Pituitary (2012) 15:160–165

DOI 10.1007/s11102-012-0388-6

Bronchial carcinoid tumors metastatic to the sella turcica

and review of the literature
Olga Moshkin • Fabio Rotondo • Bernd W. Scheithauer •

Mark Soares • Claire Coire • Harley S. Smyth •

Miklos Goth • Eva Horvath • Kalman Kovacs

Published online: 8 April 2012

Ó Her Majesty the Queen in Rights of Canada 2012

Abstract We review here the literature on neuroendo-
crine neoplasms metastatic to the pituitary and present an
example of the disease. Metastasis of bronchial carcinoid
tumors to the sellar region are rare. Herein, we describe the
case of a 63-year-old woman who presented with constant
cough and headaches. She had previously been operated for
carcinoid tumor of the lung. During the preoperative
investigation, a CT scan of the head revealed a sellar mass.
Six months after a left lower lobectomy, the sellar lesion
was removed by transsphenoidal surgery. The two tumors
were evaluated by histology, immunohistochemistry and
electron microscopy. Both showed identical morphologic
features, those of carcinoid tumor. Immunohistochemistry
revealed immunoreactivity for the endocrine markers,
synaptophysin and chromogranin, as well as CD-56, sero-
tonin, bombesin and vascular endothelial growth factor.
The sellar neoplasm showed nuclear immunopositivity for
thyroid transcription factor-1, supporting the diagnosis of a
metastatic bronchial carcinoid tumor. In conclusion, this is
the first report of a serotonin- and bombesin-immunopos-
itive atypical bronchial carcinoid tumor metastatic to the
sella.
Keywords Bronchial carcinoid tumor

Immunohistochemistry
Electron microscopy
Pathology

Pituitary metastasis

O. Moshkin (&) Introduction

Department of Laboratory Medicine, Peterborough Regional
Health Centre, 1 Hospital Drive, Peterborough, ON K9J 7C6,
Canada Bronchial carcinoid tumors metastatic to the sella are rare.
e-mail: omoshkin@gmail.com There were only a few reported examples of carcinoid
tumors, typical or atypical, metastatic to the pituitary or to
O. Moshkin
F. Rotondo
E. Horvath
K. Kovacs
a pituitary adenoma [1–6]. Herein, we present the case of a
Division of Pathology, Department of Laboratory Medicine,
St. Michael’s Hospital, Toronto, ON, Canada 63-year-old woman with a bronchial carcinoid tumor
metastatic to the sella with a detailed clinical, histologic,
B. W. Scheithauer immunohistochemical and ultrastructural analysis. A liter-
Department of Laboratory Medicine and Pathology,
ature review of sellar metastases of neuroendocrine neo-
Mayo Clinic, Rochester, MN, USA
plasms is also included.
M. Soares
C. Coire
Division of Pathology, Department of Laboratory Medicine,
Trillium Health Centre, Mississauga, ON, Canada
Clinical findings
H. S. Smyth
Department of Neurosurgery, Trillium Health Centre, A 63-year-old woman presented with persistent cough,
Mississauga, ON, Canada occasional night sweats and headaches. Some coughing
spells were associated with flushing. Her medical his-
M. Goth
Department of Medicine, Hungarian Defense Forces, tory included (a) medically controlled type 2 diabetes of 20
Military Hospital, Budapest, Hungary years duration unassociated with vascular complications;

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Pituitary (2012) 15:160–165 161

(b) hyperlipidemia, and (c) paranoid schizophrenia. She had

quit smoking 10 years prior. A computerized tomographic
(CT) scan suggested atelectasis of the left lower lobe with
likely partial bronchial obstruction. A bronchial washing
revealed tumor cells compatible with carcinoid tumor. A left
lower lobectomy and resection of a 2.5-cm tumor was per-
formed with resultant improvement of the cough and head-
aches. To assess the headaches, a preoperative CT head scan
was undertaken. It demonstrated a solid, round sellar lesion
which displaced the pituitary superiorly. The tumor involved
the intracavernous segments of both carotid arteries. The
tumor appeared to be calcified and had significantly eroded
the clivus. Magnetic resonance imaging (MRI) showed the
3-cm lesion to enhance (Fig. 1). The differential diagnosis
included pituitary adenoma and a metastasis. Six months
after the lung lobectomy, a follow-up MRI scan showed
growth of the sellar tumor. Clinical investigation revealed
normal blood pituitary hormone levels and normal visual
fields. Given the likelihood of future visual disturbance and
pituitary insufficiency, the patient elected to undergo sur-
gery. The pituitary mass was subtotally resected by the
transsphenoidal approach.

