefficienttherapy[22]. Competinginterests
Theauthorsdeclarethattheyhavenocompetinginterests.
Generally the diagnosis of HLRCC is made by the fre-
quently occurring cutaneous leiomyomas, which can be Authors'contributions
painful. The patient described in this study showed no CLBandCSconstructedthemanuscriptandcarriedoutpathological
examination.CS,HL,andASwereresponsiblefortheclinicalandradiological
cutaneous leimyomas at all and lack leiomyomas of the
data.HFparticipatedinpathologicalinvestigations.SMandIMcarriedout
uterus. Instead of that the patient primarily presented thegeneticexaminations.FBwasresponsibleforcriticalrevisionofthe
Behnesetal.BMCUrology2013,13:3 Page5of5
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manuscriptandhasbeeninvolvedindraftingit.Allauthorsreadand carcinoma:veryearlydiagnosisofrenalcancerinapaediatricpatient.
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