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Prospective Study of Thymic Carcinoids in Patients with Multiple Endocrine Neoplasia Type 1

Digestive Diseases Branch (F.G., Y-J.C., K.H., L.K.E., B.A., R.T.J.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Thoracic Oncology Section (D.S.S.), Surgery Branch, National Cancer Institute, NIH; Molecular Pathogenesis Unit, Surgical Neurology Branch (A.V., Z.Z., I.A.L.) National Institute of Neurological Disorders and Strokes, NIH; Nuclear Medicine Department (J.C.R.) and Diagnostic Radiology Department (A.L.), Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Robert T. Jensen, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Digestive Diseases Branch, Building 10, Room 9C-103, 10 Center Drive, MSC 1804, Bethesda, Maryland 20892-1804. E-mail: robertj{at}bdg10.niddk.nih.gov.

	Abstract

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Little is known of the natural history of thymic carcinoids in multiple endocrine neoplasia type 1 (MEN1). This is important because in 1993 they were identified as a frequent cause of death, yet only small retrospective studies and case reports exist. We report results of a prospective study of 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed over a mean of 8 yr with serial chest computed tomography, magnetic resonance imaging (MRI), chest x-ray, and, since 1994, octreoscans [somatostatin receptor scintigraphy (SRS)]. Seven patients (8%) developed thymic carcinoids. Patients with and without carcinoids did not differ in clinical, laboratory, or MEN1 tumor features, except for male gender and the presence of a gastric carcinoid. All thymic tumors were hormonally inactive. Four thymic carcinoids lacked 11q loss of heterozygosity, although it was found in three pancreatic endocrine tumors. Computed tomography and/or MRI were more sensitive than SRS or chest x-ray in detecting tumors initially or with recurrence. All patients underwent resection of the thymic carcinoid, and in all patients followed more than 1 yr, the tumor recurred. Bone metastases developed in two patients and were detected early only on MRI, not SRS. This study provides information on early thymic carcinoids and allows modifications of existing guidelines to be recommended for their diagnosis, surveillance, and treatment.

	Introduction

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MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN1) is classically associated with parathyroid hyperplasia (resulting in hyperparathyroidism), pancreatic endocrine tumors (PETs; nonfunctional > gastrinomas > insulinomas), pituitary adenomas, and adrenal adenomas (1, 2). Recent studies show that skin tumors (collagenomas, angiofibromas) and foregut carcinoids (thymic, gastric, and bronchial) are also found with increased frequency in these patients (1, 3, 4, 5, 6, 7, 8, 9, 10). Although the natural history of the classical tumors (parathyroid, PETs, pituitary, adrenal) has been extensively studied, almost nothing is known about the natural history of the foregut carcinoids, particularly thymic carcinoids. This has occurred because thymic carcinoids were not recognized as part of MEN1 until 1972 (4) or as a major cause of death until the 1990s (3, 8). At present, only two retrospective studies of 10 patients (5, 10) with thymic carcinoids with MEN1 have been reported, and there are isolated case reports, abstracts, and small series (less than five cases) primarily from retrospective reviews. The result is that almost nothing is known of the early course of thymic carcinoids, results of early diagnosis, surveillance, or treatment. All recommendations in these areas are based on the above-mentioned retrospective data. The understanding of these aspects is becoming increasingly important in the long-term management of patients with MEN1. This is occurring because, with the increased effectiveness of treatment of hyperparathyroidism and hormone excess states due to PETs (1, 2, 7), some recent studies (3, 8, 10) suggest that the development of thymic carcinoids and other foregut carcinoids is likely to become a major determinant of long-term survival in these patients.

To address these issues, in the present study we report results of the first prospective study of patients with thymic carcinoids in MEN1. As part of an ongoing prospective study of patients with MEN1 with possible PETs, 85 patients were prospectively assessed with serial chest imaging studies [computed tomography (CT), magnetic resonance imaging (MRI), chest x-ray] and since 1994 with somatostatin receptor scintigraphy (SRS, octreoscan). The identification of seven patients (8%) with thymic carcinoids allowed their clinical presentation, surveillance, treatment, and molecular alterations to be studied and provided a basis for proposing revised guidelines for diagnosis and management of thymic carcinoids in patients with MEN1.

	Materials and Methods

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A total of 128 consecutive patients with MEN1, with or without Zollinger-Ellison syndrome (ZES), and 57 consecutive patients with sporadic ZES evaluated between July 1975 and October 2001 at the National Institutes of Health (NIH) were considered for this study. Patients with MEN1 were eligible for the present study if they had regular follow-up chest imaging evaluations with CT or MRI and, since 1994, SRS.

