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Thymic Neuroendocrine Carcinoma (Carcinoid) in Multiple Endocrine Neoplasia Type 1 Syndrome: The Italian Series

Department of Internal Medicine and Endocrine Sciences, Thoracic Surgery, Institute of Pathology University of Perugia (P.Fe., N.A., G.D., F.P., R.R., F.S., G.A.), 06100 Perugia, Italy; Department of Internal Medicine, University of Florence, and Regional Center for Hereditary Endocrine Tumors (A.F., M.L.B.), Florence 50100, Italy; Department of Thoracic Surgery, University of Torino, San Giovanni Battista Hospital (P.Fi.), Torino 10100, Italy; Department of Internal Medicine and Gastroenterology, University of Bologna (P.T.), Bologna 40100, Italy; and Department of Clinical Science, Endocrine Section, University of Rome La Sapienza (G.T.), Rome 00100, Italy

Address all correspondence and requests for reprints to: Dr. P. Ferolla, Department of Internal Medicine and Endocrine Sciences, University of Perugia, Via E. Dal Pozzo, 06100 Perugia, Italy. E-mail: pferolla{at}tin.it.

	Abstract

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Neuroendocrine tumors may occur in the setting of multiple endocrine neoplasia type 1 (MEN1) syndrome. Among these, a probably underestimated prevalence of well differentiated neuroendocrine thymic carcinoma (carcinoid), a neoplasm characterized by very aggressive behavior, has been described. We report characterization of the seven Italian cases in which this association occurred among a series of 221 MEN1 patients (41 sporadic and 180 familial cases; prevalence, 3.1%). All of the patients were male, and six of seven (85%) were heavy smokers. No associated hormonal hypersecretion was detected. The first diagnosis was between the second and fifth decades. Familial clusters were present in three of seven (42.8%). No genotype-phenotype correlation was found. All seven cases were associated with hyperparathyroidism. In one patient, prophylactic thymectomy revealed a small nodular lesion suggestive of a thymic carcinoid, providing evidence that preventive thymectomy might prevent additional growth of an occult thymic carcinoid. These findings confirm that thymic carcinoids are associated with a very high lethality, with a near-total prevalence in smoker males. Therefore, prophylactic thymectomy should be considered at neck surgery for primary hyperparathyroidism in MEN1 male patients, especially for smokers, and, due to the frequent familial clusters distribution of this pathology, in subjects with affected relatives presenting this feature. Thus, we recommend screening every patient affected with a neuroendocrine thymic neoplasm for MEN1 syndrome.

	Introduction

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THYMIC LOCATION IS one of the rarest sites of neuroendocrine tumors (carcinoid) reported in the literature. Since 1972, when eight cases of this neoplasm were first described as a different entity from thymomas (1), about 150 cases have been reported. Moreover, an association with multiple endocrine neoplasia type 1 (MEN1) was described (2). Nevertheless, thymic location of carcinoid tumors in MEN1 patients is still considered an extremely rare finding, described in fewer than 30 cases. Despite the recognized associated lethality in MEN1 patients, the real incidence, appropriateness of diagnostic procedures, prophylactic and therapeutic management, and timing of follow-up remain to be established. To address these issues, we have analyzed the seven Italian cases in which this association occurred. These are the only Italian cases in which this association has been demonstrated, according to the Italian Register for Multiple Endocrine Neoplasia in 221 MEN1 patients (41 sporadic and 180 familial cases). A recent prospective study of eight cases has been recently published (3). Some relevant differences between the two series are analyzed and discussed (3).

	Patients and Methods

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Patients

The patients were followed during the period between 1990 and 2003 at the Departments of Internal Medicine and Endocrine Sciences of University of Perugia, the Department of Internal Medicine and Gastroenterology of University of Bologna, the Department of Thoracic Surgery of University of Torino, and the Endocrine Section of University of Rome La Sapienza.

