0021-972X/05/$15.

00/0 The Journal of Clinical Endocrinology & Metabolism 90(5):2603–2609

Printed in U.S.A. Copyright © 2005 by The Endocrine Society
doi: 10.1210/jc.2004-1155

Thymic Neuroendocrine Carcinoma (Carcinoid) in

Multiple Endocrine Neoplasia Type 1 Syndrome: The
Italian Series
P. Ferolla, A. Falchetti, P. Filosso, P. Tomassetti, G. Tamburrano, N. Avenia, G. Daddi, F. Puma,
R. Ribacchi, F. Santeusanio, G. Angeletti, and M. L. Brandi
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

Neuroendocrine tumors may occur in the setting of multiple one patient, prophylactic thymectomy revealed a small nod-
endocrine neoplasia type 1 (MEN1) syndrome. Among these, a ular lesion suggestive of a thymic carcinoid, providing evi-
probably underestimated prevalence of well differentiated dence that preventive thymectomy might prevent additional
neuroendocrine thymic carcinoma (carcinoid), a neoplasm growth of an occult thymic carcinoid. These findings confirm
characterized by very aggressive behavior, has been de- that thymic carcinoids are associated with a very high lethal-
scribed. We report characterization of the seven Italian cases ity, with a near-total prevalence in smoker males. Therefore,
in which this association occurred among a series of 221 MEN1 prophylactic thymectomy should be considered at neck sur-
patients (41 sporadic and 180 familial cases; prevalence, 3.1%). gery for primary hyperparathyroidism in MEN1 male pa-
All of the patients were male, and six of seven (85%) were tients, especially for smokers, and, due to the frequent familial
heavy smokers. No associated hormonal hypersecretion was clusters distribution of this pathology, in subjects with af-
detected. The first diagnosis was between the second and fifth fected relatives presenting this feature. Thus, we recommend
decades. Familial clusters were present in three of seven screening every patient affected with a neuroendocrine thy-
(42.8%). No genotype-phenotype correlation was found. All mic neoplasm for MEN1 syndrome. (J Clin Endocrinol Metab
seven cases were associated with hyperparathyroidism. In 90: 2603–2609, 2005)

T HYMIC LOCATION IS one of the rarest sites of neu-

roendocrine tumors (carcinoid) reported in the litera-
ture. Since 1972, when eight cases of this neoplasm were first
has been recently published (3). Some relevant differences
between the two series are analyzed and discussed (3).

described as a different entity from thymomas (1), about 150

Patients and Methods
cases have been reported. Moreover, an association with
multiple endocrine neoplasia type 1 (MEN1) was described Patients
(2). Nevertheless, thymic location of carcinoid tumors in The patients were followed during the period between 1990 and 2003
MEN1 patients is still considered an extremely rare finding, at the Departments of Internal Medicine and Endocrine Sciences of
University of Perugia, the Department of Internal Medicine and Gas-
described in fewer than 30 cases. Despite the recognized troenterology of University of Bologna, the Department of Thoracic
associated lethality in MEN1 patients, the real incidence, Surgery of University of Torino, and the Endocrine Section of University
appropriateness of diagnostic procedures, prophylactic and of Rome La Sapienza.
therapeutic management, and timing of follow-up remain to In agreement with the international guidelines for diagnosis and
therapy of MEN1 patients (4), the diagnosis of MEN1 was based on the
be established. To address these issues, we have analyzed the coexistence of at least two of the three main MEN1-related endocrine
seven Italian cases in which this association occurred. These tumors (parathyroid adenomas, enteropancreatic endocrine tumors, and
are the only Italian cases in which this association has been pituitary tumor) in each case. Furthermore, a diagnosis of familial MEN1
demonstrated, according to the Italian Register for Multiple (at least one MEN1 case plus at least one first-degree relative with one
Endocrine Neoplasia in 221 MEN1 patients (41 sporadic and of three of the main MEN1-related endocrine tumors) was formulated
for all patients except case 5.
180 familial cases). A recent prospective study of eight cases 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
First Published Online February 15, 2005 test is defined as ongoing in these patients.
Abbreviations: CGA, Chromogranin A; CT, computed tomography; Thymectomy was performed in all patients through median sternot-
DTPA, diaminetriaminepentacetate; FDG, 18-fluorodeoxyglucose; omy due to the dimension of neoplasm in six patients (cases 1, 2, and
MEN1, multiple endocrine neoplasia type 1; MRI, magnetic resonance 4 –7) and to the coexistence of two mediastinal parathyroids in the
imaging; NSE, neuronal-specific enolase. prophylactic procedure (case 3).
JCEM is published monthly by The Endocrine Society (http://www. The diagnosis of neuroendocrine thymic carcinoma was formulated
endo-society.org), the foremost professional society serving the en- on the basis of morphology and immunohistochemical reactivity for the
docrine community. pan-neuroendocrine markers chromogranin A (CGA), synaptophysin

