Case of hereditary papillary renal cell carcinoma.

1.1 MB·English

by  Mustafa, Sadaf

(cid:1)CASE REPORT
Case of hereditary papillary renal cell
carcinoma
Sadaf Mustafa, MD1*, Nima Jadidi1, Sheila F. Faraj, MD2 and
Ronald Rodriguez, MD, PhD3
1Department ofInternal Medicine,Union MemorialHospital, Baltimore, MD,USA; 2Department of
Pathology, Johns Hopkins UniversitySchool ofMedicine,Baltimore, MD, USA;3Department of
Urology, JohnsHopkins University SchoolofMedicine, Baltimore, MD,USA
Renalcellcarcinomaisthemostcommontypeofrenalmalignancyanditoriginatesfromtherenaltubular
epithelium. Due to the diversity in the histopathological and molecular characteristics, it is typically
subclassified into five different categories. Papillary renal cell carcinoma is one subclassification and it
includestwovariants:sporadicandhereditary.Althoughthehereditaryformcomprisesasmallernumberof
cases of papillary renal cell carcinoma, an understanding of the molecular pathways and genetic changes
continuestoplayasignificantroleinthedevelopmentofnewtargetedtherapies.Alongwithrecommending
appropriate lifestyle modification, further investigation into the molecular pathogenesis of hereditary
papillary renal cell carcinoma will continue to be invaluable for the clinical management of renal cell
carcinoma. In this article, we discuss a case of the hereditary papillary renal cell carcinoma along with an
overviewofthe disease.
Keywords: familialpapillaryrenalcellcarcinoma;hereditaryleiomyomatosisandrenalcellcarcinoma;metproto-oncogene;
hepatocytegrowthfactor/scatterfactor;renalcancer
Received:15 September 2011; Revised:1 December 2011; Accepted:7 December 2011;Published:26January2012
Accordingtothe2011cancerstatisticscompiledby metastatic disease; however, their use in preventing
the American Cancer Society annually, the recurrence after surgical excision has not proven effica-
incidence rate of renal cancer has increased cious. Because of our growing understanding of the
between 2 and 3% since 1992. This trend has been molecular pathways leading to renal cancer, many new
attributed to earlier detection of renal cell cancer in targetedtherapieshavebeendevelopedinthelastdecade.
patients as opposed to a true increase in cancer occur- Hereditary forms of papillary renal cancer comprise
rence. Mortality rates have been decreasing for both a very small portion of newly diagnosed renal cancers
genders since 2002. Evidence suggests that cigarette (2). Nevertheless, an understanding of familial renal
smoking and obesity are significant modifiable risk cancer syndromes has led to greater insights into kidney
factors (1). Preventative efforts to curtail these risk tumor formation and potential therapeutic targets.
This article includes a case history of a patient with
factors will continue to play a large role in lowering the
hereditary papillary renal carcinoma (HPRC) and
occurrence of renal cancer. The decrease in mortality of
a relevant case discussion. The importance of the case
renalcancerinthepastdecadehasbeenpartlyattributed
lies in the early identification of this rare familial
to its earlier detection and treatment. More than half
form and its timely treatment.
of the newly diagnosed cases are discovered at an
early stage. Surgical excision of the tumor is typically
the primary recommended treatment modality. The Case report
5-year survival rate for these patients is greater than We present a case of 61-year-old Caucasian male who
90%. Medical management is typically reserved for presented with a history of right renal mass that was
locally invasive or metastatic disease. Renal cancers discovered incidentally 5 years ago. Since then he was
tend to be resistant to many standard chemotherapeutic followed by serial CT scans annually. On these scans, it
agents as well as radiation therapy. Interferon-alpha appearedtobeaminimallyenhancingexophyticmassof
and interluekon-2 had traditionally been the mainstay less than 2 cm in largest diameter in the posterior upper
in treatment of non-resectable tumors and late-stage pole of the right kidney. The patient had no symptoms
JournalofCommunityHospitalInternalMedicinePerspectives2011.#2011SadafMustafaetal.ThisisanOpenAccessarticledistributedundertheterms 1
of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-
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Citation:JournalofCommunityHospitalInternalMedicinePerspectives2011,1:9468-DOI:10.3402/jchimp.v1i4.9468
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SadafMustafaetal.
and was otherwise in a good state of health. His family arenaltumorshouldbeclassifiedassuchifatleast75%
history was remarkable for renal neoplasm; his mother of the tumor consists of papillary structures (3).