In agreement with the international guidelines for diagnosis and therapy of MEN1 patients (4), the diagnosis of MEN1 was based on the coexistence of at least two of the three main MEN1-related endocrine tumors (parathyroid adenomas, enteropancreatic endocrine tumors, and pituitary tumor) in each case. Furthermore, a diagnosis of familial MEN1 (at least one MEN1 case plus at least one first-degree relative with one of three of the main MEN1-related endocrine tumors) was formulated for all patients except case 5.

All members were asked to undergo DNA mutational analysis after giving informed consent. All released the consent except for cases 4 and 6, who prefer to delay the analysis. For this reason, in Table 1 the genetic test is defined as ongoing in these patients.

The diagnosis of neuroendocrine thymic carcinoma was formulated on the basis of morphology and immunohistochemical reactivity for the pan-neuroendocrine markers chromogranin A (CGA), synaptophysin and neuronal-specific enolase (NSE) according to the World Health Organization (WHO) classification criteria (5).

Circulating CGA was measured by RIA and ELISA (CIS Biointernational, Gif-sur-Yvette, France; and DakoCytomation, Glostrup, Denmark). NSE was measured by RIA (CIS Biointernational). Urinary 5-HIAA was determined using HPLC.

Ectopic Cushing’s syndrome was excluded using 24-h urinary free cortisol excretion and rhythm of plasma cortisol and ACTH, including a midnight sample during sleep. Only in selected cases were the high dose dexamethasone suppression test and CRH stimulation test performed, and the results of these tests were negative.

MEN1 gene mutational analysis

Mutational analysis of the MEN1 gene was performed and confirmed in two independent laboratories (Florence and Perugia). DNA was extracted from peripheral blood leukocytes using a microvolume extraction method, NucleoSpin Blood Quick Pure (Macherey-Nagel, Easton, PA) according to the manufacturer’s instructions. Encoding regions (exons 2–10) and exon-intron junctions were amplified by PCR, with specific couples of primers located in the flanking intronic regions, in a 50-µl volume containing 50–100 ng DNA, 1x PCR buffer [67 mM Tris-HCl, 16.6 mM (NH₄)SO₄, and 0.01% Tween 20], 2.5 mM MgCl₂, 0.25 mM deoxyribonucleotides, 0.4 µM of each primer, and 1 U Polytaq (Polymed, Florence, Italy). PCR amplification of exons 2, 9, and 10 required 10% dimethylsulfoxide. After denaturation at 94 C for 3 min, the samples were amplified in 35 cycles of 30 sec at 94 C, 30 sec at the specific annealing temperature for every pair of primers, and 1 min at 72 C. A final extension at 72 C for 5 min was performed. The PCR products were tested by 2% ethidium bromide-stained agarose gel electrophoresis, then purified by NucleoFast 96 PCR plates for PCR product purification (Macherey-Nagel, Easton, PA). One aliquot of each PCR product was sequenced, with both forward and reverse primers, using the BigDye Terminator Purification Kit (Applied Biosystems, Foster City, CA) in a reaction consisting of 25 repeated cycles of denaturation for 10 sec at 96 C, annealing for 5 sec at 50 C, and extension for 2 min at 60 C. The sequencing products were then purified with Montage SEQ96, Sequencing Reaction Cleanup Kit (Millipore Corp., Bedford, MA) and analyzed on the ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). The sequences obtained were compared with wild-type reference sequence of the MEN1 gene (U93237) (6).