This study is part of the ongoing prospective study of patients with ZES with or without MEN1 at the NIH since 1975, as approved by the Clinical Research Committee of the National Institute of Diabetes and Digestive and Kidney Diseases. All patients gave informed consent for this study.

Diagnostic criteria for the presence of MEN1 syndrome included a combination of a PET with hyperparathyroidism, pituitary disease, genetic testing, or any of the above, and a family history compatible with MEN1 syndrome as described previously (11, 12). The presence of a PET was determined by surgery (n = 42) or by biochemical and imaging studies (n = 27). If patients were suspected to have ZES, the diagnosis was established as described previously (13) and included the combination of an elevated fasting serum gastrin concentration with the presence of gastric acid hypersecretion [i.e. basal acid output (BAO) >15 mEq/h in patients without previous gastric acid reducing surgery or >5 mEq/h in patients with previous gastric acid reducing surgery] or a positive secretin provocative test (an increase in serum gastrin 200 pg/ml following secretin stimulation; Refs. 13 and 14). Serum gastrin levels were drawn during fasting and were determined by Bioscience Laboratories (New York, NY) and Mayo Clinical Laboratories (Rochester, MN).

Study protocol

During the initial evaluation at the NIH, all patients underwent a comprehensive interview and physical examination, with particular attention to the history and presence of symptoms compatible with MEN1 as described previously (11, 12). This review included questions about symptoms compatible with gastric acid hypersecretion (diarrhea, abdominal pain, or esophageal reflux disease responding to gastric antisecretory treatment) and personal or family history of nephrolithiasis or other symptoms compatible with the presence of the MEN1 (11, 12). The onset of MEN1 was determined as the time of onset of symptoms compatible with MEN1, including nephrolithiasis, pituitary disease, symptomatic PET, or the detection of a PET or abnormal plasma values of hormones or serum calcium in an asymptomatic patient with a family history of MEN1 (11, 12). The onset of the ZES was determined as the time of onset of continuous symptoms compatible with gastric acid hypersecretion as described previously (13). The duration of ZES was calculated from the time of disease onset until the death of the patient or October 15, 2001.

During the initial evaluation at the NIH, all patients underwent studies to determine the presence of MEN1, including urinary cortisol, plasma PTH (intact and midmolecule), ionized calcium, total calcium, serum albumin, prolactin, insulin, ACTH, proinsulin, GH, glucagon, gastrin, as well as an MRI or CT of the pituitary and adrenal glands. Since 1998, tests for urinary 5-hydroxyindolacetic acid (5-HIAA) and N-methylhistamine, as well as plasma serotonin, pancreatic polypeptide, and histamine and a chest CT were also performed. To establish the diagnosis of ZES, patients underwent a gastric acid analysis (BAO and maximal acid output; Ref. 15), fasting serum gastrin measurements, and a secretin provocative test. The secretin provocative study was performed with a bolus injection of 2 clinical units/kg body weight of secretin (16).

To define the extent and localization of PETs, abdominal imaging studies were performed as described previously (17, 18), and they included bone scanning (19), abdominal ultrasonography, CT with or without iv and oral contrast, MRI, and selective abdominal angiography if results on the above studies were unclear. Since June 1994, SRS was performed after iv injection of 6 mCi of [¹¹¹In-DTPA-DPhe¹]octreotide with whole-body views and single photon emission CT (SPECT) imaging of chest and abdomen obtained as described previously (17, 18).

CT of the chest, chest x-ray, SRS, and since 2000, MRI of the chest were performed to assess for a possible thymic carcinoid. If a patient had an abnormality on chest CT scan, MRI, or SRS that was unclear, the patient was reassessed in 3–6 months with repeat chest imaging studies as well as bone scan and MRI of the spine. If a patient was found to have an unequivocal mediastinal lesion on any imaging study, thoracotomy was performed after a careful evaluation of the patient’s clinical status. If at surgical exploration a thymic carcinoid was found, postoperative treatment with radiation therapy was recommended in all patients; and if the disease was extensive, chemotherapy (etoposide with cisplatin or paraplatin) was recommended. Postoperatively, patients were evaluated for recurrence every 6 months with chest CT, chest MRI, SRS, spine MRI, and bone scan, in addition to routine protocol studies.

If a patient was suspected to have metastases to the liver on imaging studies, the diagnosis of metastatic PET to the liver was confirmed by either CT- or ultrasound-guided percutaneous liver biopsy or by a laparotomy whenever possible (n = 10). If there was evidence of an extrahepatic PET of 2.5 cm or larger and there was no evidence of diffuse metastatic liver disease, patients underwent exploratory laparotomy (n = 42) as described previously (18, 20). Postoperatively, patients were evaluated at 3–6 months and then yearly as described previously (18, 20). Possible PET recurrence and/or growth were reassessed yearly, as described above. Patients with liver metastases were evaluated every 3–6 months as described previously (18, 21).

