
==== Front
Int J Surg Case Rep
Int J Surg Case Rep
International Journal of Surgery Case Reports
2210-2612
Elsevier

S2210-2612(24)00950-7
10.1016/j.ijscr.2024.110169
110169
Case Report
Poorly differentiated squamous cell carcinoma of unknown primary location a case report of perineal presentation
Houry Younes a1
Taghouan Anas anas.taghouan@gmail.com
a⁎1
Rais Hamza a
El Omri Ghassane a
Rachid Moussaab a
Jaouad Mohamed Reda Cherkaoui b
Heddat Abdeljalil a
a Department of Urology, Cheikh Khalifa International University Hospital, Mohammed VI University of Sciences and Health (UM6SS), Casablanca, Morocco
b Department of Radiology, Cheikh Khalifa International University Hospital, Mohammed VI, University of Sciences and Health (UM6SS), Casablanca, Morocco
⁎ Corresponding author. anas.taghouan@gmail.com
1 Both authors contributed equally and are considered co-first authors.

13 8 2024
9 2024
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© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction

Cancers of unknown primary origin (CUP) pose a significant clinical challenge, representing a small percentage (1 to 5 %) of overall cancer cases. The patient is a 31-year-old male who has been diagnosed with poorly differentiated infiltrating squamous cell carcinoma, which has been classified as CUP. The exceptional perineal presentation and diagnostic process serve as a reminder of the diverse nature of CUPs and the crucial role played by advanced imaging methods and a multidisciplinary approach. The inclusion of this case, the seventh one in the literature, deepens our understanding of CUPs.

Presentation of case

A 31-year-old man came in with a gradual onset of perineal pain that had been worsening for the past six months. A nodular lesion in the urogenital triangle, infiltrating the bulbo spongiosus muscle, was surgically removed. The histopathology results confirmed a poorly differentiated squamous cell carcinoma. Despite conducting extensive examinations, the multidisciplinary team was unable to determine the source of the tumour, classifying it as CUP. One year post-surgery, the patient remains in complete remission.

Discussion

The management of CUPs can be challenging because of the variety of their origins and presentations. The importance of advanced imaging, pathological and biological techniques, as well as meticulous surgical intervention, is emphasized in this case, as it helps in avoiding unnecessary adjuvant therapies.

Conclusion

This case highlights the significance of a customized and interdisciplinary approach in effectively managing CUPs, especially when they present in unusual ways. Timely surgical intervention, backed by comprehensive imaging and pathological analysis, can result in positive results.

Highlights

• Rare perineal presentation of CUP in a 31-year-old male with no significant history

• Successful surgical excision of poorly differentiated squamous cell carcinoma

• Complete resolution and remission of symptoms without adjuvant therapy

• Advanced imaging and a meticulous surgical approach facilitated an accurate diagnosis.

• Multidisciplinary strategy highlights tailored management for favorable outcomes.

Keywords

Male
Neoplasms, unknown primary/diagnosis*
Neoplasms, unknown primary/epidemiology*
Neoplasms, unknown primary/therapy*
Carcinoma, squamous cell*/surgery
Carcinoma, squamous cell*/pathology
Pelvic neoplasms*
Abbreviations

CUP cancers of unknown primary origin

18-FDG PET scan 18F-fluorodeoxyglucose positron emission tomography/computerised tomography

MRI magnetic resonance imaging

PSA prostate-specific antigen

TAP-CT computed tomography thorax-abdomen-pelvis,

SUV standardised uptake values

HPV human papillomavirus
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pmc1 Introduction

Cancers of unknown primary origin (CUP) represent a significant clinical challenge, accounting for approximately 1 % to 5 % of all cancer diagnoses [1]. The exceptional aspect of this case is the uncommon location and the patient's clinical characteristics [1,2], which contribute to our comprehension of CUP and its management. This contribution emphasizes the importance of tailoring diagnostic and therapeutic approaches to the intricate and varied nature of these uncommon cases. This case study presents a rare instance of poorly differentiated infiltrating squamous cell carcinoma in the perineum of a male patient, with the primary location being unknown. This is the seventh reported case in the literature and involves a 31-year-old patient with no significant medical history or apparent risk factors [3].

