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The association of adrenocortical carcinoma and thyroid cancer in a child with Peutz-Jeghers syndrome
Şule Yalçin ª,*, Elif Kirliª, Arbay 0. Ciftcia, İbrahim Karnakª, Nicoletta Resta”, Rosanna Bagnulo‘, Zuhal Akçörenb, Diclehan Orhanb, Mehmet Emin Şenocak a
aDepartment of Pediatric Surgery, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
bDepartment of Pediatric Pathology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
“Department of Biomedicine in Childhood, Section of Medical Genetics, University of Bari “A. Moro,” Bari, Italy
Received 5 May 2010; revised 4 January 2011; accepted 10 January 2011
Key words: Peutz-Jeghers syndrome; malignancy; adrenocortical cancer; thyroid cancer; child
Abstract Peutz-Jeghers syndrome (PJS) is a rare, dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps, mucocutaneous hyperpigmentation, and an increased risk of cancer. We present a 16-month-old child diagnosed with PJS, who had distinguishing features compared with the previously reported cases with respect to her clinical presentation, associated malignancies, and genetic analysis. To our knowledge, this is the first report of adrenocortical carcinoma in association with PJS, as well as the first instance of associated thyroid cancer in a child with PJS. We briefly review the relevant literature and highlight the recent progress achieved in the investigation of the syndrome. @ 2011 Elsevier Inc. All rights reserved.
Peutz-Jeghers syndrome (PJS) is an inherited, autosomal dominant disorder with the diagnostic features of hamarto- matous polyps, mucocutaneous hyperpigmentation, and an increased risk of malignancy [1]. The first presentation is generally caused by the intestinal complications of the polyps at approximately 10 to 13 years [2]. The significant increase in the incidence of gastrointestinal (GI) and extraintestinal malignancies emphasizes the importance of investigation of the genetic aspects of this association and lifelong surveil- lance of patients with PJS for cancer screening.
Herein, we report a child with PJS, who had the characteristic components of PJS but had distinguishing features from the previous case reports with respect to her clinical presentation and associated malignancies. To our knowledge, this is the first case of PJS associated with an
adrenocortical carcinoma (ACC) and the first child with PJS with associated thyroid cancer. Five adults with PJS and thyroid cancer were reported previously. We also discuss the recent recommendations regarding the management of polyposis, genetic analyses, and cancer screening programs based on the continuing investigation of the syndrome.
1. Case report
A 16-month-old girl was admitted to the hospital with the complaints of fever, vomiting, and weight loss of 2-month duration. Physical examination revealed an estimated 8 × 10- cm fixed and firm abdominal mass filling the left side of the abdomen. The external genitalia showed signs of virilization with pubic hair and clitoromegaly. Radiologic investigation with abdominal ultrasonography and computed tomography showed a 10 × 12-cm left suprarenal mass pushing the spleen
* Corresponding author. Tel .: +90 312 3115541; fax: +90 312 3115541. E-mail address: suleyal@hacettepe.edu.tr (Ş. Yalçin).
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superiorly and the left kidney inferiorly (Fig. 1). A core needle biopsy of the mass was obtained, and the result was consistent with an adrenocortical tumor. The suprarenal mass was totally excised. It weighed 410 g, measured 11 x 9 x 7 cm, and was encapsulated. Histologic examination revealed polygonal large cells with eosinophilic cytoplasm and pleomorphic nuclei, some of which contained pseudoinclu- sions (Fig. 2). Although the tumor did not infiltrate the capsule, tumor cells were observed within the vessels and sinuses of the tumor. Widespread necrosis and hemorrhage within the mass and adrenal tissue in the proximity of the capsule were noted. Findings were consistent with ACC. The patient was followed up without any adjunctive therapy other than postoperative steroid replacement, and there was no recurrence of disease.
At 5 years, the patient was admitted with complaints of vomiting and abdominal pain experienced the previous week.
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Hyperpigmentation of the oral mucosa and lips was noticed on physical examination (Fig. 3). An abdominal ultrasound study showed an intussusception. A barium enema was normal. An exploratory laparotomy was performed, and a small bowel intussusception 30.0 cm in length was noted (jejunoileal) and manually reduced. The lead point was a polyp located 30 cm distal to the ligament of Treitz. A 9.0-cm intestinal segment containing the polyp was resected, and an end-to-end small bowel anastomosis was performed. No other palpable polyps were detected during the procedure. However, the specimen contained 2 hamartomatous polyps in close proximity that were histologically confirmed as PJ polyps.