2603

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2604 J Clin Endocrinol Metab, May 2005, 90(5):2603–2609 Ferolla et al. • Thymic Carcinoid in MEN1

and neuronal-specific enolase (NSE) according to the World Health

Dead, Met
Dead, Met

Dead, Met
Outcome
Organization (WHO) classification criteria (5).

Cured
Circulating CGA was measured by RIA and ELISA (CIS Biointerna-

Alive

Alive
Met
tional, Gif-sur-Yvette, France; and DakoCytomation, Glostrup, Den-
mark). NSE was measured by RIA (CIS Biointernational). Urinary
Follow-up 5-HIAA was determined using HPLC.
(months) Ectopic Cushing’s syndrome was excluded using 24-h urinary free

120
60
36
72

96
28

26
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 per-
Familial

formed, and the results of these tests were negative.

cluster
Yes
Yes
Yes

Yes
No

No

No
MEN1 gene mutational analysis
(⬎30/d)
(⬎30/d)
(⬎20/d)

(⬎20/d)
Mutational analysis of the MEN1 gene was performed and confirmed
Cigarette
smoking

in two independent laboratories (Florence and Perugia). DNA was ex-

tracted from peripheral blood leukocytes using a microvolume extrac-
tion method, NucleoSpin Blood Quick Pure (Macherey-Nagel, Easton,
Yes
Yes
Yes
Yes
Yes
Yes

No

PA) according to the manufacturer’s instructions. Encoding regions

GC, Gastric carcinoid; Met, metastases; PA, pituitary adenoma; PET, pancreatic endocrine tumor; PH, parathyroid hyperplasia.

(exons 2–10) and exon-intron junctions were amplified by PCR, with

Cushing
Ectopic

specific couples of primers located in the flanking intronic regions, in a

No
No
No
No
No
No

No

50-␮l volume containing 50 –100 ng DNA, 1⫻ 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 ␮m of each primer, and 1 U Polytaq (Polymed,
Intensely positive
Intensely positive

Intensely positive

Florence, Italy). PCR amplification of exons 2, 9, and 10 required 10%

Not performed
Not performed

Not performed

dimethylsulfoxide. After denaturation at 94 C for 3 min, the samples

Octreoscan

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
Positive

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
Negative
Negative
Negative
Negative
Negative
Negative

Negative

sequenced, with both forward and reverse primers, using the BigDye
5HIIA
study

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, Sequenc-
Splicing 893⫹I(G⬎C) exon 4-intron 4

ing Reaction Cleanup Kit (Millipore Corp., Bedford, MA) and analyzed
on the ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). The
Frameshift 66,67ins5bp exon 2
Frameshift 66,67ins5bp exon 2

sequences obtained were compared with wild-type reference sequence

MEN1 gene mutations

of the MEN1 gene (U93237) (6).

Missense Thr /Arg exon 7

Results
Table 1 summarizes the main features of the Italian pa-
344

tients with MEN1 and thymic carcinoid. All of the patients

were men, with a mean age at presentation of 38.7 ⫾ 9.9 yr
Not possible

(age range, 29 –52 yr); aside from case 7, they were heavy
Ongoing

Ongoing

smokers (⬎20 cigarettes/day). All of the patients had hy-

perparathyroidism, and four also exhibited pituitary ade-
noma and pancreatic tumor. All patients, except case 6, were
asymptomatic at presentation, and thymus involvement was
PA, PET