2 Presentation of case

We present, in accordance with the SCARE guidelines [4], a case of perineal poorly differentiated squamous cell carcinoma of unknown primary location.

A man, aged 31, came to the outpatient clinic complaining of increasing pain in the perineal region for the past six months. The symptoms began slowly, with the pain intensifying as time went on. The pain was characterized as a general discomfort, without spreading to other areas or being affected by any specific triggers.

There was no significant personal history for him, he did not smoke, and there was no family history of cancer. Throughout the clinical examination, the patient exhibited stable hemodynamics and respiration, had no fever, and was in a generally healthy state. He reported no dysuria or participation in risky sexual activities. The urological examination showed no abnormalities, with a normal spermatic cord and no detectable varicocele. The digital rectal examination was unremarkable; the patient reported no intestinal disturbances, no rectal bleeding, no tenesmus, no rectal syndrome, and no transit problems. The rest of the somatic examination showed no signs of tumour syndrome or lymphadenopathy, except for a slight subcutaneous induration of approximately 2 cm in the anterior urogenital triangle of the perineum, located in the median raphe. It corresponded to a hard, painless, fixed nodule with ill-defined borders (Fig. 1).Fig. 1 Slight subcutaneous induration in the anterior urogenital triangle of the perineum, located on the median raphe (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 1

Pelvic magnetic resonance imaging (MRI) revealed a T2 hyperintense nonspecific subcutaneous nodular lesion in the urogenital triangle, with well-defined borders and heterogeneous enhancement, measuring 22.5 × 21.8 × 20 mm in size, infiltrating the bulbo spongiosus muscle in places. The anal canal appeared normal and unaffected (Fig. 2).Fig. 2 Postcontrast pelvic magnetic resonance imaging in axial section demonstrating a non-specific subcutaneous nodular lesion in the urogenital triangle of the perineum with intense and heterogeneous enhancement, infiltrating the bulbo spongiosus muscle in places (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

The complete blood count and urine cytobacteriological examination were normal. Prostate-specific antigen (PSA) levels were normal and the prostate had a normal consistency. Cystoscopy revealed a normal urethra and endoluminal bladder wall.

Due to the proximity of the lesion to the anal canal, he was referred for a gastroenterological consultation. A combination of clinical history, digital rectal examination, and anoscopy revealed no abnormalities.

There was an indication for the surgical removal of the tumour. Preintervention considerations included thorough patient optimisation. The patient was evaluated for any comorbidities and measures were taken to manage any existing conditions. Before surgery, prophylactic antibiotics and analgesia were administered to the patient. Antiemetics were given to manage nausea.

A surgical intervention was planned that used a superior perineal approach in relation to the location of the nodular lesion. The procedural steps included identifying the skin and subcutaneous tissue, followed by the location of the tumour after the incision of the perineal membrane (Fig. 3-a). The lesion of approximately 2 cm was then isolated from the bulbo spongiosus muscle (Fig. 3-b), facilitating its complete excision with macroscopically healthy margins (Fig. 3c-d).Fig. 3 Procedural steps for complete tumour excision.

a: Localization of the tumour following the incision of the perineal membrane.

b: Identification of the tumour after cutting through the perineal membrane.

c: Complete removal of the tumour using a curved bipolar clamp.

d: Clean resection bed with macroscopically healthy margins.

Fig. 3

The patient was placed under general anaesthesia with endotracheal intubation. The patient was positioned in a lithotomy position to provide optimal access to the perineal region. The surgical field was prepared using a povidone‑iodine solution. The incision was made using a scalpel and the perineal membrane was carefully dissected to expose the underlying tumour.

