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\begin{document}

\title{Metastatic signet-ring cell carcinoma of the testis: an unusual
presentation A case report in Syria}



\author[1]{Mohammed Mayo}%
\author[1]{Zain Alsayed Ahmad}%
\author[1]{Hassan Alshaker}%
\author[1]{Leen Jarjanazi}%
\author[1]{Rima Sanaa}%
\author[1]{Yara Bilal}%
\author[1]{Anwar Chammout}%
\affil[1]{University of Aleppo Faculty of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\textbf{Introduction}

Metastasis in the testes is a relatively rare occurrence, accounting for
only 0.02\% to 2.5\% of all testicular tumors and is more common in
older individuals. Identifying the primary site of tumors that resemble
those found in both the gastrointestinal tract (GIT) and testis can be
challenging. This is where immunohistochemistry plays a crucial role in
making an accurate diagnosis, leading to proper treatment.{[}1{]}

While primary malignancies in the small intestine are uncommon,
accounting for only about 2.3\% of all malignancies in the digestive
system and 0.42\% of all malignancies, it is essential to recognize the
rare subtypes, such as signet-ring cell carcinoma (SRCC). SRCC is
typically found in the stomach, but it can also occur in other organs
such as the pancreas, breasts, bladder, ovaries, esophagus, lungs, and
large intestine.{[}2{]}

This report highlights an unusual case of a 44-year-old male patient
with signet-ring cell mucinous adenocarcinoma metastasis of unknown
source in the right testis, possibly originating from the small
intestine.

\textbf{case presentation} :

A 44-year-old male presented with right testicular swelling, heaviness,
and weight loss for the past 3 months. He is a heavy smoker and
non-alcoholic with no past medical, surgical, or family history. The
physical examination was normal except for the painful testicular mass.
Echography of the testis showed a solid mass measuring 10.5x8x6 cm in
the right testicle with irregular borders and increased vascularity. A
Computerized Tomography (CT) scan with contrast showed multiple
metastases within the chest lymph nodes, ribs, liver, pancreas, adrenal
glands, periaortic lymph nodes, axillary lymph nodes, and groin lymph
nodes. Bone scintigraphy demonstrated abnormal accumulation of the
radiotracer in the 2\textsuperscript{nd} and 7\textsuperscript{th} ribs,
the head of the left humerus, and throughout the right femur. The
previous tests assumed a primary testicular cancer with metastasis,
although alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human
chorionic gonadotropin (HCG) were normal. The team excised the right
painful testicle and sent it for pathological studies.

Surprisingly, the pathology report of the right testicle came with a
final diagnosis of testicular signet-ring cell carcinoma metastasis
(Figure 1) with positive CK7, CK20, and CDX2 immunostains (Figure 2),
which suggests a primary origin from either the stomach or small
intestine. The upper and lower endoscopies with biopsies from the
stomach and colons were normal. In line with the pathology report, the
team suspected that the tumor was most likely from the small intestine.
However, we could not confirm our suspicion due to the lack of equipment
that can visualize the small intestine. Therefore, the primary origin of
the tumor remains unknown.

SRCC is a rare and aggressive type of cancer that can explain the
presence of multiple metastatic lesions in this patient. So, no further
evaluation was performed to look for other metastatic sites due to the
critical condition of the patient at the time of presentation. And the
team suggested FOLFOX chemotherapy treatment protocol, after ruling out
the gastric origin and suspecting intestinal origin. Follow up is not
yet reported.

Figure 1: Proliferation of signet ring cells with the displacement of
the nucleus to the side by intracellular mucin. With accumulation of
extracellular mucin.