PA, PET
PA, PET
PA, PET
Other MEN1

diagnosed incidentally or in the context of a periodical fol-

features

GC

low-up in recognized MEN1 patients. The patients, aside

from case 6, remained asymptomatic until a later stage of the
PH,

PH,
PH,
PH,
PH,
PH

PH

disease. In cases 2 and 4, thymic carcinoid was the first

clinical manifestation of MEN1, but asymptomatic hyper-
Chest pain,
Presenting

dyspnea
symptoms

parathyroidism was already present. In all patients, except

case 3, the diagnosis was suspected on the basis of enlarge-
None
None
None
None
None

None
TABLE 1. Main features

ment 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]
Age (yr)/sex
(diagnosis)
39/M
47/M
41/M
23/M
29/M
40/M

52/M

diaminetriaminepentacetate (DTPA)-d-Phe-octreotide (Oc-

treoscan, Tyco-Mallinckrodt, St. Louis, MO), calculated us-
ing Krenning scale, was very high in cases 1, 2, and 6 in
primitive tumor and in its metastasis and was weak, but
1
2
3
4
5
6

Case 7
Case
Case
Case
Case
Case
Case

diffuse, in case 5.
No carcinoid syndrome was evidenced and urinary hy-

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Ferolla et al. • Thymic Carcinoid in MEN1 J Clin Endocrinol Metab, May 2005, 90(5):2603–2609 2605

FIG. 1. Chest CT scan at diagnosis of cases 1 and 2, showing a large mass in the anterior mediastinum (maximum diameter, 9 cm).

droxyindolacetic acid studies were negative in all cases. plete and prolonged remission of the disease has been
Among serum markers, only a slight increase in NSE and achieved in patients 4 – 6. Patient 3 appears to be definitively
CGA circulating levels was detectable. cured.
Full follow-up of all patients was carried out. Three pa- The results of the mutational analysis for the MEN1 gene
tients (cases 1, 2, and 7) died with diffuse metastasis 60, 36, are listed in Table 1.
and 26 months, respectively after surgery. One patient (case
5) is alive with stable disease and loco-regional metastasis 96 Discussion
months after surgery. Two patients (cases 4 and 6) showed The Italian series presented here confirms that thymic
no evidence of the disease 28 and 120 months after surgery. neuroendocrine carcinoma (carcinoid) in MEN1 patients is
Case 3, who underwent prophylactic thymectomy, is disease most commonly diagnosed as an anterior mediastinal mass
free 84 months after surgery. Familial clusters were present usually revealed by chest x-ray or CT scan, by accident, or in
in cases 1, 2, 4, and 5. The brother of case 1 is affected with the context of a periodical clinical follow-up. The most re-
a metastatic bronchial carcinoid. liable imaging technique is still a matter of debate. Routine
Metastatic diffusion of the primary thymic neoplasm was chest x-ray may not be adequate for screening and follow-up
present in cases 1, 2, 5, and 7. According to WHO and of thymic carcinoid in MEN1 patients, because the profile of
Masaoka criteria at surgery, cases 1, 2, 6, and 7 can be con-
sidered 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 nod-
ules 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 diam-
eter was 8.6 ⫾ 1.3 cm.
Case 2 showed multiple osteoblastic bone metastasis (Fig. 3).
Palliative therapeutic options consisted of radiometabolic
treatment with yttrium 90-labeled octreotide for case 2, high
doses (1500 ␮g/d) of cold octreotide for cases 1 and 2, che-
motherapy with cisplatin-etoposide and long-acting 60 mg
lanreotide or 30 mg LAR octreotide in cases 5 and 6, and
surgery alone in cases 3, 4, and 7. Partial response and sta- FIG. 2. Macroscopic section of the mediastinal mass shown in Fig. 1.
bilization of the disease was achieved in cases 1 and 2. Com- The presence of multiple necrotic areas is evident (arrows).