	Results

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Table 1 summarizes the main features of the Italian patients with MEN1 and thymic carcinoid. All of the patients were men, with a mean age at presentation of 38.7 ± 9.9 yr (age range, 29–52 yr); aside from case 7, they were heavy smokers (>20 cigarettes/day). All of the patients had hyperparathyroidism, and four also exhibited pituitary adenoma and pancreatic tumor. All patients, except case 6, were asymptomatic at presentation, and thymus involvement was diagnosed incidentally or in the context of a periodical follow-up in recognized MEN1 patients. The patients, aside from case 6, remained asymptomatic until a later stage of the disease. In cases 2 and 4, thymic carcinoid was the first clinical manifestation of MEN1, but asymptomatic hyperparathyroidism was already present. In all patients, except case 3, the diagnosis was suspected on the basis of enlargement of the mediastinal profile at standard chest x-ray. In all patients, except case 3, a computed tomography (CT) scan of the chest was diagnostic (Fig. 1). The uptake of the [¹¹¹In]diaminetriaminepentacetate (DTPA)-D-Phe-octreotide (Octreoscan, Tyco-Mallinckrodt, St. Louis, MO), calculated using Krenning scale, was very high in cases 1, 2, and 6 in primitive tumor and in its metastasis and was weak, but diffuse, in case 5.

View larger version (52K): [in this window] [in a new window]   FIG. 1. Chest CT scan at diagnosis of cases 1 and 2, showing a large mass in the anterior mediastinum (maximum diameter, 9 cm).

Full follow-up of all patients was carried out. Three patients (cases 1, 2, and 7) died with diffuse metastasis 60, 36, and 26 months, respectively after surgery. One patient (case 5) is alive with stable disease and loco-regional metastasis 96 months after surgery. Two patients (cases 4 and 6) showed no evidence of the disease 28 and 120 months after surgery. Case 3, who underwent prophylactic thymectomy, is disease free 84 months after surgery. Familial clusters were present in cases 1, 2, 4, and 5. The brother of case 1 is affected with a metastatic bronchial carcinoid.

Metastatic diffusion of the primary thymic neoplasm was present in cases 1, 2, 5, and 7. According to WHO and Masaoka criteria at surgery, cases 1, 2, 6, and 7 can be considered widely invasive due to direct extension into adjacent structures such as pericardium, large vessels, and lung, whereas cases 4 and 5 were only minimally invasive, with invasion of the mediastinal fat. At a later stage, case 1 became classifiable as being with implants due to the multiple nodules found at thoracoscopy on the pleural surface. All of the cases were classified as atypical carcinoid according to WHO classification criteria due to the presence of necrosis (Fig. 2) and a mitotic count ranging from two to 10 mitoses/10 high power fields. Aside from case 3, the mean maximum diameter was 8.6 ± 1.3 cm.

View larger version (87K): [in this window] [in a new window]   FIG. 2. Macroscopic section of the mediastinal mass shown in Fig. 1. The presence of multiple necrotic areas is evident (arrows).

View larger version (169K): [in this window] [in a new window]   FIG. 3. Anterior view of [111In]DTPA-D-Phe-octreotide scintigraphic scan 24 h after injection of labeled octreotide in case 2, showing intense uptake at the mediastinal level in residual mass, in one lymph nodal metastasis, and in one fontal bone metastasis. Less intense pituitary uptake is shown. A, Total body scan; B, detail of head uptake. TR, Thymic residual mass; LM, lymph node metastasis; CM, cerebral metastasis; P, pituitary uptake.

The results of the mutational analysis for the MEN1 gene are listed in Table 1.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The Italian series presented here confirms that thymic neuroendocrine carcinoma (carcinoid) in MEN1 patients is most commonly diagnosed as an anterior mediastinal mass usually revealed by chest x-ray or CT scan, by accident, or in the context of a periodical clinical follow-up. The most reliable imaging technique is still a matter of debate. Routine chest x-ray may not be adequate for screening and follow-up of thymic carcinoid in MEN1 patients, because the profile of the great vessel and the heart does not allow diagnosis until the tumor reaches a metastatic stage. In contrast, in all of our patients but one, CT scan of the chest was diagnostic (Fig. 1). Therefore, the screening and follow-up programs for carcinoid tumors in MEN1 patients suggested in the international guidelines (4), which include a chest x-ray performed yearly and a CT scan of the chest every 3 yr, risk missing more aggressive thymic carcinoid characterized by early local invasion, distant metastases, and frequent recurrence even many years after excision (7, 8, 9, 10), as in cases 1, 3, and 5. Some relevant guidelines have been suggested from a recent published prospective study (3). However, some differences from our findings are analyzed in this study.