Figure 2 A, B: CK20 Positive immunostain. C, D: CK7 Positive
immunostain. E, F: CDX20 Positive Immunostain

\textbf{Discussion}

Metastasis of gastrointestinal tumors to the testes is a rare
occurrence, and the identification of the primary site can pose a
significant challenge in diagnosis and treatment planning {[}3{]}. This
is a rare case of a 44-year-old male with signet-ring cell mucinous
adenocarcinoma metastasis in the right testis, possibly originating from
the small intestine. Notably, the metastasis in the testis was the only
clinical manifestation observed, making this presentation uncommon.

Tumors can spread to the testis through various pathways, including
hematogenous dissemination, retrograde migration through the lymphatic
system, retrograde extension along the spermatic cord, and seeding of
peritoneal surfaces, including the tunica vaginalis. {[}1{]}
Subsequently, Tumor cells may migrate through the abdominal ring and
over the open Haller's habenula to reach the testis, mimicking the
pattern of migration seen in Krukenberg tumor in women. {[}1{]}

Nonetheless, the incidence of secondary metastasis to the testis is
relatively low, which may be attributed to its unique anatomical
features. The testes are situated in the scrotum, supported by scrotal
tissue and spermatic cords. The serosal tunica vaginalis invaginates the
testes, becoming separated from the processus vaginalis and peritoneal
cavity just before birth. {[}1{]} Additionally, the relatively low
temperature of the scrotum creates an unfavorable environment for
metastatic tumor cells to survive, which explains the rarity of
testicular metastases. {[}1{]}

Signet-ring cell carcinoma (SRCC) is a rare subtype of adenocarcinoma
characterized by the presence of cells with abundant intracytoplasmic
mucin, displacing the nuclei to the periphery. Although SRCC is more
commonly associated with gastric cancer, it has been reported in other
organs, including the small intestine. The prognosis for patients with
SRCC in the small intestines is generally poor, with a five-year
survival rate of 16.1\%. {[}4{]} Early detection and appropriate
treatment are essential in improving patient outcomes.

The patient's history of heavy smoking may have contributed to the
development of the metastasis. The lack of significant past medical,
surgical, or family history suggests that the patient was not at high
risk for testicular cancer or metastatic disease. However, the patient's
smoking history may have increased the risk of developing cancer and
contributed to the development of this metastatic disease.{[}5{]}

Based on the physical findings of a painless, firm, and irregular mass
arising from the testicle, a testicular tumor was suspected, and a
radical orchiectomy of the right testes was deemed necessary for
effective management of the patient's condition. {[}6{]} Despite the
normal levels of AFP, LDH, and HCG, the possibility of a stromal tumor
could not be ruled out. The procedure made the pathological diagnosis
and staging possible, thereby aiding in the determination of the
appropriate course of action.

While the imaging findings initially provided evidence of a primary
testicular cancer with metastasis. The ultimate identification of the
primary site of origin was achieved through the use of
immunohistochemical markers. Specifically, positive staining for CK7,
CK20, and CDX2 strongly suggested a gastrointestinal origin, with the
stomach or small intestine being the most likely source. {[}7{]} This
highlights the critical role that immunohistochemistry plays in
determining the primary site of origin in metastatic tumors, especially
in cases where imaging studies are inconclusive. Furthermore, upper and
lower endoscopies with biopsies from the stomach and colon were
performed to identify the primary site, but no abnormalities were
detected. The lack of equipment to visualize the small intestine limited
the ability to confirm the suspicion of the small intestine as the
primary site.

Once gastric SRCC was ruled out and an intestinal primary carcinoma is
suspected, FOLFOX might be a proper treatment option. As it is used for
surgically unresectable metastatic colorectal cancers and has shown
activity in small intestinal adenocarcinomas. {[}8{]}

Unfortunately, the rarity of SRCC of the small intestine, and the lack
of clinical trials made it difficult to evaluate the effectiveness of
the chosen therapy, further emphasizing the uncertainty surrounding the
optimal treatment for this type of cancer.

