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\begin{document}

\title{Thymic Neuroendocrine Tumor Presenting With Cushing Syndrome, As A rare
initial presentation}



\author[1]{ahmad matarneh}%
\author[2]{abdelrahman hamad}%
\author[2]{elhadi Elouzi}%
\author[2]{Nabil mahmood}%
\author[2]{Mohammad Khair  Hamad }%
\author[2]{mousa Hussein}%
\author[2]{Mohamed Yassin}%
\affil[1]{Hamad medical corporation}%
\affil[2]{Hamad Medical Corporation}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\selectlanguage{english}
\begin{abstract}
we report a 24 years old female patient, who presented with features of
crushing syndrome. upon evaluation, she was found to have ectopic
Adrenocorticotropic hormone (ACTH)--dependent Cushing's syndrome due to
a thymic tumor. histopathology confirmed ACTH secreting tumor. she was
treated With Video-assisted thoracoscopic surgery and had a successful
recovery.%
\end{abstract}%



\sloppy


Thymic Neuroendocrine Tumor Presenting With Cushing Syndrome, As A rare
initial presentation

Ahmad S Matarneh\textsuperscript{1}, Abdelrahman O
Hamad\textsuperscript{1}, Mohammad K Hamad\textsuperscript{1}, Elhadi B
Elouzi\textsuperscript{2} , Nabil S Mahmood\textsuperscript{3} , Mousa S
Hussein\textsuperscript{4} ,Mohamed A Yassin\textsuperscript{5}

\begin{enumerate}
\tightlist
\item
  Department of Internal Medicine, Hamad Medical Corporation, Doha,
  Qatar
\item
  Department of Endocrinology, Hamad Medical Corporation, Doha, Qatar
\item
  Department of Radiology, Hamad Medical Corporation, Doha, Qatar
\item
  Department of Pulmonology, Hamad Medical Corporation, Doha, Qatar
\item
  Department of Medical Oncology, Hamad Medical Corporation, Doha, Qatar
\end{enumerate}

Running title: Thymic Carcinoid Tumor Causing Cushing syndrome

*Corresponding Author Dr Ahmad Samir Salam Matarneh Department Internal
Medicine Hamad Medical Corporation Alrayyan street. Doha, Qatar Tel:
+97455957396 Fax: --44397857 E-mail: AMatarneh@Hamad.qa

\textbf{Keywords:}

Neuroendocrine Neoplasm, Thymic malignancies, Cushing's disease,
Pituitary Incidentaloma, Hypercortisolism\textbf{Key Clinical
Message:}while evaluating for the cause of Cushing syndrome, biochemical
confirmation should be pursued first, one of the rare secondary causes
that should be kept in mind is thymic neuroendocrine tum

\textbf{Abstract: Background:}

Thymic neuroendocrine tumors are a very rare group of neoplasms with
only a few cases described in the literature. These are considered
malignant predisposing them to metastasize. They can present with local
symptoms or when functional secrete hormones leading to paraneoplastic
syndromes such as acromegaly and Cushing's syndrome. Cushing's syndrome
is characterized by signs and symptoms due to exposure to excess
glucocorticoid. Establishing the diagnosis is difficult as the signs and
symptoms may not be obvious. ~Amongst several benign and malignant
causes, ectopic secretion of ACTH by non-pituitary tumors accounts for
about 10 to 15 percent of Cushing's syndrome. Most ectopic cases are
caused by neuroendocrine tumors of the lung, pancreas, or thymus. Due to
diagnostic and presentation challenges, it can often be missed. We write
this report to highlight a diagnostic dilemma we encountered and the
association of thymic neuroendocrine tumors with Cushing's
syndrome.\textbf{Case report:}We report a years old Filipina lady who
presented to the hospital with generalized fatigue and weakness. She was
found to have Cushing's syndrome and further evaluation revealed a
thymic neuroendocrine tumor that was treated with surgical excision by
VATS. The patient had an uncomplicated recovery course with
normalization of her blood pressure and hormonal
profile.\textbf{Conclusion:}Thymic neuroendocrine malignancies are a
rare group of neoplasms that can present with cushing syndrome, it
should be kept in mind while dealing with an ectopic cushing syndrome.
Mainstay of treatment is surgery, with a good overall survival and
outcomes.

