Squamous cell carcinoma of unknown primary in the pelvis after complete remission following chemoradiotherapy: A case report

Abstract

BACKGROUND

Pelvic squamous cell carcinoma of unknown primary (CUP) is extremely rare, accounting for less than one percent of all CUP cases, and its infrequency has limited the development of standardized diagnostic and treatment guidelines.

CASE SUMMARY

A 77-year-old female with a history of resected lung adenocarcinoma presented with worsening constipation. Imaging revealed a 2.5 cm mass adjacent to the right levator ani muscle. Biopsy confirmed poorly differentiated squamous cell carcinoma, positive for pancytokeratin and p40, and negative for p16, cytokeratin 7, cytokeratin 20, and neuroendocrine markers. No primary lesion was identified despite extensive evaluation. She underwent five cycles of 5-fluorouracil (1000 mg/m² continuous infusion, days 1-4) and mitomycin-C (10 mg/m² on day 1) with concurrent pelvic radiotherapy (50.4 Gy in 28 fractions). Follow-up imaging demonstrated complete remission sustained for 12 months. Electrocorticography performance status improved from 2 at diagnosis to 1 during follow-up.

CONCLUSION

This case highlights the potential role of chemoradiotherapy in managing pelvic squamous cell CUP, achieving durable remission in selected patients.

Key Words: Squamous cell carcinoma; Cancer of unknown primary; Pelvic malignancy; Chemoradiotherapy; Human papillomavirus negative; p40 positive; Pelvic floor tumor; Case report

Core Tip: This case report describes an elderly woman with pelvic squamous cell carcinoma of unknown primary (CUP), an entity accounting for less than 1% of CUP cases. A comprehensive diagnostic workup ruled out common primaries, and multidisciplinary evaluation led to chemoradiotherapy with 5-fluorouracil and mitomycin-C plus radiotherapy. The patient achieved complete remission for 12 months with improved functional status. This report emphasizes the value of imaging, pathology, and individualized multidisciplinary management in achieving durable remission in rare pelvic squamous CUP.

INTRODUCTION

Carcinoma of unknown primary (CUP) refers to metastatic malignancy without an identifiable primary despite extensive evaluation[1]. CUP constitutes about 2% of all cancers, with squamous histology representing fewer than 5%[1,2]. Within this group, pelvic CUP is exceedingly rare, accounting for less than 1% of cases[3,4]. The rarity is highlighted by population-based studies that estimate incidence rates at fewer than 1 case per million annually. Epidemiologic reviews also note that women are slightly more predisposed, often presenting in the sixth to eighth decade of life[5]. Pathogenesis may involve both human papillomavirus (HPV)-driven and non-HPV molecular pathways. HPV-associated cases are typically linked to oncogenic subtypes leading to p53 and retinoblastoma protein inactivation, whereas non-HPV-driven pathways may involve mutations in tumor protein 53, Kirsten rat sarcoma viral oncogene homolog, or alterations in epidermal growth factor receptor signaling[6,7]. These mechanisms complicate both diagnosis and management. Despite advances in imaging and immunohistochemistry, CUP remains challenging due to its heterogeneity and lack of standardized guidelines. Multidisciplinary evaluation and individualized therapy remain the cornerstones of care. This report presents a rare case of pelvic squamous CUP with complete remission following chemoradiotherapy.

CASE PRESENTATION

Chief complaints

A 77-year-old woman presented with gradually worsening constipation over six months.

History of present illness

The constipation was not accompanied by rectal bleeding, prolapse, or other pelvic symptoms. Symptoms progressively worsened, prompting further evaluation.

History of past illness

The patient had no significant medical history other than a previously resected and curatively treated lung cancer. She had no known history of HPV or Epstein-Barr virus infections.

Personal and family history

No relevant personal or family medical history was reported.

Physical examination

General physical examination, including perineal and abdominal assessment, was unremarkable. Digital rectal examination during colonoscopy identified a firm, lobulated mass in the right perirectal area with mobile overlying mucosa showing no obvious abnormalities.