In patients with progressive liver metastases, antitumor treatment was initiated with chemotherapy (22) or hormonal treatment, with either interferon (23) or octreotide (21), and then followed up every 3–6 months to assess the treatment response. MRI of the spine and bone scan were performed to assess for the presence of bone metastases (19) in all patients with liver metastases and since 1995 at least once in patients with evidence of PET or in any patient with a thymic carcinoid. In any patients with positive imaging for possible bone metastases (n = 3), further investigation was performed to determine the possible primary source. If the diagnosis still remained unclear, bone biopsies were performed (n = 1).

DNA extraction

Tumor tissue from the thymic carcinoid tumors of four patients with MEN1 (Tables 1 and 2, patients 3–6) was obtained by microdissection from fresh frozen or paraffin-embedded fixed 5-µm sections. PET tissue was also microdissected from three of the four patients (Tables 1 and 2, patients 3–5). More than 95% of the microdissected tissue was tumor. Tumor genomic DNA was obtained by 3-d digestion of tumor tissue in 30 µl TE solution (pH 8.0; 10 mM Tris, 1 mM EDTA, 0.5 mg/ml proteinase K, 0.5% Tween 20) at 37 C. Normal control genomic DNA was isolated from peripheral blood leukocytes of each patient by using the PUREGENE DNA isolation kit (Gentra System, Minneapolis, MN). DNA was stored at 4 C until PCR amplification.

Six MEN1 microsatellite gene markers (D11S 4191, D11S 480, PYGM, D11S 4946, D11S 449, and INT-2) spanning the MEN1 locus were obtained from Research Genetics, Inc. (Huntsville, AL) on the basis of published papers (24, 25). The template DNA of both tumor and leukocytes was amplified by PCR using GeneAmp PCR system 9700 Thermo-cycler (PE Applied Biosystems, Foster City, CA) with the following conditions: 94 C for 5 min, 94 C for 45 sec, annealing at 59 C for 45 sec, and extension at 72 C for 45 sec for a total 30 cycles or 35 cycles. Each reaction contained 1.5 µl of 10x PCR buffer, 1.5 µl of tumor DNA or normal control DNA (about 10–20 ng), 10 pmol of each primer, 2.5 U of gold Taq polymerase (PE Applied Biosystems), and 130 µM each of deoxynucleoside triphosphate. The final concentration of Mg²⁺ was 1.5 mM. -P³²-dCTP (0.1 µl/reaction; >3000 Ci/mmol) was also included in each PCR. After PCR, products were mixed with loading dye (1:1 vol/vol), denatured at 95 C for 10 min, then chilled immediately at 4 C. Four or 5 µl of products were analyzed by electrophoresis through a 6% or 8% denaturing polyacrylamide gel in 1x Tris-borate EDTA buffer. The gels were then dried and exposed to x-ray films (Kodak X-Omat AR, Eastman Kodak Co., Rochester, NY) with or without an intensive screen for 8 h to 3 d. The intensity of signals in the films was analyzed and quantified by using Kodak Image station 440 system (Eastman Kodak Co.). Loss of heterozygosity (LOH) was defined as a reduction of at least 50% observed in the allelic ratio between the tumor and normal DNA from the same patient (24).

Statistics

Descriptive statistics were used for basic demographic features. All data are reported as means ± SEM. Means were compared by the Mann-Whitney U test. Proportions were compared by Fisher’s exact test. Differences with P values less than 0.05 were considered significant. The unpaired Student’s t test was used for comparisons with the data from the literature. Analyses were performed using the StatView statistical package (SAS Institute, Inc., Cary, NC).