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2606 J Clin Endocrinol Metab, May 2005, 90(5):2603–2609 Ferolla et al. • Thymic Carcinoid in MEN1

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, FIG. 4. Preoperative [111In]DTPA-D-Phe-octreotide scintigraphic
cerebral metastasis; P, pituitary uptake. scan 24 h after injection of labeled octreotide, showing intense uptake
at the mediastinal level in case 6 (arrow).

the great vessel and the heart does not allow diagnosis until have also been reported to colocalize thymic involvement
the tumor reaches a metastatic stage. In contrast, in all of our and parathyroid hyperplasia in MEN1 patients (12)
patients but one, CT scan of the chest was diagnostic (Fig. 1). Magnetic resonance imaging (MRI) is also recommended
Therefore, the screening and follow-up programs for carci- for early detection of thymic involvement in MEN1 (3), but
noid tumors in MEN1 patients suggested in the international it is more expensive, and its use in the follow-up is not always
guidelines (4), which include a chest x-ray performed yearly feasible in patients with previous sternotomy. On the con-
and a CT scan of the chest every 3 yr, risk missing more trary, as a preoperative diagnostic procedure MRI may play
aggressive thymic carcinoid characterized by early local in- a crucial role in detecting pericardial or large vessel invasion
vasion, distant metastases, and frequent recurrence even and, therefore, in assessing the indication of surgical treat-
many years after excision (7–10), as in cases 1, 3, and 5. Some ment and its modality (Figs. 5).
relevant guidelines have been suggested from a recent pub- The role of positron emission tomography scan in the
lished prospective study (3). However, some differences detection of thymic carcinoid remains to be established. A
from our findings are analyzed in this study. preliminary report has evidenced the efficacy of this diag-
The usefulness of somatostatin receptor scintigraphy (Oc- nostic test using 18-fluorodeoxyglucose (FDG) (13). However
treoscan) as a pre- and postoperative diagnostic and fol- other researchers have reported that a thymic biopsy or re-
low-up technique in MEN1 patients (11) was confirmed in section, performed on the basis of increased thymic uptake
four of our seven patients (Figs. 3 and 4). This test makes it of FDG, revealed only normal thymic tissue (14). Therefore,
possible to evidence distant intra- and extrathoracic metas- to prevent unnecessary resections, additional studies are
tases involving lymph nodes, liver, bone, skin, and adrenal needed to clarify the relationship between histopathology
glands that are often present (20 –30% of cases) at diagnosis findings and physiological uptake of FDG in the thymus (14,
and is a prerequisite for cold or radiolabeled somatostatin 15). For some researchers, the use of [11C]5-hydroxytrypto-
analogs therapy, as shown here in four of seven patients. phan is preferable for its specificity and accuracy in neu-
However, contrary to this report (Fig. 2), in a recently pub- roendocrine tumors (16), because whole-body positron emis-
lished series, no uptake was evidenced in a bone metastasis sion tomography with [11C]5-hydroxytryptophan was
(3). The power of detection of somatostatin receptor scintig- diagnostic in a case of ACTH-secreting thymic carcinoid that
raphy in small diameter thymic lesions and its possible role was not detectable by any other method, including octreotide
as an intraoperative procedure to guide complete tumor scintigraphy, MRI, and CT (16).
resection have not been completely established. Other scin- In the present report distant metastases were present at
tigraphic tracers, such as [99mTc]methoxyisobutylisonitrile, diagnosis in six of seven patients. The high frequency of bone

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Ferolla et al. • Thymic Carcinoid in MEN1 J Clin Endocrinol Metab, May 2005, 90(5):2603–2609 2607

