\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Clival Ectopic Pituitary Prolactinoma was Successfully Managed by
Transsphenoidal Surgery: A Rare Case Report}



\author[1]{Marah Mansour}%
\author[2]{Zeinah  Khozamah}%
\author[3]{Abdulmonem  Naksho}%
\author[4]{Roaa Roaa}%
\author[4]{Aliaa Aliaa Al Sabbagh}%
\author[5]{Ahmad  Deeb}%
\affil[1]{Faculty of Medicine, Tartous University}%
\affil[2]{Ibn Al-Nafees Hospital}%
\affil[3]{University of Westminster}%
\affil[4]{Damascus University Faculty of Medicine}%
\affil[5]{Al Basel hospital}%


\vspace{-1em}



  
  \date{June 03, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Clival Ectopic Pituitary Prolactinoma was Successfully Managed
by Transsphenoidal Surgery: A Rare Case Report}

\textbf{Clival Ectopic Pituitary Prolactinoma was Successfully Managed
by Transsphenoidal Surgery: A Rare Case Report}

\textbf{ABSTRACT}

Ectopic pituitary adenomas are isolated adenomas located outside the
sella turcica (in variable locations) with a normal-appearing pituitary
gland. These tumors are extremely rare and thought to often arise from
embryological remnants along the route of Rathke's pouch migration.
Ectopic pituitary adenomas can manifest in variable clinical ways
depending on hormonal activity and involvement of adjacent structures,
which can present a challenge in making a diagnosis and choosing most
appropriate management. In this case study, we report a 47-year-old male
who presented with visual disturbances, headache, generalised weakness
and hyperprolactinemia. Magnetic Resonance Imaging showed a 2 cm mass
located in the clivus invading the sphenoid sinus with an intact
pituitary gland. The patient underwent uncomplicated endoscopic
transsphenoidal surgery, during which the intersphenoid septum was
removed to reach the posterior wall and eradicate the mass successfully,
while maintaining integrity of the pituitary gland. Pathological studies
were consistent with prolactinoma, with no cytological malignant
features. Post-surgery, symptoms notably improved, serum prolactin level
dropped, and patient's condition was satisfactory on follow-up with no
long-term complications reported. The clival ectopic mass is a rare
condition that it may be located adjacent to important structures and
can be relatively difficult to reach. Therefore, surgery should be
performed carefully to maintain the nearby structures and avoid any
significant complications.

\textbf{Key message:} Ectopic pituitary adenoma is a rare neoplasm,
located in the clivus and could mimic other clival tumors. Diagnosis and
treatment could be challenging. It should be considered within the
differential diagnosis of clival tumors.

\textbf{Keywords:} Ectopic pituitary adenoma; clival tumours;
transsphenoidal surgery; prolactinoma; stalk effect; case report

\textbf{Clival Ectopic Pituitary Prolactinoma was Successfully Managed
by Transsphenoidal Surgery: A Rare Case Report}

\textbf{Introduction}

Ectopic pituitary adenomas (EPAs) are isolated adenomas located outside
the sella turcica with a normal intrasellar pituitary gland. EPAs are
thought to be extremely rare tumours {[}1{]}. The location of EPAs can
vary, with approximately 60\% of reported cases found in the sphenoid
sinus and suprasellar region, 30\% in the clivus, nasal cavity,
parasellar region, cavernous sinus, and sphenoid wing {[}2{]}. The
origin of EPAs can take one of three forms, with the most common being
adenomas derived from residual cells of Rathke's pouch which persist
along the developmental pathway of the anterior pituitary gland.
Clinical manifestations of EPAs usually depend on hormonal activity and
involvement of adjacent structures. For example, tumours extending into
the cavernous sinus or clivus can compress cranial nerves and cause
visual disturbances and facial paresthesia, while sphenoid sinus EPA can
result in headache, nasal obstruction and CSF leak {[}2{]}. The
diagnosis and management of EPAs can be challenging and usually requires
strong clinical suspicion along with magnetic resonance imaging (MRI)
findings, including normal pituitary gland, and is confirmed by
pathological studies. Computerized Tomograph (CT) can also provide
useful information such as invasion of the sphenoid sinus, and therefore
helps plan the endoscopic trans-sphenodial surgery, which is considered
the most appropriate management approach {[}3, 4{]}. In this case, we
present a clival ectopic pituitary prolactinoma.