Five days after discharge, the patient was readmitted because of recurrent vomiting. A palpable abdominal mass was palpated, and a repeated ultrasound study documented the presence of an additional intussusception. Another abdominal exploration was undertaken, which revealed a jejunojejunal intussusception measuring 30 cm. Manual reduction was performed for the invaginated segment, which included the site of the previous anastomosis as the lead point. No polyps were palpable. She had an uneventful postoperative course and was discharged in satisfactory condition.
The child remained symptom free for the following 5 months, when a swelling was noted on the right anterior neck. At this time, she was 6 years. There was no history of previous radiation exposure. Cervical ultrasonography revealed 2 nodules measuring 6 × 5 mm on the right thyroid lobe. Fine-needle aspiration of the mass was consistent with the diagnosis of follicular neoplasm. Right thyroid lobecto- my and isthmectomy were initially performed. Histologic examination of the specimen revealed small nodules of tumor, the largest of which was 0.7 cm in diameter consistent with papillary thyroid carcinoma (PTC) (Fig. 4). Thus, the left lobe was also removed (completion thyroidectomy). Histologic investigation showed no evidence of tumor in the left lobe. The postoperative follow-up with thyroid ultraso- nography and [131-uptake screening revealed no residual or recurrent disease. Patient follow-up is continuing in accordance with the screening program of PJS. Mutational analysis for STK11 was performed for our patient and revealed a missense mutation leading to the amino acid change E199D in the kinase domain. This mutation has not been previously described. The mutation was not present in the parents and in 100 normal chromosomes. Furthermore, PolyPhen (http://genetics.bwh.harvard.edu/pph/) analysis classified this constitution as possibly damaging.
2. Discussion
The estimated prevalence of PJS is 1 in 8300 to 280,000 individuals [1]. The initial presentation for most patients is usually a result of complications related to the GI polyps often between the age of 10 to 13 years [1,2]. Although PJ polyps occur most frequently in the small intestine and, especially, the jejunal segments, involvement of the stomach (30%) and colon (10%) may be observed. In addition, polyps may rarely occur in the nasal passages and gallbladder. This wide variation in polyp localization should promote investigation of the entire alimentary tract, both during the initial surgical management of a complicated case as well as for future surveillance. Videocapsule endoscopy as a first-line screen- ing procedure and double-balloon or intraoperative entero- scopy for therapeutic purposes are the recommended approaches in an effort to avoid the need for recurrent laparotomies; the benefits and drawbacks of these procedures should be considered specific to each situation [1,3-6].
Unlike the usual presentation associated with GI symp- toms owing to bleeding or intussusception, the first presentation for our patient was a huge suprarenal mass without the characteristic signs of PJS (ie, mucosal hyper- pigmentation or polyposis). The second admission 4 years later was consistent with the classic presentation of the syndrome, but the presenting age was younger than the median of 10 years reported in the literature. Surgical management was performed for the intussusception with manual exploration of the entire GI tract. Recurrence of the
intussusception 2 weeks after the initial operation required a second laparotomy, which revealed the site of previous anastomosis as the lead point rather than a polyp, and this differs from the other reported underlying pathologies necessitating repeated laparotomy [2,3].
The germ-line mutation in the serine/threonine kinase gene STK11/LKB1 on chromosome 19p13.3 is linked to the manifestations of PJS in 30% to 80% of cases [7]. Inactivation of this tumor suppressor gene may explain the significantly increased risk of both GI (esophageal, gastric, duodenal, intestinal, colorectal, pancreatic) and extraintest- inal (breast, ovary, cervix, uterus, testis, lung) malignancies in PJS, in addition to the other suspected mutational mechanisms of gene loci not yet clearly identified [8].