	Results

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A total of 128 consecutive patients with MEN1 were considered for this study. Forty-three of these patients were not eligible because they were assessed at the NIH when chest CT scans or MRI were not routinely performed on each admission; thus, they lacked serial chest CT scans or MRI and did not meet this study entrance requirement. In the 85 consecutive patients with MEN1 included in this study, serial chest CT scans were performed in 99% of patients, SRS in 98%, and chest MRI in 80%. Chest CT scans and SRS studies were performed in all 57 patients with sporadic ZES and all were included. An anterior mediastinal mass consistent with a thymic carcinoid was identified in 7 of 85 (8%) patients with MEN1 and in none of the 57 (0%) patients with a sporadic ZES, a difference that was significant (P < 0.026). A thymic carcinoid was found at surgery in each of the seven cases. The clinical and laboratory characteristics of the seven patients with MEN1 and thymic carcinoid are shown in Table 3. The mean age at study was 55 yr, all patients were men, and ZES was present in six of seven (86%) patients. In no case was the thymic carcinoid the initial manifestation of the MEN1. The mean duration from MEN1 onset to the discovery of the thymic carcinoid was 19 yr, and the mean follow-up duration from carcinoid resection to death or October 15, 2001, was 5 yr (range, 0.13–15.26 yr; Table 3). Symptoms such as cough or vague chest pain were present in only two patients at the initial presentation of the thymic carcinoid and in one patient at the time of diagnosis of a recurrence (Tables 1 and 3). None of the patients had evidence of Cushing’s or carcinoid syndrome due to the thymic carcinoid (Tables 1 and 3). However, the serum chromogranin A level was increased in six of the seven patients with a median increase of 9-fold (Table 3). During the evaluation at the time the thymic carcinoid was discovered, preoperative imaging studies including chest x-ray, CT, and MRI were performed in six patients and SRS in four patients. Thymic carcinoid was detected in 100% (6 of 6) on CT scan and MRI, in 75% (3 of 4) on SRS, and in 66% (4 of 6) on chest x-ray (Tables 1 and 3).

View larger version (55K): [in this window] [in a new window]   Figure 1. SRS and CT scan findings in a patient (patient 2; Table 1) with MEN1 and ZES before and after initial resection of a thymic carcinoid tumor. Left panels, top and middle, SRS results at two time periods 4 months apart before the initial resection of a thymic carcinoid (Thymic Tumor). The prominent focus in the chest detected on SRS whole body image on 9/18/96 (middle) was seen faintly 4 months earlier (top). The dotted arrow shows a PET localized by the SRS. Resection of an 11-cm thymic carcinoid was performed on 10/15/96, and the left bottom panel shows the lack of uptake of isotope in the chest post resection. Right panels, CT images. A preoperative CT on 9/16/96 (middle) showed a 7.5-cm anterior mediastinal mass (Thymic Tumor). The postoperative CT (bottom) shows a complete resection of the chest mass. This patient (NIH no. 1205559) also has hyperparathyroidism, a pituitary adenoma, and a gastric carcinoid tumor.

View larger version (43K): [in this window] [in a new window]   Figure 2. CT and SRS results in a patient (patient 2; Table 1) with MEN1 and ZES with recurrence 29 months after the initial thymic carcinoid resection. A 3-cm anterior mediastinal mass (Thymic Tumor) was detected on a chest CT (middle), whereas the SRS (coronal view, top) failed to detect it but showed a pituitary adenoma. The patient was asymptomatic. At reoperation, a 3-cm thymic carcinoid tumor as well as two regional lymph nodes were resected, and the patient was treated with intraoperative radiation to two adjacent regions with a dose of 1500 rads to each site as well as with postoperative external beam radiation of 4500 rads total. A postoperative chest CT scan was negative (bottom). This patient’s initial presentation is shown in Fig. 1.

View larger version (82K): [in this window] [in a new window]   Figure 3. Imaging results in a patient (patient 5; Table 1) with MEN1 and ZES demonstrating development and growth of a thymic carcinoid tumor. Left, Serial preoperative chest CT scans. The CT on 6/28/00 (middle) showed a small anterior mediastinal soft tissue mass (Thymic Tumor), whereas the CT scan on 1/19/95 (top) was negative. This lesion grew rapidly, more than doubling in size in 6 months by 12/13/00 (bottom). At this time, the patient had a PET detected but not an anterior mediastinal lesion on the SRS done on 12/12/00 on the whole body image (right, top). The thymic carcinoid was faintly seen on a sagittal SPECT image (right, bottom). The patient was asymptomatic. This patient (NIH no. 2448786) also had hyperparathyroidism.

View larger version (105K): [in this window] [in a new window]   Figure 4. Serial bone imaging studies in a patient (patient 5; Table 1) with MEN1 and ZES showing development of bone metastases from a thymic carcinoid. Top, Left and middle panels show results of two MRIs of the lumbar spine (3 yr apart). On 12/12/00, L4 and S1 bone metastases were detected. Top right panel, At the same time, an MRI of the thoracic spine showed T2 and T5 metastases. At this time (12/00), the bone scan (bottom, middle panel) and the SRS SPECT image (bottom, right panel) showed only a thoracic spine metastasis. Three years before these evaluations on 12/21/97, both the MRI of the spine (top, left panel) and bone scan (bottom, left panel) were negative. On 12/14/00, a CT-guided biopsy of the L4 lesion was consistent with metastatic thymic carcinoid. The patient (NIH no. 2448786) was asymptomatic with metastatic bone disease from the thymic carcinoid. This patient’s thymic carcinoid development is shown in Fig. 3.