Morphologic findings

Both tumor specimens were investigated histologically,

including hematoxylin–eosin (H&E) and periodic acid-
Schiff stains, as well as the Gordon-Sweet silver method
for reticulin fibers. Immunohistochemistry and transmis-
sion electron microscopy were also undertaken. Methods of
the former have previously been described [7].
Light microscopy indicated the identity of the pulmon-
ary and sellar lesions. Both featured mild pleomorphism,
moderate to high cellularity, and an endocrine architectural
pattern coupled with nuclear uniformity and a delicate,
‘‘salt and pepper’’ chromatin pattern (Fig. 2a). Occasional
mitoses were identified. Lymphovascular invasions and
lymph node metastases were noted in association with the
lung tumor. Immunohistochemically, both tumors showed
positive staining for synaptophysin (ICN, Costa Mesa, CA;
1:40, SY38), chromogranin (Chemicon, Temecula, CA;
1:500, LK2H10), CD56 (Monosan/Caltag, San Francisco,
CA; 1:25, 123C3), and thyroid transcription factor-1 (TTF-
1) (Dako, Carpinteria, CA; 1:1,000, 8G7G3/1) (Fig. 2b),
the latter being a marker of lung and thyroid neoplasms.
Additional immunoreactivities included serotonin (Dako,
1:80 BRD, 5HT-H209) (Fig. 2c), bombesin (Abcam,
Cambridge, MA; 1:1,000, ab86037) (Fig. 2d) and vascular
endothelial growth factor (Neo Markers, Fremont, CA;
VG1, 1:20 BRD). Negative stains included PAS, calcito-
nin, gastrin, cholecystokinin, and carcinoembryonic anti-
gen (CEA). Immunostains for somatostatin as well as of
Fig. 1 Post-gadolinium-enhanced MRI image (a coronal, b sagittal
views) showing a large sellar mass
corticotropin- and growth hormone-releasing hormones
were inconclusive. The Ki-67 labeling index varied from a
low of 2 % to a focal maximum of 15 %.
Electron microscopy documented identical features in
both tumors, including nests and lobules of closely apposed
small tumor cells separated by thin fibrovascular septa
(Fig. 3). Cells were often elongate with relatively large
heterochromatic nuclei, partly exhibiting a ‘‘salt and pep-
per’’ heterochromatin pattern, and scant cytoplasm forming
elongate processes. Rough endoplasmic reticulum was
scant, Golgi complexes appeared inactive, but free polyri-
bosomes were numerous. Mitochondria were normal in
number and appearance. Electron dense secretory granules
were evident in every cell, especially within their pro-
cesses, and measured 98–192 nm (mean, 146 nm). In some

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162
Fig. 2 Resected sella mass is composed of nests and sheets of mildly
pleomorphic small cells with ‘‘salt and pepper’’ nuclear chromatin pattern
(a H&E). Immunohistochemistry demonstrates immunoreactivity for
Fig. 3 Transmission electron micrograph shows small carcinoid cells
with dense neurosecretory granules and ‘‘salt and pepper’’ chromatin
pattern
areas, both tumors were very cellular, featured small het-
erochromatic nuclei with an appearance suggestive of
small cell carcinoma. Nonetheless, secretory granules were
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Pituitary (2012) 15:160–165
thyroid transcription factor-1 (b TTF-1), serotonin (c), and bombesin (d).
(a–d original magnification 9200)
present in every cell. The sellar tumor appeared more
cellular, pleomorphic and undifferentiated than did the
primary lung tumor. A diagnosis of atypical carcinoid
tumor was made.
Discussion
Several clinically distinct and morphologically varied
lesions occur in the sellar region. Most frequent are pituitary
adenomas, of which approximately 50 % secrete hormones
in excess to produce a variety of endocrine abnormalities.
These include acromegaly/gigantism, galactorrhea/amen-
orrhea, Cushing disease and hyperthyroidism. Adenohy-
pophyseal hyperplasia may also cause clinical signs of
hyperfunction [8]. Nonendocrine neoplasms affecting the
sella region typically result in diabetes insipidus, hypopi-
tuitarism but may induce hyperprolactinemia by the
so-called ‘‘stalk section effect’’ [9]. Chief among these are
craniopharyngioma, meningioma, germ cell tumors, and
metastatic carcinoma. The latter are particularly frequent in
late stage disease. Given its direct arterial supply, metas-
tases more often affect the posterior lobe, the result being
diabetes insipidus. Most frequent primary sites of these
Pituitary (2012) 15:160–165 163

Table 1 Literature review: presentation and treatment of primary tumor

Case Year Reports Age Gender Primary tumor Clinical symptoms Treatment of primary tumor