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 fea-
tures or with inappropriate antidiuretic hormone secretion
have also been reported (25). Other nonendocrine syndromes
associated with thymic carcinoids are represented by poly-
myositis, 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 sup-
port 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 hor-
mones 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 con-
trast 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,
FIG. 5. Preoperative chest MR showing the absence of pericardial or even when invasion and metastases were present, as in the
large vessel invasion by a large mass (neuroendocrine thymic carci-
majority of the cases described in this report. Most of the
noma) in the anterior mediastinum in case 6.
reported cases were associated with a poor prognosis, even
after apparently radical surgical excision. In contrast, when
metastasis, as in case 2 (Fig. 3) (16, 17), must be underlined, possible, radical surgery, including the reexcision of any
because associated primary hyperparathyroidism in MEN1 recurrences, remains the treatment of choice in terms of sur-
patients represents a confounding factor in the early detec- vival (28 –30). Cold and radiolabeled therapies with soma-
tion of bone metastasis-associated hypercalcemia. Sporadic tostatin analogs may play important roles (31, 32).
reports of PTH or PTHrP secretion from thymic neoplasm Clusters have been reported in some families (8) and in
appeared in the international literature (18), and Funk et al. four of seven of our patients (Fig. 6), but in agreement with
demonstrated that PTHrP, which is known to exhibit neu- other reports, mutational analysis of the MEN1 gene in our
roendocrine and growth factor actions, is produced by epi- families confirmed the absence of genotype-phenotype cor-
thelial cells of the mature thymus (19). relations (8, 9). Linkage of heterozygosity studies in the
Primary hyperparathyroidism was present in all patients 11q13-MEN1 region were negative, and some researchers
in our series, and an increased incidence of primary hyper- also postulated a role for a putative tumor suppressor gene
parathyroidism has also been reported in sporadic nonneu- in chromosome 1p in the pathogenesis of a subset of thymic
roendocrine thymic neoplasm. In our experience, a case of carcinoids (9).
thymic neoplasm, not included in this report, presented with Despite its rarity, thymic carcinoid is a major cause of
associated primary hyperparathyroidism and a familial his- death in MEN1, and the management of carcinoid tumors has
tory of melanoma, but no mutation of the MEN1 gene. An- an impact on the survival of patients with this syndrome (9,
other Italian case of this association, in the absence of any 10). For this reason, in agreement with others, we recom-
other MEN1 feature, has been recently reported (20). Due to mend that prophylactic thymectomy should be considered in
the young age of both patients at diagnosis, the possibility of the course of neck exploration for parathyroidectomy, par-
MEN1 phenocopies cannot be ruled out. ticularly in male smokers and families in which close rela-
Less frequently, thymic involvement may be the first di- tives present with this feature. The need for total or subtotal
agnosed disorder in MEN1 syndrome (cases 2 and 4), and an parathyroidectomy in hyperparathyroid MEN1 patients
association with carcinoid syndrome and myasthenia gravis makes thymectomy feasible at the same time as surgical or
has never been described, not even in metastatic disease. The neck exploration. Transcervical thymectomy is the preferred
age at diagnosis ranges generally between the third and fifth surgical approach (4), even if some reports have cast doubt
decades, as in all our patients, but patients between 15 and on the complete efficacy of this approach (7).
70 yr of age have also been reported (21, 22). Cushing’s Unlike total thyroidectomy for medullary thyroid carci-
syndrome has been reported in about one third of sporadic noma in MEN2, there is no preventive surgery feasible for
cases, but never in MEN1 patients. In contrast, approxi- MEN1-related malignancies, and prophylactic thymectomy
mately 10% of patients with ectopic ACTH syndrome have could be considered, at the moment, the only exception to
a sporadic neuroendocrine carcinoma of the thymus (23). this rule.
Recently, ectopic GHRH secretion alone and GHRH- and The absence of symptoms until the late stage of disease and

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2608 J Clin Endocrinol Metab, May 2005, 90(5):2603–2609 Ferolla et al. • Thymic Carcinoid in MEN1

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; f, MEN1, affected; 䡺, not
affected; , not screened.

the lack of effective radio- and chemotherapeutic approaches Acknowledgments

and appropriate biochemical markers (mild increases in NSE
and CGA were found in our patients, but the concomitant Received June 22, 2004. Accepted February 9, 2005.
gastroenteropancreatic neuroendocrine tumor in three of Address all correspondence and requests for reprints to: Dr. P. Fe-
rolla, Department of Internal Medicine and Endocrine Sciences, Uni-
seven patients must be taken into account) sustain the need
versity of Perugia, Via E. Dal Pozzo, 06100 Perugia, Italy. E-mail:
for prophylactic thymectomy. Indeed, case 3 provides the pferolla@tin.it.
first histological evidence that prophylactic thymectomy is This work was supported by a research grant from the University of
able to prevent additional growth of occult microscopic thy- Perugia (to P.Fe. and G.D.), a grant from the Patients Association Vivere
mic carcinoids (Fig. 7). 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.).
In conclusion, our experience confirms that prophylactic
thymectomy should be considered in male MEN1 patients,
especially if they are smokers, and should be mandatory in References
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