\textbf{CASE PRESENTATION}

A 47-year-old male presented to the ENT Department (Ear, Nose, and
Throat) with a parietal and occipital headache, retro-orbital pain,
transient blurry vision, fatigue, and difficulty completing routine
tasks. The family and medical history were unremarkable. Laboratory
findings showed elevated serum prolactin of 269ng/ml. MRI with contrast
of sphenoid sinus and pituitary gland revealed a 2 cm mass within the
clivus invading the sphenoid sinus. The mass showed moderate enhancement
with peripheral calcifications. The pituitary gland and its stalk were
normal, Fig.1 (A, B, C). The mass was totally resected via
trans-sphenoidal endoscopic surgery. The posterior portion of the nasal
septum was resected, and the inlet was expanded while maintaining the
integrity of the sphenopalatine artery. The intersphenoid septum was
removed to reach the posterior wall of the sphenoid, which was invaded
by the tumour. However, the pituitary gland was notably intact. The
neoplastic mass looked friable and it was carefully resected without any
vascular or neurologic complications. The internal carotid arteries
(ICAs), cranial nerves III/IV/V/VI, and the optic chiasm were all
maintained Fig.2 (A, B, C, D). The postoperative period was uneventful.
The gross examination revealed fragments of tan, white tissue measuring
about 1.2\selectlanguage{ngerman}×1×0.5 cm with bony chips. Microscopic examination showed a
loosely infiltrating tumour composed of irregular cords and small nests
of uniform small oval-to-polygonal-shaped cells surrounded by dense
hyaline stroma and bone. In isolated areas, dystrophic calcifications
are noted. Immunostains were performed for prolactin, Ki-67, CD138,
Epithelial Membrane Antigen, CD45, CD34, S-100, protein, synaptophysin,
chromogranin, and CD56. The tumour cells were strongly positive for
prolactin, while the others were negative. No cytological malignant
features were shown, Fig.3 (A, B, C, D, E, F). Postoperatively, the
patient recovered rapidly, his symptoms notably improved, and serum
prolactin level dropped to 26ng/ml. On an 18-month follow-up, the
patient's condition was satisfactory with no long-term complications.

\textbf{DISCUSSION AND CONCLUSIONS}

EPAs are rare extrasellar pituitary adenomas without any correlation
with the components located inside the sella turcica. They are often
found along the migration pathway of Rathke's pouch; however, the exact
pathogenesis remains unclear {[}3, 4{]}. Unlike our case where the
patient is a male, EPAs tend to present more in females, and most
frequently between the fourth and seventh decades of life, with the mean
age at diagnosis being 51.4 years old {[}3{]}. In this case, we report
an EPA located in the clivus which represents the third most common
location for EPAs, after the sphenoid sinus and suprasellar region
{[}4{]}. Establishing the diagnosis of EPAs can be challenging as
presentation varies widely depending on several factors, including
anatomy, hormonal activity, and involvement/ invasion of surrounding
structures {[}2{]}. When considering the differential diagnosis (DD),
the clivus can be affected by a number of conditions, including lesions
arising within the clivus or from adjacent structures with chordoma
being the most common tumour of this region, which can be usually
differentiated from EPAs on imaging inspection. However, a biopsy is
usually required to confirm the diagnosis {[}4, 5{]}. Other DD include
intraosseous meningioma, chondrosarcoma, solitary plasmacytomas,
myelomas, astrocytoma, craniopharyngioma, germ cell tumour,
non-Hodgkin's lymphoma, melanoma, and metastases {[}1, 4{]}. Stalk
effect due to a nonfunctional adenoma should be considered in DD of
elevated prolactin levels. However, prolactin levels
\textgreater{}200-250 ng/mL are suspected of prolactinomas whereas
prolactin levels resulting from the pituitary stalk compression are
generally \textless{}100 ng/mL and rarely exceed 250ng/mL {[}6{]}.
Consistent with the presenting complaints in our report, clival EPAs,
similar to other clival lesions, are known to exhibit mass effect
symptoms, such as headache and focal cranial nerve palsy {[}7, 5{]}.
58\% of EPAs are functional tumours. In some clival diseases,
endocrinopathy may result from the infiltration of the pituitary. Clival
EPAs can invade adjacent structures causing destructive features such as
bone erosion, in keeping with the tumour in our case which invaded the
sphenoid sinus {[}4, 8, 9{]}. Due to the complexity of EPAs, several
factors should be considered for treatment, including tumour size and
location, clinical manifestations, hormone-secreting type and extent of
invasion {[}4{]}. The majority of EPAs are definitively diagnosed
following surgery and histopathological examination {[}10{]}. Herein,
trans-sphenoidal endoscopic surgery was performed as a diagnostic and
therapeutic procedure. Compared with other locations (cavernous sinus,
suprasellar region and the sphenoid sinus), the clival EPAs are
relatively more difficult to reach; thus, detect and confirm with an
endoscopic biopsy. In addition, experience in EPAs treatment is often
lacking considering how rare these tumours are {[}4{]}. In conclusion,
ectopic pituitary prolactinomas in the clivus are rare and the diagnosis
may be difficult. However, a histological study is necessary to confirm
the diagnosis especially when there are no hormonal-related symptoms.

