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\begin{document}

\title{Case Report: Primary Squamous Cell Carcinoma of the Orbit in a patient
with Carney's syndrome treated with multidisciplinary approaches}



\author[1]{Md. Rahman}%
\author[2]{Rajesh Balakrishnan}%
\author[3]{Mohammad Mostofa}%
\author[4]{Mohammed Islam}%
\author[5]{Eamul Kabir}%
\author[5]{Shariful Islam}%
\author[6]{Bidoura Naznin}%
\author[6]{Arunangshu Das}%
\author[1]{Qamruzzaman  Chowdhury}%
\affil[1]{Bangladesh Specialized Hospital Limited}%
\affil[2]{Christian Medical College Vellore}%
\affil[3]{Anowara Medical Service}%
\affil[4]{Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrines and Metabolic Disorders}%
\affil[5]{Delta Medical College}%
\affil[6]{Square Hospital}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Squamous cell carcinoma (SCC) is a rare
malignancy of invasive epithelium with keratinocyte differentiation, and
it is the most common form of eyelid malignant neoplasm, comprising
5-10\% of malignancies. While SCC rarely affects the orbit, it may be
involved through local invasion from a cutaneous primary site or
extension by perineural invasion. Only 11 cases of primary orbital SCC
have been reported until now. Here, we present a case of primary
carcinoma of the right orbit with coexisting Carney's syndrome, a rare
genetic disorder associated with multiple endocrine neoplasias (MEN)
syndromes. \textbf{Case:} A 62-year-old south Asian male presented with
a painful swelling in the lateral aspect of the right eyebrow and
protrusion of the eyeball in August 2020. He had a history of excision
of Right atrial Myxoma in March 2020. Orbital computerized Tomography
(CT) and Positron Emission Tomography (PET-CT) scans revealed an
enhancing soft tissue lesion in the right orbit with involvement of
frontal and ethmoid sinuses. Biopsy confirmed HPV related poorly
differentiated squamous cell carcinoma, positive for HPV-related
markers. The patient received concurrent chemo irradiation with
Cisplatin. Follow-up done PET-CT done 3 months later showed a new lesion
appeared in the right orbital region and right lobe of thyroid. Later
had surgical excision and total thyroidectomy and Histopathological
examination (HPE) from orbit was reported as invasive SCC and from the
thyroid was reported as synchronous papillary thyroid cancer. The
patient's proptosis resolved, and subsequent PET-CT and Magnetic
Resonance Imaging (MRI) scans did not show any residual or recurrent
disease. \textbf{Conclusion:} Primary SCC of the orbit is an extremely
rare disease, and this case report presents the 12th reported case and
the first one associated with Carney's syndrome. As there is no standard
treatment regimen for primary SCC of the orbit, this case highlights the
use of multimodality treatment, including surgical excision and chemo
irradiation. The findings emphasize the importance of early detection
and management of this uncommon and life-threatening condition,
providing hope for patients and aiding in the prevention of recurrence.%
\end{abstract}%



\sloppy


\textbf{Case Report: Primary Squamous Cell Carcinoma of the Orbit in a
patient with Carney's syndrome treated with multidisciplinary
approaches.}

Md. Arifur Rahman\textsuperscript{1}, Rajesh
Balakrishnan\textsuperscript{2}, Mohammad Golam
Mostofa\textsuperscript{3}, Mohammed Rashedul Islam\textsuperscript{4},
Enamul Kabir\textsuperscript{5}, Md. Shariful Islam\textsuperscript{5},
Bidoura Naznin\textsuperscript{6}, Arunangshu Das\textsuperscript{6},
Qamruzzaman Chowdhury\textsuperscript{1}

\begin{enumerate}
\tightlist
\item
  Department of Oncology, Bangladesh Specialized Hospital Limited,
  Dhaka, Bangladesh.
\item
  Department of Radiation Oncology, CMC Vellore, India.
\item
  Department of Histopathology, Anowara Medical Service, Dhaka,
  Bangladesh.
\item
  Department of Plastic Surgery, BIRDEM General Hospital, Dhaka,
  Bangladesh.
\item
  Department of Physics, Delta Medical College Hospital, Dhaka,
  Bangladesh.
\item
  Department of Oncology, Square Hospitals Limited, Dhaka, Bangladesh.
\end{enumerate}