died of metastatic RCC with an unknown histology, This histopathological classification was modified by
whereas his brother and sister had Fuhrman grade III Delahunt and Eble who further subcategorized PRC as
PRCcarcinoma.Therewasnopersonalorfamilyhistory type1 and type2 that account for 5 and 10% of renal
of cutaneous leiomyomatosis or leiomyosarcoma. His cancers, respectively (4). Generally, type 2 PRC has a
repeated CT scan showed a well-defined homogeneous larger tumor size, higher tumor stage, and nuclear grade
hypodense1.3(cid:1)1.9cmminimallyenhancinglesioninthe than type1 and thus follows a relatively more aggressive
posterior upper pole of the right kidney and 1 mm course.Thekeyhistologicalfeaturesthatdifferentiatethe
indeterminatelesionintheleftkidneywithnoevidenceof two types are as follows:
local ordistant metastasis(Fig. 1). In lightof the strong
familyhistory,HPRCwasconsidered.Thepatientunder- (1) PRCtype1ischaracterizedbythepresenceofshort
went open partial nephrectomy of the right kidney with papillae covered by small cuboidal cells that have
no intraoperative complications. The right renal mass pale cytoplasm and small oval nuclei with barely
and frozen sections from the margins of the resection visible nucleoli. Additionally frequent glomeruloid
weresentforhistopathologythatshowedaunifocalmass papillae, papillary edema, foamy macrophages in
of 2 cm in diameter bearing PRC histology with Fuhr- papillary cores, and psammomabodies may also be
man grade III (Fig. 2) The margins were negative, and present (5).
there was no evidence of invasion of the surrounding (2) PRC type2 shows histologic features that consist of
structures. The patient had an unremarkable postopera- papillae covered by large cells with abundant
tive course and is being followed every 6 months with eosinophilic cytoplasm and large spherical nuclei
complete blood count, complete metabolic panel, and with prominent nucleoli.
serialimagingstudies.Surveillancewillcontinuethrough-
out his life due to the recurrence risk. PRC can occur in both sporadic and hereditary forms.
As outlined in Table 1, there are two well recognized
Discussion familial forms of PRC; hereditary papillary renal carci-
In1989,KovacsproposedthatPRCshouldbeconsidered noma (HPRC) and hereditary leiomyomatosis and renal
asaseparateentityofrenalneoplasmsandsuggestedthat cell carcinoma. In 1994, Zbar et al. described HPRC as
anautosomaldominantinheritedformofPRC,whichis
characterizedbyatendencytodevelopmultiple,bilateral
papillary renal tumors (6). It was in the late 1990s that
Schmidt and colleagues mapped the HPRC gene on
chromosome7q31(cid:2)34andidentifiedactivatingmutations
in the tyrosine kinase (TK) domain of met proto-
oncogene(7).Themetgeneencodesforatransmembrane
TK receptor also known as hepatocyte growth factor/
scatter factor (HGF/SF) receptor or c-Met, which is
overexpressed in the tumors with PRC type1 histology.
Themutationsarepresentontheextracellulardomainof
the receptor where the only known natural ligand, the
HGF/SF, interacts with the receptor. The activation of
intrinsic TK is essential for the HGF/MET pathway to
promotecellgrowth,motility,andproliferation;ithasan
important role in tissue repair and regeneration. The
mutations found in met gene interfere with the auto-
inhibition of TK and in fact facilitate its conversion to
the more active form by lowering the threshold for
receptor activation, stabilizing the active conformation
ofthekinase,andinsomecasesmakingitlesssusceptible
for inactivation by phosphatases (8). Interestingly, only
13%ofthepatientswithsporadicPRChavethismutation
and they show the same histologic features as that of
Fig. 1. Abdominal Computed Tomography scan image of
thepatientwithHPRC:TheabdomenCTscanwithcontrast HPRC(9).Duetotheslowprogressionofdisease,theage
of the patient showing a well defined homogeneous hypo- at presentation usually lies between the fourth and sixth
densemassof 1.3 x 1.9cmin the right kidney. decades of life. Clinical symptoms may vary from
2
Citation:JournalofCommunityHospitalInternalMedicinePerspectives2011,1:9468-DOI:10.3402/jchimp.v1i4.9468
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Caseofhereditarypapillaryrenalcellcarcinoma
Fig.2. H&Ehistologicalslideofthepatient’spapillaryrenalcellcarcinoma,FuhrmangradeIII:Lowpoweredmagnification
(50X)showing characteristic papillaryarchitecture. Non neoplasticrenal parenchymais seen on left (A). Occasional papillary
structuresdemonstratetypicalfoamyhistiocytesinfibrovascularcoresupperleftportion(100X)(B).Highpowermagnification
showingneoplasticpapillarystructureslinedbyeosinophiliccuboidalepithelialcellswithovoidnucleiandconspicuousnucleoli
(400X)(C).