To determine whether thymic carcinoid tumors in MEN1 patients demonstrate 11q13 LOH as seen in a number of other MEN1-related tumors (PET, parathyroid, pituitary, gastric carcinoids, etc.; Ref. 1), LOH studies at this locus were performed in four patients. LOH at 11q13 was examined in four thymic carcinoids from four different patients and three PETs from three of the four patients with thymic carcinoid by using six polymorphic markers spaced throughout MEN1 gene (11q13; Fig. 5 and Table 2). MEN1 LOH was found in two of the three PETs, whereas in the four thymic carcinoid tumors, no LOH was identified (Table 2). Representative results of the assessment for LOH at 11q13 in both thymic carcinoid and PETs from two patients at three different loci of 11q13 are shown in Fig. 5. In patient 3, 11q13 LOH was seen in the PET at five loci that were tested (Fig. 5, left, and Table 2), whereas in patient 4 it was shown only in the PET at two loci (Fig. 5 and Table 2).

View larger version (75K): [in this window] [in a new window]   Figure 5. Results of study of 11q13 LOH in tumors from two patients. The presence or absence of LOH was assessed at five different loci, and results at three loci on 11q13 are shown. Shown are results from normal tissue (N; i.e. leukocytes), thymic carcinoid (Th), and PET tissue (Pan). The patient numbers are the same as those in Table 1. The thin arrows show the retained allele, and thick arrows show LOH. Neither patient 3 nor patient 4 had LOH at 11q13 in the thymic carcinoid at any of the three loci. Left, Patient 3 had LOH at 11q13 in the PET at loci D11S480, PYGM, and D11S449. Right, Patient 4 had 11q13 LOH in the PET at loci PYGM and D11S449 but retained alleles at D11S480.

	Discussion

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Thymic carcinoids are reported in various retrospective studies to occur in less than 3% (69), 3% (49), 4.2% (59), and 4.9% (10) of patients with MEN1. In our study, 7 of 85 (8%) of the patients with MEN1 developed a histologically proven thymic carcinoid during the study period, which averaged 8 yr (range, 0.1–29.3 yr). A number of factors likely account for the higher frequency of thymic carcinoids in this study than reported in the above retrospective studies. These include the fact that our patients underwent regular imaging of the chest with CT and other modalities (including SRS since 1994) and that the majority had long-standing MEN1 disease, with an average age of 41 yr at their initial evaluation at the NIH, 71% had ZES, and 81% had a PET. Also, because most of our patients had PETs, if there is an unknown association between PETs and the development of thymic carcinoids, a higher frequency of thymic carcinoids could exist in our population than in patients with long-standing MEN1 without PETs. However, our data do not support the latter point because we found an equal frequency of PETs in patients with or without thymic carcinoids.

In our study, all seven of the patients with thymic carcinoids were male, which is similar to the 100% reported in two retrospective reviews of 10 cases (5, 10) and similar to the 89% reported in 89 MEN1 patients with thymic carcinoids from various case reports, small series, and abstracts referenced above. The gender effect is not specific for thymic carcinoids in patients with MEN1 because 73% of sporadic thymic carcinoids occur in males (78). This gender effect is unusual in MEN1-associated tumors, with hyperparathyroidism occurring with equal frequency in both sexes (2), as do PETs (2), whereas pituitary adenomas and bronchial carcinoids are more frequent in females (2). In our study, in 71% of the patients the thymic carcinoid was asymptomatic at the time of diagnosis, which is much higher than the 30–37% of patients reported in the two respective series of 10 cases (5, 10) and in the 89 patients in various case reports, small series, and abstracts referenced above. It is also much higher than the 37% reported in patients with sporadic thymic carcinoids (78). These results are consistent with the prospective nature of the present study, which allowed the thymic carcinoids to be detected while generally asymptomatic. These results suggest that we were detecting these tumors generally earlier than those previously reported, and therefore our study allows insights into the clinical features of these tumors in their presymptomatic period before they become advanced. This conclusion is supported by the finding that the mean size of the thymic carcinoid in our study was 6.8 ± 1.8 cm, which was significantly (P < 0.05) smaller than the 10.7 ± 0.7 cm reported in one retrospective study of 10 cases (10) and the 9.7 ± 0.7 cm reported in 39 patients in case reports, small series, and abstracts. It is also smaller than the 9.2 cm mean size reported in patients with sporadic thymic carcinoids (78). The earlier diagnosis in the present study is also supported by the finding that only 14% of patients (1 of 7) in the present study had nonresectable thymic carcinoids and/or distant metastases at the diagnosis of the thymic carcinoid compared with 100% in one retrospective study of 10 cases of MEN1 patients with thymic carcinoids (10), 61% in a literature review of 23 cases (6), and 47% in the 8 patients in case reports, small series, and abstracts referenced above.