Keywords: Primary Orbit Cancer, Squamous Cell Carcinoma, Cardiac Myxoma,
Papillary Carcinoma of Thyroid, Carney's syndrome

Corresponding Author:

Md. Arifur Rahman, Department of Oncology, Bangladesh Specialized
Hospital Limited, 21 Shyamoli, Mirpur Road, Dhaka 1207, Bangladesh.

Email:

\textbf{1.} Md. Arifur Rahman, drarifur@bshl.com.bd, sajal29@gmail.com

2. Rajesh Balakrishnan , drrajeshb77@gmail.com ,
rajeshb@cmcvellore.ac.in

3. Mohammad Golam Mostofa, dmgm.path.bd@gmail.com

4. Mohammed Rashedul Islam, rashedplastic@gmail.com

5. Enamul Kabir, smenamulbd@gmail.com

6. Md. Shariful Islam, mr.johny1@gmail.com

7. Bidoura Naznin, nazninbidoura@gmail.com

8. Arunangshu Das, arunangshu37@gmail.com

9. Qamruzzaman Chowdhury, dqzamanchow@yahoo.com

\textbf{Abstract:}

\textbf{Introduction:}

Squamous cell carcinoma (SCC) is a rare malignancy of invasive
epithelium with keratinocyte differentiation, and it is the most common
form of eyelid malignant neoplasm, comprising 5-10\% of malignancies.
While SCC rarely affects the orbit, it may be involved through local
invasion from a cutaneous primary site or extension by perineural
invasion. Only 11 cases of primary orbital SCC have been reported until
now. Here, we present a case of primary carcinoma of the right orbit
with coexisting Carney's syndrome, a rare genetic disorder associated
with multiple endocrine neoplasias (MEN) syndromes.

\textbf{Case:}

A 62-year-old south Asian male presented with a painful swelling in the
lateral aspect of the right eyebrow and protrusion of the eyeball in
August 2020. He had a history of excision of Right atrial Myxoma in
March 2020. Orbital computerized Tomography (CT) and Positron Emission
Tomography (PET-CT) scans revealed an enhancing soft tissue lesion in
the right orbit with involvement of frontal and ethmoid sinuses. Biopsy
confirmed HPV related poorly differentiated squamous cell carcinoma,
positive for HPV-related markers. The patient received concurrent chemo
irradiation with Cisplatin. Follow-up done PET-CT done 3 months later
showed a new lesion appeared in the right orbital region and right lobe
of thyroid. Later had surgical excision and total thyroidectomy and
Histopathological examination (HPE) from orbit was reported as invasive
SCC and from the thyroid was reported as synchronous papillary thyroid
cancer. The patient's proptosis resolved, and subsequent PET-CT and
Magnetic Resonance Imaging (MRI) scans did not show any residual or
recurrent disease.

\textbf{Conclusion:}

Primary SCC of the orbit is an extremely rare disease, and this case
report presents the 12th reported case and the first one associated with
Carney's syndrome. As there is no standard treatment regimen for primary
SCC of the orbit, this case highlights the use of multimodality
treatment, including surgical excision and chemo irradiation. The
findings emphasize the importance of early detection and management of
this uncommon and life-threatening condition, providing hope for
patients and aiding in the prevention of recurrence.



\textbf{Introduction:}

Primary Orbital squamous cell carcinoma is an exceedingly rare
condition. This is mainly due to absence of native squamous epithelium
of the orbit itself. SCC is the most common form of eyelid malignant
neoplasm comprising 5-10\% malignancies. It mainly affects older
patients between 50 to 75 years. Moreover, the incidence rate is very
low ranging between 0.09 to 2.42 cases per 0.1 million population
{[}1-3{]}. The number of reported cases of orbital squamous cell
carcinoma are very few. The presenting signs and symptoms can sometimes
be challenging and diagnosis is difficult. On top of that the management
is also very difficult to with irradiation and organ preservation
modality with dose constrain in the structures in the orbit and nearby
vital structures like opposite eye, lens, retina, and optic nerve
including optic chiasm. Although along with Carney's syndrome makes this
case more particular and unique.