\textbf{Conclusion}

This case report highlights the importance of immunohistochemistry in
identifying the primary site of origin in metastatic tumors,
particularly in rare presentations such as signet-ring cell carcinoma
metastasis to the testis. Further research and clinical trials are
needed to establish the optimal treatment strategies for SRCC of the
small intestine and to improve the prognosis for patients with this rare
malignancy. Finally, lifestyle modifications should be considered to
reduce the risk of developing cancer and other diseases.

\textbf{Acknowledgments:}

We would like to thank Wafik Mayo, for providing valuable mentoring
assistance during the preparation of this case report and would like to
acknowledge the use of ChatGPT, for its assistance in enhancing the
language.

\textbf{Conflict of interest:}

The authors want to declare that none of them is or was employed by any
government agency that has any function other than research and
education, and none of them is submitting this manuscript as an official
representative or on behalf of the government.

\textbf{Ethical approval:}

Not applicable

\textbf{CONSENT}

Written informed consent was obtained from the patient for publication
of this case report and accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal
on request.

\textbf{FUNDING INFORMATION}

The authors declare no source of funding for this manuscript from any
organization or any institution.

\textbf{Author contributions:}

-Anwar chamout supervised and helped in writing the manuscript.

Zein A Alsayed Ahmad, Mohammed Mayo, Hassan Alshaker and Leen Jarjanazi
wrote the manuscript. Zein A Alsayed Ahmad critically revised the
manuscript.

Anwar Chammout, Zeina Zakkour and Rima Sanaa diagnosed and treated the
case.

Yara Bilal performed histopathology tests for the case.

All authors read and approved the final manuscript.

\textbf{References:}

\textbf{1. Nakra T, Sharma A, Sharma A, Kakkar A. An unusual testicular
mass in a young male: Metastasis from occult gastric carcinoma. Indian J
Pathol Microbiol. 2022;65:440--3. Doi:10.4103/IJPM.IJPM\_976\_20.}

\textbf{2. Martins T, Umar J, Groudan K, Bharadwaj HS, Desilets D.
Mucinous Signet-Cell Adenocarcinoma of the Ileum: A Diagnostic
Challenge-Case Report and Review of the Literature. Case Rep
Gastrointest Med. 2022;2022:1--4. Doi:10.1155/2022/5703407.}

\textbf{3. Ulbright TM, Young RH. Metastatic carcinoma to the testis: a
clinicopathologic analysis of 26 nonincidental cases with emphasis on
deceptive features. Am J Surg Pathol. 2008;32:1683--93.
Doi:10.1097/PAS.0B013E3181788516.}

\textbf{4. Wu SG, Chen XT, Zhang WW, Sun JY, Li FY, He ZY, et al.
Survival in signet ring cell carcinoma varies based on primary tumor
location: a Surveillance, Epidemiology, and End Results database
analysis. Expert Rev Gastroenterol Hepatol. 2018;12:209--14.
Doi:10.1080/17474124.2018.1416291.}

\textbf{5. Testicular Cancer Risk Factors \textbar{} Risks For
Testicular Cancer.
https://www.cancer.org/cancer/types/testicular-cancer/causes-risks-prevention/risk-factors.html.
Accessed 11 Jun 2023.}

\textbf{6. Medscape. (2021, August 11). Tonsillectomy. Medscape.}

\textbf{https://emedicine.medscape.com/article/449033-overview}

\textbf{7 Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly
sensitive and specific marker of adenocarcinomas of intestinal origin:
an immunohistochemical survey of 476 primary and metastatic carcinomas.
Am J Surg Pathol. 2003;27:303--10.
Doi:10.1097/00000478-200303000-00003.}

\textbf{8. Xiang XJ, Liu YW, Zhang L, Qiu F, Yu F, Zhan ZY, et al. A
phase II study of modified FOLFOX as first-line chemotherapy in advanced
small bowel adenocarcinoma. Anticancer Drugs. 2012;23:561--6.
Doi:10.1097/CAD.0B013E328350DD0D.}\selectlanguage{english}
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