\textbf{List of Abbreviations}

PAs: Pituitary Adenomas

EPAs: Ectopic Pituitary Adenomas

CD: Cluster of Differentiation

CSF: Cerebrospinal fluid

DD: Differential Diagnosis

CT: Computed Tomography

MRI: Magnetic Resonance Imaging

ACTH: Adrenocorticotropic Hormone

ICAs: Internal Carotid Arteries

CNs: Cranial Nerves

\textbf{REFERENCES LIST}

1. Kohno, M., Sasaki, T., Narita, Y., Teramoto, A., \& Takakura, K.
(1994). Suprasellar ectopic pituitary adenoma--case
report.\emph{Neurologia medico-chirurgica} , \emph{34} (8), 538--542.
https://doi.org/10.2176/nmc.34.538

2. Agely, A., Okromelidze, L., Vilanilam, G. K., Chaichana, K. L.,
Middlebrooks, E. H., \& Gupta, V. (2019). Ectopic pituitary adenomas:
common presentations of a rare entity. \emph{Pituitary} , \emph{22} (4),
339--343. https://doi.org/10.1007/s11102-019-00954-y

3. Yang, B. T., Chong, V. F., Wang, Z. C., Xian, J. F., \& Chen, Q. H.
(2010). Sphenoid sinus ectopic pituitary adenomas: CT and MRI
findings.\emph{The British journal of radiology} , \emph{83} (987),
218--224. https://doi.org/10.1259/bjr/76663418

4. Zhu, J., Wang, Z., Zhang, Y., Li, X., Liu, J., Deng, K., Lu, L., Pan,
H., Wang, R., Yao, Y., \& Zhu, H. (2020). Ectopic pituitary adenomas:
clinical features, diagnostic challenges and management.\emph{Pituitary}
, \emph{23} (6), 648--664. https://doi.org/10.1007/s11102-020-01071-x

5. Shuman, W., Loewenstern, J., Pai, A., Bederson, J., \& Shrivastava,
R. (2019). Variability in Clinical Presentation and Pathologic
Implications of Ectopic Pituitary Tumors: Critical Review of
Literature.\emph{World neurosurgery} , \emph{122} , 397--403.
https://doi.org/10.1016/j.wneu.2018.10.200

6. Vilar, L., Fleseriu, M., \& Bronstein, M. D. (2014). Challenges and
pitfalls in the diagnosis of hyperprolactinemia. \emph{Arquivos
brasileiros de endocrinologia e metabologia} , \emph{58} (1), 9--22.
https://doi.org/10.1590/0004-2730000003002

7. Hou, L., Harshbarger, T., Herrick, M. K., \& Tse, V. (2002).
Suprasellar adrenocorticotropic hormone-secreting ectopic pituitary
adenoma: case report and literature Review. \emph{Neurosurgery}
,\emph{50} (3), 618--625.
https://doi.org/10.1097/00006123-200203000-00035

8. Thompson, L. D., Seethala, R. R., \& Müller, S. (2012). Ectopic
sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary
gland: a clinicopathologic and immunophenotypic study of 32 cases with a
comprehensive review of the english literature. \emph{Head and neck
pathology} , \emph{6} (1), 75--100.
https://doi.org/10.1007/s12105-012-0336-9

9. Horiuchi, T., Tanaka, Y., Kobayashi, S., Unoki, T., \& Yokoh, A.
(1997). Rapidly-growing ectopic pituitary adenoma within the sphenoid
sinus--case report. \emph{Neurologia medico-chirurgica} , \emph{37} (5),
399--402. https://doi.org/10.2176/nmc.37.399

10. Tajudeen, B. A., Kuan, E. C., Adappa, N. D., Han, J. K., Chandra, R.
K., Palmer, J. N., Kennedy, D. W., Wang, M. B., \& Suh, J. D. (2017).
Ectopic Pituitary Adenomas Presenting as Sphenoid or Clival Lesions:
Case Series and Management Recommendations. \emph{Journal of
neurological surgery. Part B, Skull base} , \emph{78} (2), 120--124.
https://doi.org/10.1055/s-0036-1592081

\textbf{FIGURE LEGENDS}

Fig.1 (A, B, C): MRI with contrast of sphenoid sinus and pituitary gland
in sagittal (A), transverse (B), and coronary (C) sections showing a
mass in the clivus with moderate enhancement and peripheral
calcifications.

Fig.2 (A, B, C, D): Endoscopic images of transsphenoidal surgery showing
the neoplastic mass adjacent to the intact pituitary gland (A), the
neoplastic mass adjacent to both the right and left ICAs (B, C), and the
pituitary gland after complete resection of the mass (D).

Fig.3 (A, B, C, D, E, F): Histological images of the resected mass
showing small nests of uniform small oval-to-polygonal-shaped cells
surrounded by dense hyaline stroma (A, B), negative staining for
synaptophysin, chromogranin, and CD56 respectively (C, D, E), positive
staining for prolactin (F).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/photo-2023-05-04-17/photo-2023-05-04-17}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/photo-2023-05-04-18/photo-2023-05-04-18}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/photo-2023-05-04-19/photo-2023-05-04-19}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