incidental diagnosis to a more advanced disease with Despite the complexities inherent in investigating
hematuria, abdominal pain, and abdominal mass. The cancers at the molecular level, a better understanding
patients with HPRC have bilateral, multiple, and multi- may be essential for more individualized therapy. Im-
focal renal tumors bearing type1 PRC histology, and munotherapiessuchasinterferon-alphaandinterleukin-2
microscopicallyupto3,400tumorsmaybeidentifiedina have been the main treatment options when medical
single kidney (10). No extrarenal manifestations have management is warranted; however, improved under-
been identified in these patients. CT scan with intrave- standing of the biology of renal cancers has led to the
nous contrast is preferred over ultrasound as the main
development of new targeted therapies that block the
modality for diagnosis and follow-up. These tumors are
tumor’s blood supply or disrupt other parts of renal
often mistaken for renal cysts on CT scan as they are
cancer cells. Several agents have been approved by the
typically hyperdense and have a hypovascular nature.
FDAandmanymoreareundergoingclinicaltrials.These
The treatment options may include close observation in
agents have given clinicians many more therapeutic
those cases where the mass is less than 3 cm in largest
options for patients with late stage disease. A continued
diametertonephronsparingsurgeryorpartialnephrect-
effort to understand the molecular pathways leading to
omywithlargertumorsizes.Cryoablationandminimally
thedifferentrenalcancertypeswillresultinfurthernovel
invasive radiofrequency ablation may be used as an
approachestobothtreatingrenalcancerandstoppingits
alternative for small and/or multiple tumors (2). Several
recurrenceinpostsurgicalpatients.Cliniciansshouldhave
MET kinase inhibitors such as ARQ197 and Foretinib
highindexofsuspicion,ifthereisastrongfamilyhistory
have been developed and are undergoing testing. Fore-
of renal cancers. Prompt intervention should be offered
tinib, an oral dual-kinase agent, targets TK domain of
METand VEGFR2 and is currently being evaluated in to the patient and screening to the first-degree relatives.
an ongoing multicenter phase II clinical trial for the Genetic testing should also be offered to the patient and
treatment of sporadic PRC with met mutations and the families after appropriate counseling. Early identifi-
HPRC that meet certain criteria. cation and intervention in a timely manner may provide
Table1. Hereditaryformsof PapillaryRenalCell Carcinoma.
Hereditary Geneticabnormality Histopathology ClinicalManifestations
forms
HPRC HPRCgeneMutationsinthe Shortpapillaecoveredbysmallcuboidal Nomanifestationsotherthanpapillaryrenal
tyrosinekinase(TK)domainof cellswithpalecytoplasm,smallovalnuclei cellcarcinoma
metproto-oncogene andhardlyvisiblenucleoli.
HLRCC MutationsintheHLRCCgene Papillaecoveredbylargecellsthathave Cutaneousleiomyomatosis,uterineleiomyo-
resultinginFumarateHydra- abundanteosinophiliccytoplasm,large mataorleiomyosarcomaoccurringinasso-
tasedeficiency sphericalnucleiandprominentnucleoli. ciationwithPapillaryRenalcellcarcinoma
Anoverviewofthetwohereditaryformsofpapillaryrenalcellcarcinoma(PRC).HereditaryPapillaryRenalCellcarcinoma(HPRC)and
Hereditary leiomyomatosis and Renal cell Carcinoma (HLRCC) bearing type1 and type2 PRC histology respectively. They are
characterisedbythepresenceofdistinctgeneticmutationsthatmakesHLRCCthemostaggressiveform.Theclinicalmanifestations
ofHPRCandHLRCCvarydependinguponthediseaseseverityatthetimeofpresentation;additionallyapatientwithHLRCCmayalso
havehistoryofLeiomyomas,whicharenotpresentinHPRC.
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Citation:JournalofCommunityHospitalInternalMedicinePerspectives2011,1:9468-DOI:10.3402/jchimp.v1i4.9468
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SadafMustafaetal.
more therapeutic options and reduce the morbidity 6. ZbarB,ToryK,MerinoM,etal.Hereditarypapillaryrenalcell
associatedwith renal cell carcinoma. carcinoma.JUrol1994;151(3):561(cid:2)6.
7. SchmidtL,DuhFM,ChenF,KishidaT,GlennG,ChoykeP,
et al. Germline and somatic mutations in the tyrosine kinase
Conflict of interest and funding
domainoftheMETproto-oncogeneinpapillaryrenalcarcino-
The authors have not received any funding or benefits
mas.NatGenet1997;16(1):68(cid:2)73.
from industryor elsewhere to conduct this study. 8. Dharmawardana PG, Giubellino A, Bottaro DP. Hereditary
papillary renal carcinoma type I. Curr Mol Med 2004; 4(8):
855(cid:2)68.
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