In our case, we report a case of primary carcinoma of the right orbit
who had coexistent carney's syndrome. We have also described the workup,
staging and multidisciplinary management for the orbital SCC.

\textbf{Case Presentation:}

A 62 years old south Asian gentle male {[}Fig: 1a{]}, presented in Aug
2020 to an eye specialist with the complaints of painful swelling in the
lateral aspect of right eyebrow with protrusion of the eyeball. He had a
past history of excision of Right atrial Myxoma on March 2020 {[}Fig:
2a{]} by cardiac surgeon in United Hospitals Limited, Dhaka, Bangladesh.
On examination, he had proptosis, the mass was fixed to skin, and it was
tender. Orbital CT showed an enhancing soft tissue lesion measuring 3.2
x 3 cm in the superior-medial aspect of the right orbit with orbital
roof and medial nasal bone erosion and extension to frontal sinus and
anterior ethmoid sinus, the lesion was extraconal and was abutting the
superior rectus and was compressing the right globe \& the lacrimal
gland was not involved. Staging PET-CT showed a hypermetabolic soft
tissue mass in the superior-medial aspect of right orbit (SUV max 19.95)
involving the right frontal sinus \& eroding the roof of right orbital
bone extended to ethmoidal sinus suggesting malignancy {[}Fig: 1c{]}.
PET also revealed a hypermetabolic soft tissue nodule in the right lobe
of thyroid (SUVmax - 13.4) {[}Fig: 1d{]}. PET scan did not reveal any
distal metastases in lung or liver or bone or in any lymph nodes.

He had an incisional biopsy from the right orbital mass at Bangladesh
Eye Hospitals by Eye surgeon and histopathology {[}Fig: 2a{]} was
reported as poorly differentiated squamous cell carcinoma. The slides
and block were send for a second opinion to another pathologist who
confirmed the diagnosis. The orbital mass was found to be CK5/6-Positive
{[}Fig: 2c{]}, p16-positive {[}Fig: 2d{]}, p63-positive {[}Fig: 2e{]}
and was reported as HPV related squamous cell carcinoma. FNAC from the
hypermetabolic thyroid swelling was suggestive of papillary thyroid
carcinoma. His Postoperative MRI {[}Fig: 1b{]} in Sep 2020 showed a
large heterogenous mass (AP 3.6 x TD 4.6 X CC 3.3 cm) in the superior --
medial region of right orbit with extension into right frontal sinus and
right ethmoid sinus. The superior rectus muscle was involved, and the
apex was free of tumor. There was significant proptosis due to mass
effect.

His case discussed in a multidisciplinary team (MDT) at Bangladesh
Specialized Hospital Limited owing to rarity of diagnosis and it was
decided to offer him concurrent chemo irradiation with Cisplatin in view
of organ preservation aspect. Radiotherapy was delivered at Delta
Medical College Hospital, Dhaka, Bangladesh by Rapid arc technique with
Varian True beam machine (Version 2.7) with dose of 56 Gy {[}Fig: 1g{]}
was delivered in 28 fractions that is 200 cGy per fraction along with 6
doses of concurrent cisplatin (30mg/m2) with dose of 40mg weekly
schedule. He required adaptive re-planning as he had shrinkage in his
orbital swelling while on treatment. His concurrent Chemo Radiotherapy
(CCRT) was completed in October 2020. We have observed the Dose Volume
Histogram (DVH) and the Max Dose (cGy) in PTV-56 6049.1 and other organ
at risk (OAR) like Brain Steam 2174.7, Cochlea Left 141.4, Cochlea Right
639.5, Eye Left 889.1, Eye Right 5983.7, Lens Left 252.1, Lens Right
5346.1 Left, Optic Chaism 3688.1, Optic Nerve Right 5976.2, Optic Nerve
Left 2203.5 \& Pituitary 2992.4.