The usefulness of somatostatin receptor scintigraphy (Octreoscan) as a pre- and postoperative diagnostic and follow-up technique in MEN1 patients (11) was confirmed in four of our seven patients (Figs. 3 and 4). This test makes it possible to evidence distant intra- and extrathoracic metastases involving lymph nodes, liver, bone, skin, and adrenal glands that are often present (20–30% of cases) at diagnosis and is a prerequisite for cold or radiolabeled somatostatin analogs therapy, as shown here in four of seven patients. However, contrary to this report (Fig. 2), in a recently published series, no uptake was evidenced in a bone metastasis (3). The power of detection of somatostatin receptor scintigraphy in small diameter thymic lesions and its possible role as an intraoperative procedure to guide complete tumor resection have not been completely established. Other scintigraphic tracers, such as [^99mTc]methoxyisobutylisonitrile, have also been reported to colocalize thymic involvement and parathyroid hyperplasia in MEN1 patients (12)

View larger version (82K): [in this window] [in a new window]   FIG. 4. Preoperative [111In]DTPA-D-Phe-octreotide scintigraphic scan 24 h after injection of labeled octreotide, showing intense uptake at the mediastinal level in case 6 (arrow).

View larger version (172K): [in this window] [in a new window]   FIG. 5. Preoperative chest MR showing the absence of pericardial or large vessel invasion by a large mass (neuroendocrine thymic carcinoma) in the anterior mediastinum in case 6.

In the present report distant metastases were present at diagnosis in six of seven patients. The high frequency of bone metastasis, as in case 2 (Fig. 3) (16, 17), must be underlined, because associated primary hyperparathyroidism in MEN1 patients represents a confounding factor in the early detection of bone metastasis-associated hypercalcemia. Sporadic reports of PTH or PTHrP secretion from thymic neoplasm appeared in the international literature (18), and Funk et al. demonstrated that PTHrP, which is known to exhibit neuroendocrine and growth factor actions, is produced by epithelial cells of the mature thymus (19).

Primary hyperparathyroidism was present in all patients in our series, and an increased incidence of primary hyperparathyroidism has also been reported in sporadic nonneuroendocrine thymic neoplasm. In our experience, a case of thymic neoplasm, not included in this report, presented with associated primary hyperparathyroidism and a familial history of melanoma, but no mutation of the MEN1 gene. Another Italian case of this association, in the absence of any other MEN1 feature, has been recently reported (20). Due to the young age of both patients at diagnosis, the possibility of MEN1 phenocopies cannot be ruled out.

Less frequently, thymic involvement may be the first diagnosed disorder in MEN1 syndrome (cases 2 and 4), and an association with carcinoid syndrome and myasthenia gravis has never been described, not even in metastatic disease. The age at diagnosis ranges generally between the third and fifth decades, as in all our patients, but patients between 15 and 70 yr of age have also been reported (21, 22). Cushing’s syndrome has been reported in about one third of sporadic cases, but never in MEN1 patients. In contrast, approximately 10% of patients with ectopic ACTH syndrome have a sporadic neuroendocrine carcinoma of the thymus (23). Recently, ectopic GHRH secretion alone and GHRH- and ACTH-associated secretion by a thymic carcinoid tumor have been reported in one MEN1 patient and one sporadic patient (16, 24). Sporadic associations with some MEN2 features or with inappropriate antidiuretic hormone secretion have also been reported (25). Other nonendocrine syndromes associated with thymic carcinoids are represented by polymyositis, pericarditis, clubbing, or polyarthritis. Late-onset symptoms include chest pain, cough, shortness of breath, dyspnea, and the superior vena cava syndrome. As in our patients, hydroxyindolacetic acid evaluation does not support the diagnosis of a carcinoid syndrome.