\textbf{Introduction}

Cushing's syndrome is a syndrome that manifests with signs and symptoms
of hypercortisolism and usually affects multiple systems. Depending on
the level and duration of exposure to high cortisol levels the
presentation varies with the most commonly observed findings being
obesity, round (moon) facies with acne, high blood pressure, and high
blood sugar with multiple electrolytes derangements {[}1{]}. Moreover,
the presentation might differ between men and women, where men can
present at a younger age as compared to females who can present at a
later age with symptoms of gonadal dysfunction such as amenorrhea and
other menstrual abnormalities being more common
{[}2{]}\textsuperscript{.} Diagnosis usually is divided into two phases.
The first is to establish the diagnosis which requires a high clinical
suspicion along with confirmatory laboratory studies, such as high
cortisol levels, and in-suppressible cortisol with the administration of
low dose dexamethasone (1 mg). The second phase is to identify the
etiology, which is done by administering high dose dexamethasone (8 mg);
failure to suppress cortisol indicates an ectopic source of ACTH
secretion {[}3{]} The treatment choice depends on the underlying
etiology. One of the secondary causes of Cushing's syndrome is
neuroendocrine tumors of the thymus. These tumors may secrete ACTH
leading to the rapid development of hypercortisolism and ultimately
Cushing's syndrome {[}4{]}. Thymic malignancies are a rare group of
diseases composing around 1\% of all malignancies. Of these
malignancies, thymic neuroendocrine tumors comprise 2-5\% and are
considered the least common {[}4{]}\textsuperscript{.} They inherently
occur more in males with a median age of diagnosis around the 5th decade
of life {[}5{]}. These are usually aggressive and malignant with the
potential to metastasize. Hence treatment should be prompt to remove the
thymus gland. The response is variable depending on the prognostic
factors{[}5{]}\textsuperscript{}\textbf{Case presentation:}We report A
24 years old Filipina lady, who was recently diagnosed with hypertension
and hypothyroidism and presented to our hospital with generalized
fatigue and weakness that had been going on for three months before
presentation. She had increased abdominal girth along with acne and
occasional difficulty while getting up from chairs or walking. On
examination, she was thinly built with a slightly rounded face
containing numerous acnes. A slight hump on her back was noted. She also
had proximal bilateral weakness mainly in the lower limbs. Her Blood
pressure was found to be 163/67 mmHg. Labs showed her 8 AM cortisol
level to be high (2636nmol/l, Reference range {[}133-537 nmol/L{]}) with
a high ACTH (114pg/ml, Reference range {[}7.2-63.3 pg/ml{]}). A low dose
dexamethasone suppression. test~ failed to suppress cortisol with a
reading of (3572nmol/l ), but then high dose dexamethasone suppression
test showed a cortisol level of (2959 nmol/l, Reference range {[}133-537
nmol/L{]}), which meant failure to suppress Cortisol suggesting the
cause to be an ectopic source.~ A chest, abdomen and pelvic CT scan were
done which showed findings of a small thymic neuroendocrine
tumor\textbf{Figure} 1.(axial contrast-enhanced CT Study at the level of
mid-thoracic regions shows a small peripherally enhancing solid
abnormality within the thymus (Circle)) )associated with bilateral
adrenal hypertrophy \textbf{figure} 2.(Axial contrast-enhanced CT study
at the level of the upper abdomen shows a smooth enlargement of both
adrenal glands in keeping with hypertrophy ( arrows).~ This further
confirmed the suspected diagnosis of Cushing's syndrome secondary to a
thymic neuroendocrine tumor. She underwent surgical excision of the
tumor by right Video-assisted thoracoscopic surgery (VATS) with en-block
excision of the mediastinal mass and total removal of anterior
mediastinal fat. Samples were sent to pathology which was consistent
with a typical carcinoid tumor (ACTH expressing). The tumor expressed CK
AE1/AE3 and Synaptophysin that was confined to the thymus. Following the
surgery, her ACTH dropped to 6.1 pg/m and cortisol to 399 nmol/l, along
with improvement in her symptoms and blood pressure with titration down
on her antihypertensives with no postoperative complications.

