Colonic adenocarcinoma and bilateral malignant ovarian

PATHOLOGICA 2004;96:117-120
CASE
REPORT
Colonic adenocarcinoma and bilateral malignant
ovarian sex cord tumor with annular tubules
in Peutz-Jeghers syndrome
Adenocarcinoma del grosso intestino e sex cord tumor bilaterale ovarico maligno
con tubuli anulari nella Sindrome di Peutz-Jeghers
A. AYADI-KADDOUR, S. BOURAOUI, K. BELLIL, S. BELLIL, N. KCHIR, M.M. ZITOUNA, S. HAOUET
Anatomy and Pathologic cytologic laboratory, La Rabta Hospital, Bab Saadoun, Tunisia
Key words
Peutz-Jeghers syndrome • Malignant transformation • Ovary •
Sex cord tumor with annular tubules
Summary
Parole chiave
Sindrome di Peutz-Jeghers • Trasformazione maligna • Ovaie •
Sex cord tumor con tubuli anulari
Riassunto
Peutz-Jeghers syndrome is characterized by multiple polyps
throughout the gastrointestinal tract in association with mucocutaneous pigmentation. Although Peutz-Jeghers syndrome polyps
are hamartomas, frequent association of this syndrome with both
gastrointestinal and non-gastrointestinal tumours had led to reassessment of the cancer risk in this hereditary disorder. The
most common gynaecological tumors in this syndrome are adenoma malignum of the uterine cervix and ovarian sex cord tumor, particularly sex cord tumor with annular tubules. The question of malignant change in a polyp or of the association of gastro intestinal carcinomas still discuss. The authors report a case
of Peutz-Jeghers syndrome in a young patient who developed a
colonic adenocarcinoma in a hamartomatous polyp together with
an incidentally discovered bilateral malignant sex cord tumours.
We discuss its association with certain benign and malignant tumors and the risk of rare complications of these hamartomatous
polyps. Although malignant tumors are increasingly reported in
association with the Peutz-Jeghers syndrome, to our knowledge,
there have been no previous reports of such an association in the
literature.
La sindrome di Peutz-Jeghers è caratterizzata da polipi multipli
distribuiti nel tratto gastroenterico associati a pigmentazione
muco-cutanea. Nonostante la natura amartomatosa dei polipi
nella sindrome di Peutz-Jeghers la frequente associazione con
neoplasie ha condotto alla rivalutazione del rischio neoplastico
in questa patologia ereditaria. Le neoplasie ginecologiche più frequenti in questa sindrome sono l’adenoma maligno della cervice
uterina ed il sex cord tumour ovarico, nella variante con tubuli
anulari. La problematica della trasformazione maligna di un
polipo o della associazione con carcinoma gastro-intestinali è tuttora oggetto di discussione. Gli autori riportano il caso di un giovane paziente con sindrome di Peutz-Jeghers che ha sviluppato
un adenocarcinoma del grosso intestino in un polipo amartomatoso con diagnosi consensuale di sex cord tumour maligno bilaterale. Viene discussa l’associazione tra sindrome di PeutzJeghers e alcune neoplasie maligne e benigne ed il rischio di rare
complicanze dei polipi amartomatosi. Anche se il numero di report
relativi alla associazione tra sindrome di Peutz-Jeghers e tumori
maligni è aumentata, non ci sono in letteratura precedenti casi
che riferiscano una associazione quale quella da noi osservata.
Introduction
Case report
Peutz-Jeghers Syndrome (PJS) is a rare genetic disease
characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyps, most frequently
found in the small intestine. In women, this syndrome
is frequently associated with hormonally secreting tumours it increases the risk for gastrointestinal and other
malignancies 1. In order to illustrate the genetically determined neoplastic potential of the PJS 2, the authors
report an unusual case of colonic adenocarcinoma developed within a hamartomatous polyp and associated
with a malignant ovarian sex cord tumor with annular
tubules (SCTAT).