Our report confirms the strong prevalence of these tumors in male heavy smokers (>95%). Male predominance could be partly explained by the action that sex hormones exert on thymocyte proliferation and maturation, because sex hormones have a strong influence in the development of thymus tumors in spontaneous thymoma BUF/Mna rats (26), and estrogens act as inhibitors of thymoma growth (27). In contrast to the thymic carcinoid, a female prevalence has been reported in MEN1-associated bronchial carcinoid. Therefore, the finding of thymic and bronchial carcinoids in case 1 and his brother is of interest.

At least one third of the MEN1 patients reported with thymic carcinoid were asymptomatic at the time of diagnosis, even when invasion and metastases were present, as in the majority of the cases described in this report. Most of the reported cases were associated with a poor prognosis, even after apparently radical surgical excision. In contrast, when possible, radical surgery, including the reexcision of any recurrences, remains the treatment of choice in terms of survival (28, 29, 30). Cold and radiolabeled therapies with somatostatin analogs may play important roles (31, 32).

Clusters have been reported in some families (8) and in four of seven of our patients (Fig. 6), but in agreement with other reports, mutational analysis of the MEN1 gene in our families confirmed the absence of genotype-phenotype correlations (8, 9). Linkage of heterozygosity studies in the 11q13-MEN1 region were negative, and some researchers also postulated a role for a putative tumor suppressor gene in chromosome 1p in the pathogenesis of a subset of thymic carcinoids (9).

View larger version (9K): [in this window] [in a new window]   FIG. 6. Pedigree of cases 1–3. P, Pancreatic neuroendocrine tumor; PA, pituitary adenoma; PH, parathyroids hyperplasia; ZE, Zollinger-Ellison syndrome; TC, thymic carcinoid; BC, bronchial carcinoid; C.R.1, C.R.2, and C.R.3, case reports 1–3, respectively; , MEN1, affected; , not affected; , not screened.

Unlike total thyroidectomy for medullary thyroid carcinoma in MEN2, there is no preventive surgery feasible for MEN1-related malignancies, and prophylactic thymectomy could be considered, at the moment, the only exception to this rule.

The absence of symptoms until the late stage of disease and the lack of effective radio- and chemotherapeutic approaches and appropriate biochemical markers (mild increases in NSE and CGA were found in our patients, but the concomitant gastroenteropancreatic neuroendocrine tumor in three of seven patients must be taken into account) sustain the need for prophylactic thymectomy. Indeed, case 3 provides the first histological evidence that prophylactic thymectomy is able to prevent additional growth of occult microscopic thymic carcinoids (Fig. 7).

View larger version (145K): [in this window] [in a new window]   FIG. 7. One small microscopic section of the thymic remnants in the case 3 showing one small nodular lesion suggestive of thymic carcinoid (hematoxylin and eosin stain). TC, Thymic carcinoid; TR, thymic remnants.

	Footnotes

 
This work was supported by a research grant from the University of Perugia (to P.Fe. and G.D.), a grant from the Patients Association Vivere la Speranza-Amici di Emanuele Cicio (to P.Fe., G.A., and F.S.), and Ente Cassa di Risparmio di Firenze (to M.L.B. and A.F.).

First Published Online February 15, 2005

Abbreviations: CGA, Chromogranin A; CT, computed tomography; DTPA, diaminetriaminepentacetate; FDG, 18-fluorodeoxyglucose; MEN1, multiple endocrine neoplasia type 1; MRI, magnetic resonance imaging; NSE, neuronal-specific enolase.

Received June 22, 2004.

Accepted February 9, 2005.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ferolla, P. Articles by Brandi, M. L. Search for Related Content PubMed PubMed Citation Articles by Ferolla, P. Articles by Brandi, M. L. Related Collections Endocrine Oncology