Sutures used for the procedure included 3-0 Vicryl for subcutaneous closure and 4-0 Monocryl for skin closure. The excision was performed using standard surgical instruments and the tumour was removed with a safety margin of healthy tissue. The use of a superior perineal approach allowed minimal invasiveness and optimal visualization of the lesion.

The surgical team was led by a senior urologist with extensive experience in perineal surgeries. The team also included a resident surgeon and a surgical nurse.

Post-intervention considerations included monitoring the patient in the recovery room for any immediate complications. The patient was instructed about postoperative care, including wound care, pain management, and activity restrictions. The patient was advised to avoid heavy lifting and strenuous activities for at least two weeks. Follow-up appointments were scheduled to monitor the healing process and ensure that there was no recurrence of the tumour.

Any changes in the intervention, such as the decision to use a superior perineal approach and specific types of sutures, were made based on intraoperative findings and the need for optimal results. Intraoperative photographs were taken to document the procedure and ensure thorough removal of the tumour. The excised tissue was sent for histopathological examination to confirm the diagnosis and assess the margins.

The postoperative course was uneventful. Pathological examination of the surgical specimen revealed a poorly differentiated squamous cell carcinoma. Microscopically, the tumour exhibited sheets and nests of atypical squamous cells with abundant eosinophilic cytoplasm and large hyperchromatic nuclei. There were frequent mitotic figures and necrosis areas. The tumour infiltrated the surrounding connective tissue and muscle fibres of the bulbo spongiosus muscle. Immunohistochemical staining was positive for cytokeratin AE1/AE3 and cytokeratin 5/6, confirming the squamous cell origin of the carcinoma. CK 7, CK 20, and desmin were notably negative. The Ki-67 proliferation index was approximately 60 %, indicating high proliferative activity. The tumour was classified as pT2, indicating invasion of the muscularis propria, and graded as G3, reflecting poor differentiation. No lymphovascular or perineural invasion was observed in the sections examined.

After a month of undergoing surgery, the patient exhibited complete disappearance of the initial painful symptoms. The interdisciplinary team decided to conduct an 18-FDG PET scan, a TAP-CT, and tumour marker research to exclude the presence of any additional cancerous sites.

The patient fasted for at least 8 h before intravenous administration of 170 MBq of 18F-FDG, 1 h before imaging. The blood sugar level was measured prior to injection of 18F-FDG and was 0.86 g/l. A non-enhanced low-dose CT scan was obtained for attenuation correction prior to the FDG PET/CT scan. The uptake of 18F-FDG uptake in the lesions was measured using standardised uptake values (SUV) calculated by generating a manual region of interest on the site of abnormally increased 18F-FDG activity. The intensity of uptake, defined by SUVmax, and the appearance of the uptake appearance (homogenous/diffusely nonhomogenous vs. nonhomogenous with a photopenic center), were evaluated. The patient's reference values were 1.50 for the mediastinal SUV and 3.44 for the liver SUV. 18F-FDG PET-CT revealed a well-defined hypermetabolic left internal iliac lymph node with SUV at 7.72 (Fig. 4). The TAP-CT scan showed no abnormalities.Fig. 4 PET-CT axial (A) and sagittal views of a well-defined hypermetabolic left internal iliac lymph node with SUV at 7.72 (blue arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Serum tumour markers: Comprehensive blood tests, including carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), carbohydrate antigen 19-9 (CA 19-9), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH), were all within normal ranges, suggesting no evidence of specific malignancies typically associated with elevated levels of these markers.

A laparoscopic lymph node dissection was performed under general anaesthesia with the patient in the supine position. The procedure involved standard laparoscopic instruments (Karl Storz, Germany) and absorbable Vicryl and Monocryl sutures. Prophylactic antibiotics and analgesics were administered. The surgery was performed by a senior surgeon with extensive experience in laparoscopic procedures, assisted by a team of residents and nurses. Intraoperative findings were documented and excised lymph nodes were sent for histopathological examination, which did not reveal neoplastic pathology. Post-operatively, the patient had an uncomplicated recovery, with instructions on wound care and activity restrictions. Follow-up appointments were scheduled and the patient was advised to avoid strenuous activities for two weeks.