He developed an exophytic growth in the lateral aspect of right orbit,
three months' post completion of CCRT and a repeat PET CT {[}Fig: 1e{]}
showed a 19 x 13 mm hypermetabolic (SUV max 11.25) lesion in the right
anterior lateral angle of the orbit. The frontal sinus, superio-medial
aspect of right orbit, ethmoid sinus showed no uptake confirming the
good response to CCRT. There was persistence of hypermetabolic lesion in
the right lobe of thyroid (SUVmax 13.12). His case was re-discussed in
MDT, and he underwent excision of the new lesion in the right orbital
region along with reconstruction, Right eye tarsorrhaphy and Total
thyroidectomy in Jan 2021 at Square Hospitals Limited. The HPE showed
invasive squamous cell carcinoma of the right orbit with deep margin
involvement. The bone was involved by tumor and the tissue from the
frontal sinus was uninvolved. The total thyroidectomy specimen was
consistent with papillary carcinoma of thyroid of the right lobe {[}Fig:
2f{]} (Size 2cm, margins clear, 1 LN with tumor, LVSI present --
pT1N1aMx).

At his last follow in June 2023 up his vision is near normal in left eye
and poor vision in Right (Finger counts), proptosis had resolved, and
his last 3 consecutive PET CT {[}Fig: 1f{]} \& MRI (last on December
2023) did not show any residual or recurrent disease {[}Fig: 1h{]}.

\textbf{Discussion:}

Squamous cell carcinoma of the orbit is an extremely rare disease and
till date 11 cases have been reported so far. Our case is the
12\textsuperscript{th} case and first case in a patient with carney's
syndrome (Table 1). However, it is progressive and life-threatening. Mr.
Kaiser, our patient, male, 62 years old, a case of carcinoma of right
orbit with bone erosion and frontal and ethmoidal sinus involvement. The
patient visited with burning sensation, itching and watering from both
eyes. On examination, we found a painful swelling in lateral side of
right eyebrow and protrusion of the same eyeball. A case report in 2012
by Peckinpaugh JL. et al. mentioned a patient, male, 63 years old,
visited with the symptoms of diplopia, ophthalmoplegia, eye pain and
forehead numbness {[}5{]}. In our case, the soft tissue mass measured
3.2 cm in the superior-medial aspect of the right orbit, lesion was
extraconal abutting superior rectus muscle and compressing right globe
which abuts the sclera. A similar case report in 2017 by Campos Arbulu
et al. where the patient was 73 years old, and the lesion was around 3.5
cm, located in superior orbit abutting the frontal sinus {[}6{]}.
Another report in 2012 by Peckinpaugh JL et al. had a female patient, 43
years old, whose lesion's size was not reported, but located in the
orbital apex {[}5{]}.

Diagnosis was based on clinical examination as well as modalities like
CT-Scan, PET CT-Scan, excision biopsy, etc. Another case report in 2011
by Saha et al. detected the disease based on MRI of brain, orbit, sinus
(initially negative) repeats MRI brain, orbit 1 year later, excisional
biopsy via trans frontal craniotomy, and systemic evaluation by clinical
oncologist {[}7{]}.

The challenge in management of SCC of orbit includes inoperability or
complete excision. In our case bone erosion was present and radiotherapy
dose escalation up to 60-66Gy {[}8{]} despite needs of SCC due to
constrains is also challenging, but we are able to deliver only 56Gy in
our case. Appropriate guidelines of concurrent chemo are not established
and no evidence of neoadjuvant treatment reported.