Our results provide insights into the temporal pattern of development of thymic carcinoids in relation to the other manifestations of MEN1 and support the conclusion that they are generally a late manifestation of the disease. In no patients was the thymic carcinoid the initial manifestation of the MEN1. All patients had hyperparathyroidism at the time of the diagnosis of the thymic carcinoid, and the average duration from the initial manifestation of MEN1 to the diagnosis of thymic carcinoid was 19 yr, with a range of 6.5–29 yr. The mean age of onset of any manifestation of MEN1 was 30.6 yr; age of diagnosis of hyperparathyroidism, 33.6 yr; ZES, if present, 34.5 yr; any PET, 37.3 yr; pituitary disease, 51.1 yr; and thymic carcinoid, 49.8 yr. This temporal pattern is consistent with previous retrospective studies and case reports that report a mean age of 33.6 yr for diagnosis of MEN1 in 46 patients with thymic carcinoids and MEN1, and an age of 42.5–46.7 yr at the time of diagnosis of the thymic carcinoid (5, 6, 10, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 43, 45, 47, 50, 55, 57, 59, 60, 61, 62, 63, 66, 68, 69, 71, 73, 76). The late onset of thymic carcinoid is consistent with the results of two retrospective studies of 10 patients with thymic carcinoids with MEN1 in which 100% of the patients had hyperparathyroidism (5, 10) and with 89 patients in case reports, short series, and abstracts in which 95% of the patients with thymic carcinoids with MEN1 had hyperparathyroidism. Similarly, in these studies (5, 10) 50–57% of the patients had PETs, and 10–32% had pituitary disease at the time of diagnosis of the thymic carcinoid.

Although thymic carcinoids in patients without MEN1 can be hormonally active and cause Cushing’s syndrome in up to 40% of cases (5, 53, 78, 79) and some patients with MEN1 have been reported in which the thymic carcinoid ectopically releases a hormone causing a clinical syndrome (i.e. acromegaly; Ref. 76), in none of the patients in our study was the thymic carcinoid causing a hormone excess state. This result is consistent with previous case reports and retrospective reviews of cases of thymic carcinoids in MEN1 in the literature (5, 10). The fact that these tumors are hormonally inactive likely contributes to their insidious development, that in most retrospective series these tumors were only detected late in their clinical course, and that they are becoming an increasing cause of death in MEN1 patients (3, 5, 6, 10, 46).

The best imaging study to perform to detect early small thymic carcinoid tumors in patients with MEN1 is unclear. From retrospective studies, it has been recommended that either chest CT, MRI, or possibly SRS has the greatest sensitivity for detecting small tumors (5, 10, 37, 80). Normal thymus possesses somatostatin receptor subtype sst₂, which binds radiolabeled octreotide analogs with high affinity (81, 82, 83). Furthermore, most carcinoid tumors overexpress somatostatin receptors, and SRS has been a sensitive modality to detect other small carcinoid tumors (84, 85). A number of recent studies have reported that SRS can detect thymic carcinoids in patients with and without MEN1 (5, 37, 39, 69, 79, 86, 87, 88). In our study, CT and MRI were equally sensitive in detecting the thymic carcinoid initially or during recurrence in all cases, whereas both plain chest x-ray and SRS did not detect a thymic carcinoid initially or its recurrence in some cases. These results showing the lower sensitivity of chest x-ray compared with CT scan are consistent with findings in retrospective studies (5, 10). Before the present study, only one study in abstract form (73) has reported a patient with a thymic carcinoid with MEN1 with a negative SRS, whereas the other 19 such patients who were examined all had positive SRS results (5, 37, 38, 39, 55, 59, 69, 71, 73, 76), suggesting that SRS might be a sensitive modality for detecting these tumors in these patients. However, our result demonstrates that SRS is less sensitive than CT scan for both the initial detection and for detecting recurrences of thymic carcinoids in these patients and, therefore, should not be performed routinely. Furthermore, SRS is now widely used to detect distant metastases from gastrointestinal neuroendocrine tumors (carcinoids and PETs) because of its high sensitivity and because it allows easy total body imaging (19, 83, 89). However, in our study in patients with bone metastases due to thymic carcinoids, the SRS did not identify these early in their course.