The diagnostic process involved thorough clinical examinations, MRI, PET scan, histopathological analyses, and well-directed surgery. Despite these efforts, the primary tumour location could not be identified, leading the multidisciplinary team to classify the tumour as CUP.

The treatment strategy was determined on the basis of the stage and grade of the tumour. Classified as stage pT2N0M0, the tumour was locally advanced without regional lymph node involvement or distant metastasis. The grade was G3, indicating a poorly differentiated squamous cell carcinoma. Complete surgical resection with clear margins was successfully performed.

Although the poor differentiation and potential aggressiveness of the tumour could have justified adjuvant therapy, the multidisciplinary team opted against it. This decision was influenced by the patient's excellent response to surgery, complete resolution of symptoms, and the absence of detectable metastatic disease in follow-up imaging, including PET and CT scans. This case highlights the importance of a multidisciplinary and personalised approach in managing CUP.

The patient underwent routine quarterly follow-ups. One year after intervention, both the perineal clinical examination and the control abdominopelvic CT showed complete resolution of symptoms (Fig. 5) with no detectable abnormalities.Fig. 5 Follow-up abdominopelvic CT scan showing complete resolution without local recurrence.

Fig. 5

3 Discussion

CUPs are metastatic malignancies with no identifiable origin, despite thorough imaging and evaluation. Theories suggest that they are the result of tiny, undetectable primary lesions or represent unique metastatic entities without a primary tumour [5].

CUPs account for 1 % to 5 % of all malignancies, with a median age of diagnosis around 60 years and a higher prevalence in men [6]. Most CUP cases are carcinomas, subdivided into well or moderately differentiated adenocarcinomas (60 %), undifferentiated or poorly differentiated adenocarcinomas (30 %), squamous cell carcinomas (5 %) and undifferentiated neoplasms (5 %) [7]. Squamous cell carcinoma of unknown primary origin in the pelvic cavity is extremely rare [2].

A review by Hermans KEPE et al. highlighted the influence of lifestyle on CUP risk, identifying smoking as a significant risk factor, while only presenting limited suggestive evidence for alcohol consumption, diabetes mellitus, and family history of cancer [8]. This agrees with our patient, who did not present notable risk factors.

Symptoms of CUPs, such as weakness, enlargement of the lymph nodes without pain, and weight loss, are generally nonspecific [9]. Therefore, the remarkable preservation of the general health status of our patient is atypical.

The diagnosis of CUP should occur in specialised oncological centres by experienced multidisciplinary teams, including oncologists, radiologists, pathologists, geneticists, immunologists, and other medical specialists [9].

This goal is achieved through a combination of histopathological examinations confirmed by immunohistochemistry, along with electron microscopy, molecular diagnostics, and advanced imaging techniques such as CT, MRI, mammography, and FDG-PET [9]. Our patient underwent thorough tests, including PET scan, MRI, CT scan, histopathology, immunohistochemistry, and laparoscopic surgery, in our well-equipped hospital with experienced teams, meeting the requirements for the diagnosis of CUP.

The prognosis for patients with CUP is poor, with most surviving less than a year after diagnosis. Several poor prognostic factors include being male, having a performance status greater than 1, high comorbidity scores, being older than 64 years, a history of smoking for 10 pack years, and experiencing weight loss. Positive prognostic indicators include having isolated inguinal adenopathy (squamous carcinoma) or a single small, potentially resectable tumour [7]. Although male, our patient exhibited factors that favour a good prognosis.

Patients diagnosed with CUP typically receive empiric chemotherapy [9]. However, those with isolated inguinal lymph nodal metastatic squamous cell carcinoma or a single metastatic lesion are considered to have restricted disease. These patients undergo local dissection, with or without local radiation treatment, often achieving long, disease-free survival [7]. It is also interesting to note that in the only series of male patients with squamous pelvis carcinoma classified as CUP, 2 out of 6 had iliac lymph node metastases [4].

