THYROID Volume 21, Number 11, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2011.0063
Papillary Thyroid Carcinoma in Peutz-Jeghers Syndrome Vincenzo Triggiani,1 Edoardo Guastamacchia,1 Giuseppina Renzulli,2 Vito Angelo Giagulli,1 Emilio Tafaro,1 Brunella Licchelli,1 Francesco Resta,3 Carlo Sabba`,3 Rosanna Bagnulo,4 Patrizia Lastella,4 Alessandro Stella,4 and Nicoletta Resta 4
Background: Peutz-Jeghers syndrome (PJS) is a rare dominantly inherited disease characterized by the association of gastrointestinal hamartomatous polyposis, mucocutaneous hyperpigmentation, and increased risk of cancer at different target organs. Its occurrence with differentiated thyroid cancer, particularly papillary thyroid carcinoma (PTC), even if rare, has been described. Summary: We here present a case of PTC observed in a PJS patient and a review of the literature aiming at discussing the utility of thyroid surveillance in the management of these patients. A 22-year-old woman presenting with hyperpigmented lesions of the lips and hamartomatous polyps in the stomach, duodenum, jejunum, and ileum, leading to the suspicion of PJS, was submitted to genetic analysis. Mutation scanning of the Liver Kinase B1 (LKB1) gene identified the presence of the truncating mutation E265X, thus confirming the clinical diagnosis. Beside the endoscopic, radiologic, and echographic evaluations required by the standard surveillance guidelines, the patient had a neck ultrasound (US), which showed a 5 · 4 · 6 mm hypoechoic nodule in the right thyroid lobe. The nodule contained microcalcifications and a perinodular vascular pattern. The cytological preparations derived from US-guided fine-needle aspiration biopsy of the nodule demonstrated the presence of PTC. The patient underwent a video-assisted total thyroidectomy and the histological examination revealed a follicular variant of papillary microcarcinoma. Radioactive iodine therapy was not performed because of the small size of the lesion. The patient was started on levothyroxine therapy to keep the serum thyrotropin levels suppressed. Both the sequencing and the multiplex ligation–dependent probe amplification analysis could not identify any LKB1 mutation in the tumor specimen, and the methylation-specific polymerase chain reaction assay excluded hypermethylation of the LKB1 promoter as the mechanism of inactivation for the remaining normal allele in the tumor. Conclusions: Although other mechanisms of LKB1 silencing may be responsible for its inactivation in the thyroid cancer, we cannot rule out that the occurrence of thyroid carcinoma could be a coincidental finding in this patient. However, the case here presented suggests that US of the thyroid could possibly become an integral part of the evaluation and the follow-up program adopted for PJS patients.
Introduction
P
eutz-Jeghers syndrome (PJS) is a rare condition inherited in an autosomal dominant pattern, with incomplete penetrance. The diagnosis is usually made based on the presence of mucocutaneous hyperpigmentation of the lips and the buccal mucosa in association with hamartomatous polyposis of the gastrointestinal (GI) tract and increased cancer risk at different sites (1,2). The incidence of the syndrome ranges from 1 in 8300 to 1 in 280,000 live births (3,4). PJS is commonly diagnosed in the third decade of life, although one-third of the cases are identified in children before the age of 10 years (5).
The hamartomatous polyposis is usually confined to the small bowel in 90% of the patients, often in the jejunum, and less frequently in the ileum and duodenum (6), but polyps can also be found in the stomach (24% of the cases), colon (9%), as well as extraintestinal sites such as nose, bladder, gallbladder, bronchi, and ureter (7). Polyps are responsible for clinical manifestations including acute intestinal intussusception, bleeding anemia due to polyp ulceration, chronic abdominal pain, or anal prolapse of rectal polyps (5). PJS patients have increased risk for malignancies in the GI tract as well as in several extraintestinal sites including the pancreas, breast, uterus, ovary, and testes (8,9). Few cases of differentiated thyroid carcinomas have been described so far.
1 Endocrinology and Metabolic Diseases; 2Pathology Unit ‘‘C. Golgi’’; 3Rare Diseases Center; and 4Department of Biomedicine in Childhood, Section of Medical Genetics; ‘‘Aldo Moro’’ University of Bari, Bari, Italy.