\textbf{Discussion:}We present a rare case of Cushing's syndrome
encountered. The initial presentation was suggestive of an
endocrinopathy, which was confirmed by biochemical tests revealing
hypercortisolism secondary to an ectopic source. CT scan revealed a very
small tumor confined to the thymus. After resecting the tumor, the
symptoms and laboratory findings related to Cushing's syndrome improved
with no postoperative complications.

There is very little evidence in the literature describing the
relationship of Cushing's syndrome with a thymic Neuroendocrine tumor
{[} 6{]}. Thymic NET's are usually rare and account for a small
percentage of malignancies, occurring more in males at a the ratio of
3:1 {[}7{]}.Functional Thymic tumors tend to have a more complicated
course, and rapid onset of the development of clinical symptoms when
associated with an endocrinopathy. Suspicion of such tumors should be
raised and sought when diagnosing an ectopic Cushing's syndrome. They
are detected by imaging studies, such as CT scan of the chest, FDG PET,
or Dotatate PET CT~ which are also useful to detect any ~~synchronous
metastasis{[}8{]} ~Surgical excision remains the mainstay of treatment
and prognosis depends on the presence of metastasis and histopathologic
parameters such as mitotic activity{[}8{]}

\textbf{Conclusion:} While investigating the causes of Cushing's
syndrome, ectopic sources should always be considered

There is limited data available on the association between Cushing's
syndrome and thymic neuroendocrine tumors currently. Thymic
neuroendocrine tumors are considered malignant, and the mainstay of
treatment is surgical excision. Prognosis depends on several factors
most crucial being that of early diagnosis and absence of distant
metastasis.

\textbf{Author's contribution:}Ahmad S matarneh: manuscript write up,
Data collection and clinical care. Adbelrahman O hamad: clinical care,
study planning and design Mohammad Khair: clinical care Elhadi ouzi:
clinical care Mousa S Hussein: Clinical care. Nabil sherif mahmood:
clinical care Mohammad yassin: Mentor

\textbf{Conflict of interest:}None declared.\textbf{Ethical approval:}
approved by Hamad medical corporation, MRC number MRC-04-20-451

\textbf{Acknowledgments:} We thank the internal medicine department at
Hamad Medical Corporation for giving us the chance and support to
conduct this work.\textbf{Funding information:}Qatar national library

\textbf{References:}

1 Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: epidemiology
and developments in disease management. Clinical epidemiology.
2015;7:281.

2 Buliman A, Tataranu LG, Paun DL, Mirica A, Dumitrache C. Cushing's
disease: a multidisciplinary overview of the clinical features,
diagnosis, and treatment. Journal of medicine and life. 2016
Jan;9(1):12.

3 Pappachan JM, Hariman C, Edavalath M, Waldron J, Hanna FW. Cushing's
syndrome: a practical approach to diagnosis and differential diagnoses.
Journal of clinical pathology. 2017 Apr 1;70(4):350-9.

4.Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing but NET: a review
of neuroendocrine tumors and carcinomas. Neoplasia. 2017 Dec
1;19(12):991-1002.

5 Filosso PL, Ruffini E, Solidoro P, Roffinella M, Lausi PO, Lyberis P,
Oliaro A, Guerrera F. Neuroendocrine tumors of the thymus. Journal of
thoracic disease. 2017 Nov;9(Suppl 15):S1484.

6 Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic
origin, related to carcinoid tumor. Clinicopathologic study of 8 cases.
Cancer. 1972 Apr;29(4):1061-74.

7 Lawrence L, Zhang P, Choi H, Ahmad U, Arrossi V, Purysko A, Makin V. A
unique case of ectopic Cushing's syndrome from a thymic neuroendocrine
carcinoma. Endocrinology, diabetes \& metabolism case reports. 2019 Feb
22;2019(1).

8~ Chaer R, Massad MG, Evans A, Snow NJ, Geha AS. Primary neuroendocrine
tumors of the thymus. The Annals of thoracic surgery. 2002 Nov
1;74(5):1733-40.

Figures legends: figure 1: axial contrast-enhanced CT Study at the level
of mid-thoracic regions shows a small peripherally enhancing solid
abnormality within the thymus (Circle figure 2: Axial contrast-enhanced
CT study at the level of the upper abdomen shows a smooth enlargement of
both adrenal glands in keeping with hypertrophy ( arrows)\selectlanguage{english}
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