In our case, after a multidisciplinary consultation meeting, the patient chose not to undergo complementary treatment, avoiding the complications associated with radiation therapy and chemotherapy, particularly given his young age. The patient experienced complete resolution of initial symptoms and remained in complete remission one year after surgery. This underscores the importance of tailoring treatment strategies to individual cases.

A notable challenge emerges in a small subset of cases, particularly within poorly differentiated carcinomas and squamous cell carcinomas, where the diagnostic process is hampered by the absence of specific immunohistochemical markers [10]. New techniques to identify the primary of CUP offer hope; Genomic profiling, gene expression profiling, epigenetics, proteomics, liquid biopsy, and other methods require further studies to assess their clinical utility [11]. Regarding targeted therapies, although these treatments have not greatly improved overall survival rates, they could significantly help patients with responsive tumours [6].

Human papillomavirus (HPV) infection is closely related to squamous cell carcinomas of the oropharynx, cervix, and anus. The role of HPV/p16 in the carcinogenesis and prognosis of CUP is better established in the head and neck than in the pelvis [12]. Research shows that microsatellite analysis can sometimes detect a cell clone in the otherwise benign epithelium as the origin of metastases, even before histopathology reveals clear signs of dysplasia or malignancy [13]. Our patient did not undergo Gene Expression Profiling, including HPV test, due to its inaccessibility and the excellent results achieved only through surgery.

One weakness of our study is the limited scientific literature on the specific perineal location in males. This is only the seventh reported case [4]. The available series show an overall survival rate of 75 % with a median follow-up of 23 months [4]. Radical surgical treatment, followed by adjuvant chemotherapy in patients with a localized tumour and good baseline status, achieves higher survival rates than previously published data [4]. Our patient was significantly younger than the average age of 69 years in the series. The series also reports performing extensive and mutilating surgeries, such as pelvic exenteration and total penectomy, when feasible [4]. However, in our case, the localized nature of the pathology led to complete remission following a simpler surgical procedure.

4 Conclusion

Treatment of CUP cancers remains a significant challenge in the field of oncology. This case illustrates the diagnostic and therapeutic complexities associated with CUP, emphasising the importance of a multidisciplinary approach in the treatment of these patients. Despite the often bleak prognoses associated with CUP, precise identification of the histological type and the use of targeted surgical strategies can lead to favorable outcomes, as evidenced by the complete resolution of symptoms and the absence of recurrence one year after surgery in this case. This emphasizes the importance of ongoing research on CUP to enhance diagnostic and treatment choices. The development of gene expression profiling and targeted treatments presents a promising outlook for more precise diagnoses and successful therapies in the future, even though their impact on survival rates is still unknown.

Consent to participate

Written and informed consent taken.

Consent for publication

Written and informed consent were taken.

Code availability

Not applicable.

Ethical approval

Not applicable.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Author contribution

Houry Younes and Anas Taghouan: Conceptualization, Methodology, Investigation, Resources, Visualization, Writing - Original Draft, Writing - Review & Editing.

Hamza Rais: Investigation, Resources, Visualization.

Ghassane El Omri: Investigation.

Moussaab Rachid: Investigation.

Mohamed Reda Cherkaoui Jaouad: Conceptualization and Visualization.

Abdeljalil Heddat participated in Conceptualization, Supervision and Project administration.

All authors have approved the final version of the manuscript.

Guarantor

Anas Taghouan.

Research registration number

Our cases do not involve ‘First in Man’ studies and thus do not require registration in a registry. However, we acknowledge the importance of clinical trial registration for transparency and credibility in research. We are prepared to provide additional information if needed to ensure adherence to ethical and regulatory standards.

Conflict of interest statement

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Availability of data and materials

On request, email the corresponding author.
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