1 2010 Feletti, A 65 M Pituitary metastasis of Merkel Progressive hemianopia

295 cell carcinoma diagnosed with sellar lesion
compressing the optic
chiasm
2 2009 Santarpia, L Young F Diabetes insipidus and Panhypopituitarism, optic Surgery (years prior)
419 panhypopituitarism due to chiasm compression
intrasellar metastasis of
medullary thyroid cancer
3 2008 Alacasio 50 M Small cell lung carcinoma Metastases to pituitary and Combined chemotherapy
765 iris (cisplatin–etoposide)
Central diabetes insipidus
4 2008 Gur, C 293 55 F Pancreatic neuroendocrine Sellar mass, ophthalmoplegia Sandostatin, chemotherapy,
tumor (undiagnosed) and headaches mimicking and radiotherapy
invasive null cell pituitary
adenoma
5 2008 Williams, 23 F Medullary thyroid carcinoma Visual loss, diabetes
MD 199 metastatic to the pituitary insipidus, MEN2b
gland
6 2008 Bhatoe, HS 38 M Medullary thyroid carcinoma Visual field defects and Surgical excision of thyroid
63 painless thyroid nodule; gland Craniotomy and sub
lobulated pituitary mass frontal excision of pituitary
metastatic tumor
7 2007 Tanaka, H 54 F Small cell lung carcinoma Sudden onset of diabetes Chemotherapy with CDDP
793 with Cushing syndrome due insipidus and 1 month and VP-16
to ectopic ACTH secretion later—bloody sputum
8 2007 Takei, H 49 M Small cell lung carcinoma 1 month hx of headache,
637 diplopia and blurred vision.
Exam: bilateral
hemianopsia and left 6
nerve palsy. MRI: Pit
adenoma? A biopsy of
pituitary lesion—small cell
carcinoma on cytologic
touch imprint; additional
workup revealed a mass in
the right lung
9 2006 Nasr, C 44 F GH-releasing hormone- Acromegaly diagnosed during (Bx proven). After delivery,
4776 secreting, endocrine pregnancy. After delivery, radiation and chemotherapy
carcinoma metastatic to adjuvant therapy, 7 years to lung and skeletal
pituitary causing stable, then bitemporal metastases. 7 years stable
somatotroph hyperplasia hemianopia.
with adenomatous
transformation
10 2006 Bouaziz, H 49 M Small cell lung carcinoma Acute adrenal failure with Left lung mass and
259 polyuria and polydipsia as mediastinal adenopathy;
well as a pituitary tumor Lung biopsy—small cell
syndrome carcinoma. Hypertrophy of
left adrenal. Hepatic nodule;
liver biopsy—Sarcoidosis
11 2005 Schleich, F 55 M Small cell lung carcinoma Polyuria and polydipsia Chemotherapy
355 metastatic to pituitary Follow up lung CT scan
revealed 3.5 cm mass and
transbronchial biopsy
confirmed the diagnosis of
small cell carcinoma
12 2005 Harzallah, L 40 M Small cell lung carcinoma
117 metastasized to pituitary

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164 Pituitary (2012) 15:160–165

Table 1 continued
Case Year Reports Age Gender Primary tumor Clinical symptoms Treatment of primary tumor

13 1984 Chandra, V 58 F Metastatic small cell Pituitary apoplexy and

59 carcinoma of lung hyperprolactinemia.
presenting as Cushing 17 months later, Cushing
syndrome and pituitary syndrome,
apoplexy diagnosed hyperpigmentation,
postmortem hypercortisolemia, and
anasarca. Ectopic ACTH
syndrome. Died 26 months
after episode of pituitary
apoplexy
14 1993 Sanguinetti, 61 M Small cell lung carcinoma Polyuria, polydipsia
CM 130 metastatic to hypothalamic-
neurohypophysial region
15 1993 Tabata, M 62 M Small cell lung cancer Paraneoplastic Cushing Intensive chemotherapy
235 associated with Cushing syndrome; elevated ACTH without significant effect.
syndrome and DI and urinary 17-OHCS. Dead of disease after
Obesity, hypertension, 5 months of chemotherapy
hyperglycemia, persistent
hyperkalemia, alkalosis. No
hx of diabetes mellitus. Left
visual field defect