Treatment for papillary cancer and follow-up is also difficult.
Treatment modalities included excision of right atrial myxoma, excision
biopsy, concurrent chemo radiotherapy followed by plastic surgical
reconstruction due to recurrence and total thyroidectomy for synchronous
papillary thyroid cancer. Another case report by Blandford et al., in
2018, male patient, 63 years of age, was treated with right orbitotomy
with excisional biopsy, orbital chemoirradiation {[}9{]}. In this case
for recurrence surgery was challenging in view of local failure and
organ preservation, so plastic and reconstructive surgeons who able to
do a prefect surgery for the residual disease in combination with ENT \&
head neck surgeons of the Thyroid. Post excision biopsy showed of bone
invasion and deep margin involvement and adjuvant further treatment
option also again challenging despite of ypT4 disease with high garde-3.
Short duration of radiotherapy interval \& re-radiation with
conventional proton was also an option but MDT decided for observation
rather further adjuvant treatment.

Carneys complex is a rare genetic disorder associated with MEN syndromes
and it affects multiple glands in the body such as thyroid, pituitary
and adrenal glands. It also causes cardiac myxomas. {[}10{]}. Another
important learning point in this case was that the patient had atrial
myxoma, orbital SCC and papillary carcinoma of the thyroid almost at the
same time. He had fulfilled two of the major criteria required for the
diagnosis of carneys complex {[}11{]}. Carney's complex predisposition
to developing multiple neoplasms, necessitating regular follow-up and
early screening for new tumors.

As per our knowledge, this case is the first which reports the
development of orbital squamous cell carcinoma in a patient with carneys
complex. The implication of knowing about the carneys complex is that
this patient is predisposed to development of multiple neoplasms in
future, and he needs to be followed up regularly and screened for early
identification of new tumors. Mutations in the protein kinase A type I
alpha regulatory subunit (PRKAR1A) needs to be identified in patient and
his potentially affected at risk family members {[}12{]}. This patient
has not been tested for any mutations as we do not have the facility to
the same in our country. Malignant large cell calcifying Sertoli cell
tumors, pituitary adenomas and melanotic schwannomas commonly occur in
those with carneys complex and this needs to be kept in mind while on
follow up.

\textbf{Conclusion:}

There is no specific conventional treatment plan for primary SCC of the
orbit, which is relatively uncommon. From primary orbital radiation and
observation to orbital exenteration with adjuvant chemotherapy and
orbital radiation, we have studied a variety of research. In addition to
surgical excision and chemotherapy, we used a multimodal approach to
treat our patient that improve the survival status.

We hope that this instance draws attention to this incredibly rare
disease, provides a glimmer of hope for those suffering from an
otherwise fatal and progressing condition, and aids in the prevention of
recurrence. Further research and awareness of this condition are crucial
for improving patient outcomes and developing effective
treatment~strategies.

\textbf{References:}

1. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Survey of
ophthalmology. 1995 May 1;39(6):429-50.

2. Cook Jr BE, Bartley GB. Epidemiologic characteristics and clinical
course of patients with malignant eyelid tumors in an incidence cohort
in Olmsted County, Minnesota. Ophthalmology. 1999 Apr 1;106(4):746-50.

3. Reifler DM, Hornblass A. Squamous cell carcinoma of the eyelid.
Survey of ophthalmology. 1986 May 1;30(6):349-65.

4. El Samkary M, Eliwa T, El Sherif R (2021) Primary Squamous Cell
Carcinoma, Orbital Site: A Case Study and Systematic Review. J Clin Exp,
Ophthalmol. 12:905

5. Peckinpaugh JL, Winn BJ, Barrett RV, Jacobsen DW, Sires BS, Meyer DR,
Jian-Amadi A. Isolated squamous cell carcinoma of the orbital apex.
Ophthalmic Plastic \& Reconstructive Surgery. 2012 May 1;28(3):e72-4.

6. AL CA, Sadava EE, JM FV, Dillon HS, Mezzadri NA. Primary orbital
squamous cell carcinoma. Medicina. 2017 Jan 1;77(1):37-9.

7. Saha K, Bonshek R, Leatherbarrow B. Primary orbital squamous cell
carcinoma. Clinical \& experimental ophthalmology. 2011 Aug;39(6):582-4.

