Management of the Case of a Young Female Patient with Multiple Malignancies and Germline R24P CDKN2A Gene Mutation

doi:10.4236/jct.2013.47A004

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Journal of Cancer Therapy, 2013, 4, 18-20

http://dx.doi.org/10.4236/jct.2013.47A004 Published Online August 2013 (http://www.scirp.org/journal/jct)

Management of the Case of a Young Female Patient with

Multiple Malignancies and Germline R24P CDKN2A

Gene Mutation

Gabriella Uhercsák1, Ágnes Dobi1, Roland Gyulai2, Judit Oláh2, László Kaizer3, Katalin Ormándi4,5,

Adrienne Cserháti1, György Lázár6, Gyula Farkas6, Zsuzsanna Kahán1*

1Department of Oncotherapy, University of Szeged, Szeged, Hungary; 2Department of Dermatology and Immunology, University of

Szeged, Szeged, Hungary; 3Department of Pathology, University of Szeged, Szeged, Hungary; 4Department of Radiology, University

of Szeged, Szeged, Hungary; 5Euromedic Diagnostics Hungary Ltd., Szeged, Hungary; 6Department of Surgery, University of

Szeged, Szeged, Hungary.

Email: *[email protected]

Received April 30th, 2013; revised June 1st, 2013; accepted June 9th, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

The case of a young female patient with metachronous primary melanomas, advanced breast and pancreatic cancers is

reported. The 5 different tumors diagnosed within six years, were managed with curative intent. Genetic analysis re-

vealed the mutation of the R24P CDKN2A gene in a heterozygote form in bo th the patient and her father. Careful terti-

ary prevention during the follow-up of the patient is needed.

Keywords: Breast Cancer; Melanoma; Pancreatic Cancer; R 24P CDKN2A Gene Muta t i on

1. Introduction

The prevalence of multiple primary malignancies varies

between 0.73% - 11.7% [1,2]. The synchronous occur-

rence of primary malignancies is uncommon, but meta-

chronous primary tumors are diagnosed more frequently

due to the longer survival of the population and the suc-

cessful therapy of malignancies [3]. Depending on the

time between the diagnosis of the individual malignancy,

multiple primary malignancies can be divided into two

categories. Synchronous cancers occur within 6 months,

whereas metachronous multiple malignancies occur later

than 6 months after the diagnosis of the ﬁrst malignancy

[4]. In cases with multiple malignant diseases manifested

at a young age, the possibility of genetic predisposing

factors responsible for the elevated cancer risk is consid-

ered. The history of different cancers among the family

members may further support the suspicion of the pres-

ence of inherited gene mutation. The detection of five

different primary tumors within six years is quite rare.

Here we report the case h istory of a young female p atient

with successfully treated malignant melanomas, breast

and pancreatic cancers.

2. Case Report

In December 2006, a 1.5 cm malignant melanoma was

removed from the left waist region of a 31-year-o ld Cau-

casian female patient. From the left inguinal region one,

from the left axillary fossa four sentinel lymph nodes

were excised, that proved metastasis-free at histological

examination. Because of the stage pT2b, Clark II-III pN0

(sn), a one-year adjuvant low-dose interferon-alpha ther-

apy was given.

At a routine follow-up examination, in Febru ary 2008,

a 2 cm mass in the left axillary region was found, and

removed. Histological analysis showed a lymph node

infiltrated with anaplastic breast carcinoma, ER, PR and

HER2 negative. Imaging examinations were carried out.

Breast MRI showed multiple small foci with contrast

medium enhancement in the left breast parenchyma, and

a 13 mm lymph node in the ipsilateral axillary fossa.

Abdominal-pelvic CT showed the widening of the head

of the pancreas. On PET/CT, a 1 cm FDG accumulation

at the upper quadrants of the left breast and a 7 mm

FDG-avid lymph node in the left axillary fossa were ap-

parent. At the border of the body and tail of pancreas,

another 1.5 cm FDG-avid lesion was visible (Figure 1).

First, left mastectomy and axillary lymph node dissec-

*Corresponding a uthor.