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The Serine Threonine-Protein Kinase 11/Liver Kinase B1 (STK11/LKB1) is the gene responsible for this syndrome. It was identified in 1998 (10,11). LKB1 is located on chromosome 19p13.3 and encodes for a serine threonine kinase (12) acting as a tumor suppressor gene. Germline mutations of LKB1 are identified in nearly 90% of the patients presenting clinical manifestations of the disease (13). Timely molecular testing is important, allowing for the confirmation of the clinical diagnosis and for the patient’s enrollment in specific surveillance programs. Patient A 22-year-old woman was referred to our institution because of a suspicion of PJS. The patient presented with hyperpigmented lesions of the lips, which had appeared when she was 3 years old, thus representing the first sign of the syndrome (Fig. 1). The medical history recorded polyps in the stomach, duodenum, jejunum, and ileum at 21 years of age, detected by capsule endoscopy. All these lesions were removed and the histological examination demonstrated that all were of the hamartomatous type (Fig. 2). Genetic analysis of the serine threonine-protein kinase 11 (STK11/LKB1) gene identified the presence of the truncating mutation E265X. The patient was then followed on a regular basis with endoscopic, radiologic, and echographic procedures based on standard recommendations for patients with PJS. Echograms of the abdomen, specifically, detected no abnormalities in the ovaries, uterus, gallbladder, pancreas, and liver. Ecographic evaluation of the breast and colonoscopy were negative. A routine neck ultrasound (US) led to the discovery of a 5 · 4 · 6 mm hypoechoic nodule in the right lobe of the thyroid gland. The lesion showed microcalcifications and a perinodular vascular pattern (Fig. 3). Thyroid hormones, thyrotropin (TSH), thyroglobulin (Tg), calcitonin, and anti-thyroid peroxidase (TPO) antibodies assays were in the normal range, but antithyreoglobulin antibodies titers were slightly augmented. USguided fine-needle aspiration biopsy (FNAB) of such (micro)nodule was performed, given the young age of the patient and the high specificity of the association of hypoechoic pattern and microcalcifications (14). The cytological preparations showed several groups of thyrocytes, often arranged in
FIG. 1.
Hyperpigmented lesions of the lips.
FIG. 2. Hyperplastic gastric polyp. The polyp is lobulated with a central core of tree-like branching of the smooth muscle, surrounded by a layer of hyperplastic mucosa. Elongation and cystic changes of the foveolar epithelium are also present (hematoxylin and eosin (H&E) staining, 10 · ). syncytial tissue fragments or in microfollicular aggregates with pale nuclei showing grooves and occasionally pseudo-inclusions (Fig. 4). These features led to the diagnosis of a papillary thyroid carcinoma (PTC). A video-assisted total thyroidectomy was performed and the histology showed the presence of a follicular variant of papillary thyroid microcarcinoma, with no infiltration of the thyroid capsule (Fig. 5). Neck US did not show any metastatic lymph node. Chest radiogram was negative. Radioactive iodine therapy was not performed because of the small size of the lesion. The patient was started on levothyroxine therapy at a daily dose of 125 mcg/day to keep the serum TSH levels suppressed. Follow-up included US of the neck performed every 6 months as well as TSH, free triiodothyronine, free thyroxine, Tg, and Tg autoantibody level evaluations. Thorough LKB1 gene analysis was performed at DNA level to identify either mutations or loss of the wild-type LKB1 allele on tumor tissue. The hypothesis that the tumor could be the result of two mutational events, a germline mutation in one allele and a somatic mutation in the second allele, was investigated. Genomic DNA isolated from paraffinembedded samples of normal and tumor thyroid tissue was polymerase chain reaction (PCR) amplified for each of the nine coding exons of the LKB1 gene using intronic primers and PCR conditions as previously described.10 The PCR products were directly sequenced on an ABI310 sequencer. The search for partial or whole genome deletions/duplications of the LKB1 gene was performed with multiplex ligationdependent probe amplication (MLPA) using the salsa-probe mix P101 (MRC Holland). Further, to assess the methylation status of the wild-type LKB1 allele, we analyzed the 5¢-CpG island in the LKB1 promoter on normal and tumor thyroid tissue DNA isolated as mentioned earlier and using DNA extracted from the DLD-1 colorectal cancer cell line as a positive control for the methylation-specific PCR (MSPCR). The LKB1 promoter, in fact, is fully methylated in this cell line. Both the sequencing and the MLPA analysis failed to show the presence of any somatic LKB1 mutation in the tumor
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FIG. 3. (A) Hypoechoic nodule in the right thyroid lobe. The lesion was 5 · 4 · 6 mm in diameter and shows microcalcifications and perinodular vascular pattern (transversal scan). (B) Hypoechoic nodule in the right thyroid lobe (longitudinal scan).