8. Muto P, Pastore F. Radiotherapy in the Adjuvant and Advanced Setting
of CSCC. Dermatol Pract Concept. 2021 Oct 1;11(Suppl 2):e2021168S. doi:
10.5826/dpc.11S2a168S. PMID: 34877076; PMCID: PMC8609952.

9. Blandford AD, Bellerive C, Tom M, Koyfman S, Adelstein DJ, Plesec TP,
Perry JD, Singh AD. Case report: primary orbital squamous cell
carcinoma. Ocular Oncology and Pathology. 2019;5(1):60-5.

10. Vindhyal MR, Elshimy G, Elhomsy G. Carney Complex. {[}Updated 2022
Jul 12{]}. In: StatPearls {[}Internet{]}. Treasure Island (FL):
StatPearls Publishing; 2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK507877/

11. Hampel, H., Bennett, R.L., Buchanan, A., Pearlman, R. and Wiesner,
G.L., 2015. A practice guideline from the American College of Medical
Genetics and Genomics and the National Society of Genetic Counselors:
referral indications for cancer predisposition assessment. Genetics in
Medicine, 17(1), pp.70-87.

12. Espiard S, Bertherat J. PPNAD, Carney Complex, and Other
Micronodular Adrenal Hyperplasia. (2019): 271-282.

13. Campos Arbulu AL, Sadava EE, Sanchez Ruiz A, et al: Primary orbital
squamous cell carcinoma. Medicina (B Aires) 2017; 77: 37--39.

14. Choi DY, Lee JH, Ahn JH, et al: Primary squamous cell carcinoma of
the orbit. J Korean Ophthalmol Soc 2014; 55: 1224--1228.

15. Hromas AR, Sokol JA: Re: ``isolated squamous cell carcinoma of the
orbital apex''. Ophthal Plast Reconstr Surg 2014; 30: 442--443.

16. Ruff T, Lenis A, Diaz JA: Atypical facial pain and orbital cancer.
Arch Otolaryngol 1985; 111: 338--339.

Table 1: Literature Data Collection And Case study {[}4, 5, 7, 9,
13-16{]}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
& \textbf{Author} & \textbf{Year} & \textbf{Age} & \textbf{Sex} &
\textbf{Side} & \textbf{Site of lesion} & \textbf{Surgery} & \textbf{RT}
& \textbf{Chemo} & \textbf{CCRT}\tabularnewline
\midrule
\endhead
{[}16{]} & Ruff et al & 1985 & 53 & F & Left & Inferotemporal~orbit &
Yes & Yes & No & No\tabularnewline
{[}7{]} & Saha et al & 2011 & 56 & F & Right & Orbital apex & No & Yes &
No & No\tabularnewline
{[}5{]} & Peckinpaugh~et al & 2012 & 43 & F & Right & Orbital apex & No
& Yes & Yes & No\tabularnewline
& & & 63 & M & Left & & & & &\tabularnewline
& & & 67 & M & Right & & & & &\tabularnewline
{[}15{]} & Hromas and~Sokol & 2014 & 43 & M & Left & Inferior~interconal
space & Yes & Yes & No & No\tabularnewline
{[}14{]} & Choi et al & 2014 & 74 & F & Left & Superomedial~orbit & Yes
& Yes & No & No\tabularnewline
{[}13{]} & Arbulu et al & 2017 & 73 & F & Right & Superior~orbit & Yes &
Yes & No & No\tabularnewline
{[}9{]} & Blandford et~al & 2018 & 63 & M & Right & Superomedial~orbit &
Yes & Yes & Yes & No\tabularnewline
{[}4{]} & El Samkary~et al & 2021 & 99 & F & Left & Superolateral~orbit
& Yes & No & No & No\tabularnewline
New & Rahman et al (Our case) ** & 2022 & 62 & M & Right & Superolateral
orbit & Yes & Yes & No & Yes\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2

** - Ours is the first case of orbital tumor in a patient with carneys
syndrome.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figuer-1/Figuer-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figuer-2/Figuer-2}

\end{center}
\end{figure}

\selectlanguage{english}
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