Identification of factors that could predict which patients with MEN1 are at increased risk of developing thymic carcinoids would be of great clinical value in planning surveillance strategies. Unfortunately, we found that, except for male gender, no clinical, laboratory, or other feature of MEN1 in these patients distinguished patients with thymic carcinoids from those who did not develop them. In one study (46), an association between hyperparathyroidism and thymic carcinoids was reported; however, in our study there was no difference in the frequency of hyperparathyroidism in patients with or without thymic carcinoids, suggesting no specific association. We found a significant association of thymic carcinoids with the occurrence of gastric carcinoids (P = 0.03). Hypergastrinemia promotes the development of gastric carcinoids, and they almost exclusively occur in MEN1 patients who develop ZES (90). Although this suggests that the presence of hypergastrinemia due to the ZES might be important in the association of gastric carcinoids and thymic carcinoids, our analysis does not support this speculation. Specifically, there was no significant difference in the frequency of ZES in patients with or without thymic carcinoids, and a thymic carcinoid occurred in one patient without ZES. Nevertheless, if possible in the future, the effect of gastrin as a growth factor for these tumors should be investigated by in vitro studies as well as by using immunocytochemical studies. Furthermore, in 91 cases of thymic carcinoid and MEN1 with sufficient data reported in the literature to determine whether ZES was present, it occurred in only 25%. These results suggest that the presence of hypergastrinemia is not the common factor in the association of gastric and thymic carcinoids in patients with MEN1 and that this association may be due to the fact both of these tumors develop only late in the disease course. The question of hypergastrinemia or some other growth factor contributing to the development of thymic carcinoids in these patients is an important question because at present their molecular pathogenesis is completely unclear. This has occurred because, in our study as well as studies by others (5, 52, 73), no LOH at the MEN1 locus on 11q13 was found in thymic carcinoids. The possibility was raised in one study (5) that this lack of 11q13 LOH in thymic carcinoids in MEN1 could be due to contamination by normal tissue; however, in our study all tumors were microdissected, and using the same methodology, 11q13 LOH was detected in PETs from the same patient. This result supports the conclusion that thymic carcinoids have a different molecular pathogenesis than the parathyroid disease, pituitary tumors, PETs, and gastric carcinoids that develop in MEN1, which all demonstrate 11q13 LOH (1, 91, 92).

The natural history of early thymic carcinoids in MEN1 is almost completely unknown because almost all retrospective studies reported cases with advanced disease. In some reviews, thymic carcinoids in patients with MEN1 are reported to grow slowly with a protracted course (37, 46), whereas in other reviews they are reported to be a frequent cause of death (3, 8, 10), with as high as 90% of patients with thymic carcinoids dying from progression of this tumor within 4.5 yr (10). In our study, with a mean follow-up of 5.1 yr (range, 0.1–15.3 yr), there were no deaths due to the thymic carcinoid. However, two patients have developed bone metastases, and each of five patients followed for more than 1 yr post resection has recurrent or persistent disease. These data support the conclusion that thymic carcinoids almost always demonstrate aggressive growth and even with early diagnosis and early surgery, cure with resection only appears uncommon. These results showing the relatively early recurrence of thymic carcinoids post resection in these patients resemble the results in many patients with sporadic thymic carcinoids that led to the recommendation that routine peri- or postoperative radiation should be considered with these tumors (93, 94). However, although radiation has been used to treat malignant carcinoids in the literature (93, 95, 96, 97, 98), has been used as adjuvant treatment in thymic carcinoids (34, 37, 53, 66, 93, 94, 96, 97, 98), and has been used in a number of cases of malignant thymic carcinoids in patients with MEN1 in the literature (5, 6, 10, 26, 34, 36, 37, 38, 41, 43, 44, 45, 46, 47, 53, 57, 59, 62, 64, 65, 66, 72, 73, 75), it is at present unclear in what percentage of patients with malignant thymic carcinoids it will delay and/or prevent recurrence.

Numerous previous retrospective studies (5, 6, 10, 46, 80) have emphasized the possible importance of routine cervical thymectomy in MEN1 patients at the time of neck exploration for hyperparathyroidism to prevent the subsequent development of a thymic carcinoid. One of our patients developed a thymic carcinoid 19 yr after a parathyroidectomy and transcervical thymectomy. Seven other patients with MEN1, who have been reported recently, also developed a thymic carcinoid from 0.75–16 yr after a parathyroidectomy and cervical thymectomy (69, 72, 73, 75). These results demonstrate that this procedure does not prevent the development of thymic carcinoids. Nevertheless, cervical thymectomy may be significantly decreasing the rate of developing thymic carcinoids and, because it can be performed with negligible morbidity, it should continue to be routinely performed at the time of parathyroidectomy in both men and women. Although thymic carcinoids occur overwhelmingly in males with MEN1, 8% of cases in the literature (n = 103 cases) occur in females; therefore, cervical thymectomy should be performed in both genders at the time of parathyroidectomy.