The most striking finding in our case was the association between PJS and ACC, which to our knowledge has not been previously described in the literature. This rare tumor, with a prevalence of 4 to 12 per million population, is associated with a poor prognosis [9]. Surgery is the mainstay of treatment because response to adjuvant therapies including mitotane and radiotherapy is poor, with a high rate of recurrence and metastasis despite radical resection [10]. Advancement in the research of the molecular basis of this cancer is essential for development of better therapeutic approaches. Li-Fraumeni, Beckwith-Wiedemann, and mul- tiple endocrine neoplasia 1 are the hereditary tumor syndromes known to have an association with ACC, with a prevalence of up to 5%. Although the TP53, IGF2, H19, CDKN1C, and MEN1 genes related to the previously mentioned syndromes are known to be involved in adrenocortical carcinogenesis, absence of mutations in those genes shown in some of the genetic analyses of comparative genomic hybridization and loss of heterozy- gosity suggest the presence of other putative oncogenes or tumor suppressor genes not yet identified [9]. The associ- ation of ACC with PJS could present a new line of investigation for the ongoing genetic studies in an effort to better understand the pathogenesis of this cancer, with the aim of improving clinical outcomes.
Although the association of differentiated thyroid cancer with familial adenomatous polyposis and Cowden syndrome is well known, with prevalences of 1% to 2% and 10%, respectively, such a correlation with PJS has not yet been supported in any formal study [11]. There are only 5 reported cases of thyroid cancer in association with PJS in the literature [12-16]. All 5 were young adults ranging in age from 21 to 33 years: 3 had papillary, one had unspecified thyroid cancer, and the pathologic type in the fifth case was not mentioned. Although the papillary type of thyroid histology in our case is consistent with some of the previously mentioned case reports, the time of diagnosis for thyroid cancer was significantly earlier, at 6 years, representing the first case in childhood. A recent in vitro study providing a possible molecular explanation for the association between PJS and differentiated thyroid cancer suggests that LKB1 suppresses tumor growth by inhibiting
RET/PTC-dependent activation of oncogenic STAT-3, which is the mechanism involved in the tumorigenesis of PTC [17]. To clarify the possible association between PTC and PJS, in vivo genetic analysis seems to be obligatory given the limited number of reported cases, in addition to in vitro studies, because these established data would certainly direct the clinical practice with respect to the management and surveillance.
Screening programs for PJS are obligatory both for the prevention of GI complications related to the polyps and for early detection of relevant malignancies. Investigation and preventive removal of the polyps (>1 cm) by screening with videocapsule or double-balloon endoscopy is recommended from 8 to 10 years and should be repeated every 2 years. This may reduce the rate of emergency surgical procedures and will offer the opportunity of advanced therapeutic approaches in tertiary centers [2,3,18-20]. The increased overall cancer risk with PJS is up to 85% by the age of 70 years, which is nearly 4-fold the risk of the general population, which demands implementation of cancer screening programs. Although a strict schedule has not yet been established, the recent recommended surveillance includes the following: colonoscopy bi yearly and breast examination, Papanicolaou test, endometrial biopsy, trans- vaginal ultrasound, chest radiography, and endoscopic ultrasonography annually from the age of 20 to 25 years to screen for colorectal, breast, cervical, uterine, ovarian, lung, and pancreatic cancers, respectively [3,18,20,21]. Testicular examination and ultrasonography in suspected cases should be offered annually beginning from birth up to 12 years [3,18]. Thyroid ultrasonography is not recommended as a routine screening test because of the lack of an established association between thyroid cancer and PJS. Nevertheless, thyroid examination and ultrasonography in suspected cases should be implemented in the annual follow-up of the patients with PJS because thyroid cancer can occur earlier and with a more aggressive histologic pattern, given the knowledge of the 5 previously reported cases and our case presenting in childhood [16]. Because no significant difference was determined with respect to the cancer risk between the patients carrying mutations in the STK11/LKB1 gene and those without mutations [7,8], regular surveillance should be carried out in all cases of PJS
Our patient differs from those previously reported with respect to clinical presentation, reported malignancies, and the noticeable earlier age of occurrence for each of the cancer diagnoses. The first malignancy, ACC occurring before the diagnosis of PJS, is unique in our case because the classic PJS stigmata of hyperpigmentation and hamartomatous polyposis were not yet clinically evident. The association of the 2 malignancies in this patient (ACC as the initial presentation in PJS and the first pediatric case of PTC with PJS) also distinguishes our case from the many previously reported cancer cases. This case may impact future surveillance programs in PJS and describes the novel STK11 missense mutation E199D.
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