A 46-years old woman was admitted for rectal bleeding, pelvic pain and extreme fatigue. In the last five
months, she suffered from a left pelvic pain, vomiting,
a bloody diarrhoea and weight loss. Past medical history and family history were unremarkable. The physical examination revealed besides a melanotic pigmentation of the lips and buccal mucosa, a painful solid and irregular mass in the right upper quadrant. Serum alpha-fetoprotein (AFP) was 1190 UI/L. The serum level of CA-125 and CEA were not elevated. Colonoscopy showed an unbridgeable irregular bulky
mass and a pedunculated polyp measured 1.5 cm and
Corrispondenza
Dott. Aïda Ayadi-Kaddour, 17 Rue Ali Ben Khélifa, El Menzah
9A 1013, Tunis Tunisie – Tel. +2 16 98349140 – Fax +2 16
71765118 – E-mail: [email protected]
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located at 15 and 12 cm respectively of the anal margin. The histological examination of the endoscopic
biopsy of the colonic tumor showed a poorly differentiated adenocarcinoma. Abdominal and pelvic ultrasonography showed multiple echogenic liver nodules in
segment II, IV and VI. The ovaries were enlarged, with
ecogenic bilateral solid tumours of 35 mm and 30 mm
in diameter. At laparotomy, a recto-sigmoidal tumor, a
left ovarian mass and multiple liver metastases were
found. A left hemi-colectomy with colorectal anastomosis and bilateral ovariectomy were performed. Biopsy of hepatic lesions was done. The gross examination
of the colonic resection demonstrated a multilobular
polypoid mass measuring 4 x 3 cm diffusely infiltrating
the wall extending to the serosal surface. A sessile
polyp of 0.5 cm and a pedunculated polyp of 1 cm were seen near the colonic tumor. The left ovary measured
4 x 3 cm and showed at cut section tumor of 2.5 cm in
diameter with both solid and cystic pattern. The right
ovary measured 4 x 3.5 cm in size and its cut surface
was yellowish gray or yellow and solid with cystic
area. Microscopic examination of colonic tumor confirmed a poorly differentiated adenocarcinoma conserving the branching structure of smooth muscle (Fig. 1).
Some tubular glands with cribriform pattern lining by
atypical cells with high mitotic activity were observed
(Fig. 2). There was no evidence of adenomatous change. Three mesocolonic lymph nodes showed metastatic
deposits. The tumor cells stained strongly with cytokeratin and CEA but not for inhibin and AFP. Both polyps show similar features as characterized by core of
smooth muscle fibres in a tree-like pattern with hyperplasia of the epithelium (Fig 3). Many glandular structures exhibited abnormal branching patterns; others
were cystically dilated. The microscopic appearance of
both ovaries was similar and consistent with sex cord
tumor with annular tubules (Fig. 4). Both simple and
complex annular tubules with prominent basement
membranes were present. The cells were round with
pale abundant often lipid-rich cytoplasm, and showed
Fig. 1. Colonic adenocarcinoma conserving the branching structure of smooth muscle (HES x 100).
A. AYADI-KADDOUR, ET AL.
Fig. 2. Tubular glands with severe atypia and numerous mitotic
figures (HES x 200).
little nuclear atypia and few mitoses. These cells form
outlined nests surrounded by hyaline layers and containing eosinophilic hyaline bodies typical of annular tubules. Components of Leidig cells were found at the
periphery of the tumor. Immunohistochemical study
shows positivity for estradiol, progesterone and inhibin, and a focal stain for AFP (Figs. 5, 6). However, tumour cells were negative for CEA. Biopsy of liver lesions yielded clusters of cells with consistent cytologic
changes noted from the sex cord tumour with annular
tubules.
The post-operative course was uneventful. The patient
was then placed on a chemotherapy regime consisting
of a combination of bleomycin, cisplatin and etopsid.
Six months later, her general condition was good, and
upper gastrointestinal endoscopy revealed no polyp in
the stomach and the duodenum. The patient’s liver lesions were significantly smaller and the initially elevated AFP levels decreased during the course treatment.
Fig. 3. Low power view of the colonic polyp: Hamartomatous
polyp composed of distorted and branching crypts supported
by cores of smooth muscle (HES x 100).
PEUTZ-JEGHERS SYNDROME AND CANCER
Fig. 4. Sex cord tumor with annular tubules: note both simple
and complex annular tubules (HES x 200).
Fig. 5. Immunohistochemistry: diffuse expression of inhibin in
ovarian tumor (IHC x 400).
Fig. 6. Immunohistochemistry: focal expression of AFP in ovarian tumor (IHC x 200).
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Discussion
The PJS is an autosomal dominant disease with variable expression and incomplete penetrance of
LKB1/STK11 gene at chromosome 19p13.3 encording
for a novel 433-aminoacid serine threonine kinase 2.