The present study provides some important insights into the diagnosis, localization, natural history, and treatment of thymic carcinoids in patients with MEN1 that can affect management strategies. These are summarized in Table 7. First, for prevention, cervical thymectomy should be performed in all patients at the time of parathyroid surgery. However, because this does not prevent completely the development of thymic carcinoids and at present it cannot be predicted who will subsequently develop thymic carcinoids, all patients subsequently should continue to undergo regular surveillance for thymic carcinoids. The recommendation for routine cervical thymectomy is made with the realization that its value as a preventive measure for development of these tumors is unproven. However, because it has a low morbidity and potential value and because of the aggressive nature of these tumors and lack of predictive factors, we favor its continued routine use. Second, genetic testing should be performed in family members of a MEN1 patient to determine who should undergo regular surveillance for thymic carcinoids as well as other disease manifestations. Third, CT scan alone is sufficient to screen for thymic carcinoids. In contrast to most other carcinoid tumors (83, 84, 85), SRS does not have greater sensitivity for the detection of thymic carcinoids than CT scan, either initially or with recurrence. Therefore, our results do not support the suggestion by others that SRS is generally useful (37) and thus, should be routinely used. Furthermore, in two patients with bone metastases the SRS was negative when they first developed, whereas the MRI of the spine was positive; therefore, SRS is also not more sensitive for identifying distant metastases from thymic carcinoids in these patients as it is for other carcinoid tumors (83, 84, 85). Fourth, currently it is recommended that MEN1 patients be screened with CT scan for thymic carcinoid every 3–5 yr after 25 yr of age (9, 10, 69). Our study demonstrates that thymic carcinoids can develop rapidly. Furthermore, because of their aggressive course, the best hope is to detect them as early as possible. Therefore, we would recommend a yearly chest CT in all patients with MEN1 who are older than 25 yr of age (Table 1), particularly males. We recommend yearly screening because our results show that in some patients these tumors develop this quickly. Fifth, we recommend that patients with thymic carcinoids should have MRI of the spine initially and during follow-up to assess for bone metastases. Two (28%) of our patients with thymic carcinoids developed bone metastases, and in each case it occurred without liver metastases. This appears to be typical for this tumor because bone metastases were present in 33% of the 58 thymic carcinoids in MEN1 patients reported in the literature (6, 10, 26, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 50, 53, 55, 57, 59, 60, 61, 63, 64, 65, 66, 68, 69, 70, 72, 73, 75, 76) and liver metastases were present in only three (3%) of these patients (68, 70, 73). Because the SRS did not detect the bone metastases early in their course in our patients, MRI of the spine should be routinely used, which has been shown to be a sensitive modality to detect spinal metastases from neuroendocrine tumors (19). It is important to detect bone metastases because their presence can have a significant effect on tumor management strategies (19). Sixth, our studies show that these tumors do not demonstrate indolent growth as suggested by some previous studies (37, 46). Of all the MEN1-related tumors, as a group thymic carcinoids are the most aggressive and therefore should be vigorously sought for and treated. Because even with resection of small thymic carcinoids detected with screening, postresection recurrence has occurred in all patients followed for more than 1 yr, the question of whether postoperative radiation should be routinely used in addition should be raised. Although radiation is reported to slow the progression of some carcinoid tumors, including thymic carcinoids (93, 94, 95, 96, 97, 98), whether it will result in increased cure or delayed recurrence post resection is not established at this time. Furthermore, because of the low frequency of occurrence of this tumor, it is unlikely that this will be established in the near future. Because of the aggressive nature of these tumors in all of our patients, we would recommend routine perioperative use of radiation.

	Footnotes

 
Abbreviations: BAO, Basal acid output; CT, computed tomography; 5-HIAA, 5-hydroxyindolacetic acid; LOH, loss of heterozygosity; MEN1, multiple endocrine neoplasia type 1; MRI, magnetic resonance imaging; PET, pancreatic endocrine tumor; SPECT, single photon emission CT; SRS, somatostatin receptor scintigraphy; ZES, Zollinger-Ellison syndrome.

Received August 16, 2002.

Accepted December 4, 2002.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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