tumors include breast, lung and prostate. Less frequent are
colon, thyroid, stomach, and pancreas.
Neuroendocrine tumor metastases to the pituitary are
extremely rare [10–12]. These were recently reviewed by
Goglia et al. [13] in a detailed clinicomorphological anal-
ysis, inclusive of a review of diagnostic methods and
treatment options. These authors summarized 5 cases of
small cell lung carcinoma, 4 of bronchial carcinoid tumor,
1 of mediastinal thymic carcinoid, and 1 of GHRH-pro-
ducing pancreatic islet cell neuroendocrine tumor. In
addition, they reported a case of metastatic neuroendocrine
tumor of unknown primary site. We have expanded the list
of metastatic neuroendocrine tumors (NET) (Table 1) and
retrieved yet another 15 cases from the literature including
9 small cell lung carcinomas, 3 medullary thyroid carci-
nomas, 1 Merkel cell carcinoma, 1 pancreatic neuroendo-
crine tumor, and 1 pulmonary neuroendocrine carcinoma
secreting growth hormone releasing hormone (GHRH).
The most frequent primary tumor was small cell carcinoma
of the lung and the most common clinical presentation was
diabetes insipidus in 7 of 9 cases. Three cases of small cell
lung carcinoma were notable for associated ectopic adre-
nocorticotropic hormone (ACTH) production and devel-
oping Cushing syndrome, 2 with accompanying diabetes
insipidus and 1 with pituitary apoplexy and hyperprolac-
tinemia. Another small cell carcinoma was associated with
diabetes insipidus, panhypopituitarism, acute adrenocorti-
cal failure resistant to treatment, and hepatic sarcoidosis. In
3 cases of thyroid medullary carcinoma, diabetes insipidus
was seen in 2 instances; both patients were young women
with MEN2b. Other symptoms encountered in our study
included hypopituitarism with anterior lobe insufficiency in
3 instances, as well as headache, visual field defects, dip-
lopia, and blurred vision. Nasr et al. [6] reported the case of
a pregnant 44-year-old woman with a GHRH-producing
pulmonary neuroendocrine tumor metastatic to the pitui-
tary and causing somatotroph hyperplasia, adenomatous
transformation, and clinical acromegaly [6]. After delivery,
the pituitary mass was removed transsphenoidally and
chemotherapy as well as irradiation was administered with
success. In 3 instances (2 small cell lung carcinomas and 1
pancreatic neuroendocrine tumor), pituitary metastases
presented with manifestation of diabetes insipidus or local
mass effects prior to the discovery of the primary tumor.
Atypical bronchial carcinoid tumor metastatic to the
sellar region is very rare. Jonnakuty and Mezitis [1]
described an example metastatic to the pituitary gland from
a peripherally situated pulmonary tumor that manifested in
a 50-year-old woman with hypopituitarism, bitemporal
hemianopia, ataxia, and dysarthria [1]. Huang et al. [2],
Shimon et al. [3] and Rossi et al. [4] described pituitary
metastases in 3 patients at 1.5, 2 and 8 years after treatment
of the primary lung tumor, respectively [2–4]. Abe et al. [5]
reported metastases of a malignant carcinoid tumor of the
anterior mediastinum to a prolactin-secreting pituitary
adenoma. Lastly, Nasr et al. [6] reported a rare case of
acromegaly and somatotroph hyperplasia with adenoma-
tous transformation due to a pituitary metastasis of a

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Pituitary (2012) 15:160–165
growth hormone-releasing hormone-producing neuroen-
docrine carcinoma of the lung in 44-year-old woman [6].
Our 63-year-old patient presented with pulmonary
symptoms and headaches. A left lower lobectomy revealed
an atypical bronchial carcinoid tumor. It is of note that,
preoperatively, the head CT scan revealed a pituitary mass,
the principle differential diagnosis of which included
pituitary adenoma and metastatic tumor. Further investi-
gation was postponed given the urgent need to improve
pulmonary function. The 6-month delay prior to trans-
sphenoidal surgery was uneventful. A morphologic evalu-
ation showed the lung and pituitary tumors to be essentially
identical. Immunohistochemistry revealed positivity in
both tumors for synaptophysin, chromogranin, CD-56,
serotonin, bombesin, and VEGF. Thus, an atypical bron-
chial carcinoid tumor had metastasized to the sella pro-
ducing headaches but little or no pituitary dysfunction. The
identical tumor morphology and immunophenotype
excluded consideration of a primary pituitary tumor. The
tumors displayed immunoreactivity for synaptophysin and
chromogranin as well as for serotonin, bombesin and
VEGF. Nuclear TTF-1 immunoexpression in both tumors
confirmed a metastatic origin of this tumor from lung.
TTF-1 is a nuclear transcription factor normally expressed
in thyroid follicles and respiratory epithelium. This marker
is expressed in lung adenocarcinomas and thyroid carci-
nomas but not in tumors arising from other sites [14]. Du
Ez et al. [15] found TTF-1 to be expressed in typical and
atypical carcinoid tumors of lung but not in carcinoid
tumors originating in other organs, an observation of value
in differential diagnosis.
In conclusion, our finding of serotonin, bombesin and
VEGF immunopositivity coupled with nuclear TTF-1
expression confirmed the metastatic nature of sellar tumor
and its origin in lung.
Acknowledgments Authors thank the Jarislowsky and the Lloyd
Carr-Harris Foundations as well as Mr. Jesus Rodriguez for their
generous support. This research was funded in part by OTKA Grant
No. 68660—Hungarian Research Fund.
Conflict of interest The authors wish to disclose that there are no
relationships/conditions/circumstances that present potential conflict
of interest.
165
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