Recently an increasing number of reports underline the
neoplasic potential of this syndrome and it is now believed to increase the risk of developing gastro intestinal cancers, predominantly occurring in the duodenum
and also the colon, and extra-intestinal malignancies
particularly ovarian 3 4. There still remains the controversy as to whether gastrointestinal cancer in the PJS
arises from the Peutz-Jeghers polyps, or de novo. Firmer conclusions concerning the risk and pathogenesis
of cancer in the PJS may be provided by prospective
studies. However, the small number of patients with
this syndrome and the long interval between diagnosis
of the syndrome and the appearance of cancer are obstacles to such studies. But many epidemiological factors have led to the hypothesis of cancer arising in
Peutz-Jeghers polyps: young age of the patients at the
diagnosis of cancer, increase of gastrointestinal cancer’s risk (eighteen times greater than expected in the
general population) and reports of gastro intestinal cancers in families involved with PJS 4 5. In the last few
years, many histological arguments have been reinforcing the hypothesis of a “hamartoma-dysplasia-carcinoma” sequence, in particular the presence of high dysplasic areas in the hamartomatous polyps and the presence of branched out strips of a smooth muscle within
gastro intestinal carcinomas 6-8. In our case, the absence of adenomatous lesion in the colonic tumor, and the
presence of smooth muscule fibres, contigous to carcinomatous glands, are in-keeping with the hypothesis of
cancer arising in a hamartomatous polyp. Recently, several investigators have reported that gastrointestinal
cancers occur more frequently in PJS than described
previously, and the incidence has been reported to be
more than 10 percent 4.
In 5 to 14% of cases, the PJS is also associated to ovarian tumors, especially the sex cord tumor with annular
tubules, which would be an almost constant finding in
patient’s ovaries with this disorder, justifying a careful
examination by multiple ovarian biopsies 9 10. This unusual tumor represents 0.05 to 0.6% of all ovarian neoplasia and is associated in one-third of cases with the
PJS. The natural history and appropriate management
of this tumor are unknown 11. According to the WHO,
the SCTAT is presumed to be a variant of sex cord stromal tumour. This tumour appears to arise from granulosa cells, although the growth pattern resembles that
of Sertoli cells. The absence of germ cells and karyotypic abnormalities led to eliminate gonadoblastoma. The
SCTAT associated with PJS, is essentially benign and is
often an incidental finding, which is grossly typically
bilateral, multifocal and small, with areas of calcification 12. Histological features consist of on simple and
complex tubular formations 13. Immunohistochemical
A. AYADI-KADDOUR, ET AL.
120
study is positive for vimentin intermediate filament,
progesterone, testosterone and oestrogen receptors.
Inhibin and Mullerian-inhibiting substance (MIS) proved to be effective markers 14 15. The ACE and the
CA125 are both negative.
Our case is uncommon because of the production of
AFP that was reported in rare cases of Sertoli-Leydig
tumour associated with elevation of AFP serum. Based
on these histological observations, it appears that SCTAT is a sex cord/stromal tumour made up of cells with
differenciation in the direction of Sertoli cells rather
than granulosa cells. Malignant behavior in SCTAT has
heretofore been reported only in sporadic cases. To our
knowledge, only one case of malignant SCTAT associated to the PJS has been reported in the literature 16.
The main diagnosis of malignancy in SCTAT’s has
been because the tumour has metastasised or recurred.
Usual spread is to pelvic lymph nodes and supraclavicular lymph nodes, although it can spread to liver, peritoneum and other organs. In our case, hepatic biopsy
demonstrated that the liver lesions are metastatic SCTAT rather than metastatic colorectal carcinoma, and
confirmed the malignant potential of ovarian tumour.
Histological characteristics and the immunohistochemical phenotyping of both colonic and ovarian cancers
were consistent with sex cord tumor with annular tubules let to exclude ovarian metastases of the colonic tumor. Our case is the first patient report to have a bilateral malignant SCTAT secreting AFP and Peutz-Jeghers polyposis and an adenocarcinoma of the colon
probably arising in a Peutz-Jeghers polyp. It is particularly interesting because of this association and the
AFP detected in this ovarian neoplasia.
Taking into account the above, we recommend a full
gynaecological and gastro intestinal regular check up
with endoscopic resection of any gastro intestinal
polyp with histological examination is required in case
of PJS. This protocol may improve the prognosis and
allow a better understanding of the exact mechanism of
malignant transformation of hamartomatous polyps.
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