FIG. 4. (A) Fine-needle aspiration cytology of the thyroid papillary microcarcinoma. Medium-sized cells grouped in syncytial tissue fragments (Papanicolau, 400 · ). (B) Fineneedle aspiration cytology of the thyroid papillary microcarcinoma (follicular pattern; Papanicolau, 400 · ).
specimen and the result of MSPCR assay ruled out hypermethylation of the LKB1 promoter as the mechanism of inactivation for the remaining normal allele in the tumor. In addition, we performed further mutation search in canonical mutation hot spots in thyroid cancer by sequencing the BRAF gene exons 11 and 15 and K-RAS, N-RAS, and H-RAS genes exons 1 and 2. All of these analyses were performed on thyroid tumor tissue as previously described (15). We could not perform RET/PTC genomic rearrangement analysis by real time (RT)-PCR, because fresh or frozen tumor tissue for RNA extraction was not available. In any case, activating BRAF or K-, N-, or H-RAS point mutations and RET rearrangements are mutually exclusive events in the papillary thyroid carcinoma tumorigenesis. However, in our tumor specimen, mutations in the BRAF and RAS genes were not identified.
also include differentiated thyroid cancer (DTC) (PTC and follicular thyroid carcinoma [FTC]). About 1%–2% of patients with FAP develop PTC, which is frequently multicentric and often presenting in its cribriform-morular variant. Occasionally, PTC may represent the first manifestation of FAP (16,17). Up to 10% of patients with Cowden’s syndrome develop FTC (18), which is the most frequently diagnosed malignancy in these patients, second only to breast cancer (19). Thyroid cancer is not part of the known spectrum of PJS, and thus the finding of DTC and PJS may be coincidental and seems to be rare. In fact, this case represents only the sixth reported in the literature. A case of thyroid carcinoma in PJS has been mentioned by Spigelman et al. (20), although they did not describe either the patient’s personal history and the histology of the tumor. Reed et al. reported a case of PTC in a 21-year-old woman affected by PJS among a series of patients with thyroid neoplasia and intestinal polyps (21). Yamamoto et al. described a case of PTC in a 29-year-old Japanese woman with PJS (22). In this patient, pigmented mucocutaneous lesions were initially reported at 4 years of age, and the diagnosis of PJS was made when the patient was 22 years old, after a small bowel resection
Discussion Intestinal polyposis syndromes, such as familial adenomatous polyposis (FAP), Cowden’s syndrome, and PJS, are often associated with extraintestinal manifestations, which
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FIG. 5. Histologic features of papillary microcarcinoma. Aggregates of follicles lined by typical cells of papillary carcinoma (H&E, 400 · ).
performed because of an intussusception caused by hamartomatous polyps. Boardman et al. (23) reported a single thyroid cancer in their series of 26 noncutaneous cancers ascertained among 34 PJS patients. Finally, Zirilli et al. (24) described a 14mm nodular lesion in the right thyroid lobe of a 25-year-old Caucasian woman affected by PJS. Cytological analysis at FNAB revealed a pattern compatible with PTC, and the histological analysis after total thyroidectomy showed a Hurtlecell variant of PTC, with follicular architecture. The management of DTC in a patient with PJS does not differ from the standard guidelines for DTC. Total thyroidectomy as well as radioiodine ablation therapy is recommended, although some concern could be raised about the possible tumorigenic effects of radioiodine therapy in cancer-prone individuals such as patients affected by PJS. Prophylactic thyroidectomy is not indicated in PJS patients, given the relatively low prevalence of PTC, the potential complications of thyroidectomy, and the excellent prognosis for PTC. In any case, clinicians should be aware that the wide spectrum of cancer diseases possibly occurring in PJS patients could also include DTC, although this is rare. Consequently, US of the thyroid can be recommended to PJS patients even when no clinical sign of thyroid disease is present in the patient’s medical history. If thyroid nodules are found at US analysis, their features can help in choosing to perform USguided FNAB. In conclusion, the reported case of microcarcinoma of the thyroid in a PJS patient underlines the importance of performing a thyroid surveillance program in these patients. In fact, the few cases in the literature are not sufficient to determine if thyroid carcinoma is more aggressive in this context. The periodic evaluation of the thyroid can be extremely useful in detecting very small thyroid nodules with putative malignant potential. Disclosure Statement The authors declare that no competing financial interests exist.
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Address correspondence to: Vincenzo Triggiani, M.D. Endocrinology and Metabolic Diseases University of Bari ‘‘A. Moro’’ via Repubblica Napoletana n. 7 Bari 70123 Italy E-mail:
[email protected]