Management of the Case of a Young Female Patient with Multiple Malignancies and Germline R24P CDKN2A

Gene Mutation 19

Figure 1. PET/CT scans illustrating (a), the malignant tumor of the left breast (b), with axillary lymph node metastases, and

(c), a 1.5 cm FDG-avid lesion at the border of the body and tail of the pancreas.

tion were carried out. Histology revealed multifocal in-

vasive ductal cancer of grade III, pT1 (12 mm), lympho-

vascular invasion, pN1 (2/14), ER: negative, PR: 60%

positive, HER2: negativ e. Next, the abdominal statu s was

further investigated. At abdominal MRI a 2 cm mass in

the tail of the pancreas, at ERCP, the blockade of the

pancreatic duct at the border of the body and the tail were

apparent. Explorative laparotomy was carried out with

liver and lymph node biopsies that revealed the metas-

tatic involvement of these organs by pancreatic adeno-

carcinoma. Combination chemotherapy of gemcitabine-

cisplatin was considered as appropriate both as adjuvant

chemotherapy for the breast cancer and neoadjuvant/pal-

liative therapy for the pancreatic cancer. Six cycles were

delivered with antiemetics, granulocyte colony stimulat-

ing factor and erythropoietin therapy, and meanwhile

thoracic, abdominal and pelvic CT examinations, and

serial determinations of the tumor marker CA 19-9 were

carried out. All studies indicated continuous tumor re-

gression, and the disappearance of the pancreatic tumor

after the completion of the chemotherapy. A second

PET/CT indicated complete tumor regression, therefore a

second abdominal surgery was suggested. In May 2009,

the resection of the pancreatic tail with splenectomy was

carried out. Profound histological evaluation indicated no

tumor tissue in the specimen, nonetheless, the presence of

chronic fibrous and inflammatory changes. Since that

time, the patient, until recently, was tumor-free and has

experienced no longterm complication of the therapies.

Three months ago, at routine follow-up examinations, 2

superficial melanoma-suspicious skin lesions were de-

tected on the right arm and the abdominal wall. The ex-

cision of these lesion, indicated pTa and pTb melano-

mas, respectively, excised in toto. No sentinel lymph

node biopsy was carried out.

Since the patient reported multiple cancer cases in her

father’s family (her father suffered from laryngeal and

gastric carcinoma, her aunt deceased due to breast cancer

at a young age), genetic tests were carried out as de-

scribed previously [5]. Genetic analysis revealed that

both the patient and her father carried a R24P CDKN2A

germline mutation in a heterozygote form. At the same

time, the presence of hotspot BRCA1 and BRCA2 muta-

tions was e xc luded b y sequenci ng [5].

3. Discussion

We report here a rare case of young female patient with

multiple cancers. Genetic testing revealed a heterozy-

gotic germline mutation of the CDKN2A gene as back-

ground of the patient’s increased cancer risk. The man-

agement of each malignancy was carried out with cura-

tive intent, despite the presence or the history of other

malignancies. Heightened attention and awareness are

necessary for the pr evention and early detectio n of possi-

ble additional metachronous malignancies during the

follow-up of the patient. Efforts are made for the reha-

bilitation of the patient.

The relatively young age of the patient and the occur-

rence of multiple primary malignancies raised the possi-

bility of inherited gene mutation as predisposing genetic

factor that was strengthened by the family history. The

genetic profiling of the patient and her parents was car-

ried out. No BRCA1 or BRCA2 mutation s were detected,

however, the mutation of the CDKN2A gene [6-8] was

verified in the patient and her father as described in detail

previously [5]. The CDKN2A gene located on chromo-

some 9p21 has b een id entified as a susceptib ility gen e for

familial melanoma and less frequently for pancreatic

cancer [7-11]. The combination of melanoma and pan-

creatic cancer or melanoma and breast cancer, have been

reported in CDKN2A gene mutation carriers as rare

events [6-8]. Our patient showed very high susceptibility

to melanoma by developing multiple primary melanomas,

and developed also pancreatic and breast cancers. The

products of this gene play a role in cell arrest in the G1

phase and induce apoptosis [7]. The altered function of

this tumor suppressor gene very likely played a role in

the development of the patient’s synchronous and meta-

chronous tumors and represents a permanent risk factor

for further malignancies. Thus, the careful follow-up of

the patient and the family members is essential.

The need of the simultaneous management of the syn-

chronous breast and pancreatic cancers raised the ques-

tion what could be the opti mal on cological therapy in this

Management of the Case of a Young Female Patient with Multiple Malignancies and Germline R24P CDKN2A

Gene Mutation

case with locally advanced pancreatic cancer and liver

metastases of limited extent, and high risk breast cancer.

A polychemotherapy regimen found active both in pan-

creatic cancer [12] and breast cancer [13,14] was selected

as neoadjuvant chemotherapy for the pancreatic cancer

and as adjuvant chemotherapy for the breast tumor. We

speculate that the role of the inherited gene mutation can

not be excluded in the unexpectedly good response of the

advanced pancreatic and breast cancers to chemotherapy.

Although the metastatic spread to the pancreas or the

breast are rare events [15,16], this possibility must have

been taken into consideration during the management of

the case. The diagnosis of each primary malignancy was

carefully obtained using various imaging and pathologi-

cal methods as described in detail previously [5]. Each

malignancy was managed according to its actual stage

and pathological features.

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