Laboratory examinations

Complete blood count, basic metabolic panel, and comprehensive metabolic profile were within normal limits.

Imaging examinations

Colonoscopy revealed a tubular adenoma in the transverse colon. Computed tomography (CT) and magnetic resonance imaging demonstrated a 2.5 cm × 2.4 cm × 2.5 cm mass adjacent to the right levator ani muscle and vaginal cuff (Figure 1A). A whole-body positron emission tomography/CT scan revealed a solitary fluorodeoxyglucose-avid lesion confined to the right pelvic region, near the rectum and vagina (Figure 1B). Histopathology and immunohistochemistry: CT-guided biopsy confirmed poorly differentiated squamous cell carcinoma. Immunohistochemistry was positive for pancytokeratin and p40, and negative for p16, cytokeratin 7 and 20, GATA binding protein 3, and neuroendocrine markers (synaptophysin) (Figure 1C and D). These findings were inconsistent with the previously resected lung carcinoma.

Figure 1 Images. A: Axial T1-weighted magnetic resonance imaging showing a right-sided perirectal mass adjacent to the levator ani muscle shown by arrow; B: Fluorodeoxyglucose-positron emission tomography/computed tomography demonstrating a solitary hypermetabolic lesion in the pelvis shown by arrow, without evidence of distant disease; C: Hematoxylin and eosin-stained section showing poorly differentiated squamous cell carcinoma under 40 × magnification; D: Immunohistochemical staining positive for p40, consistent with squamous cell origin.

MULTIDISCIPLINARY EXPERT CONSULTATION

The case was reviewed in a multidisciplinary tumor board involving radiation oncology, medical oncology, and radiology, and a consensus decision for chemoradiotherapy was made.

FINAL DIAGNOSIS

Pelvic squamous cell CUP.

TREATMENT

The patient was treated with five cycles of 5-fluorouracil and mitomycin-C combined with concurrent pelvic radiotherapy.

OUTCOME AND FOLLOW-UP

The patient tolerated the regimen well. Follow-up imaging at 6 months and 1 year confirmed complete resolution of the lesion without recurrence. The patient maintained good functional status throughout follow-up.

DISCUSSION

CUP of the pelvis implies the presence of cancer in the pelvis; however, the primary site of origin of the cancer is not known, and it is present in rare instances[1,6]. CUP origin, particularly squamous cell carcinoma, is typically found in the head and neck region or the inguinal region, although it can occasionally occur in the pelvis[6,8]. This type of cancer can have various cellular origins, including adenocarcinoma, squamous cell carcinoma, neuroendocrine tumors, lymphoma, melanoma, germ cell tumors, and more[1,6,8,9]. A biopsy and pathological evaluation usually gives an idea about the nature of the tumor, prompting further evaluation and investigation to look for the primary. The architecture associated with the immunohistochemistry helps identify the nature of the tumor[1,10]. The patient described in this case report has squamous cell cancer. Squamous cell cancer of the pelvis and an unknown primary site is known to be associated with HPV infection[11]. A thorough evaluation to identify the primary site has to be done by clinical evaluation of the anal and genital regions[12]. There are no standardized guidelines for evaluating an unknown primary in the pelvis; however, most authors utilize a workup similar to that for evaluating CUP presenting in the inguinal lymph nodes[13-15].

Limited case reports that have been published for CUP of squamous cell origin in the pelvis are known to have a higher association with HPV infection. HPV virus infection is most likely of anal-genital origin[16]. p16 expression results from the activation of tumor genes such as p53 and retinoblastoma protein by HPV infection[17]. In this patient, there was no lesion or induration to suggest a lesion in the anal and genital region. However, other limited case reports that have represented similar findings have had HPV-positive lesions[15-17]. Ovarian tumors can also occasionally present with squamous cell features[18]; however, the location and normal ovaries on imaging ruled that out in the patient.

There is limited data regarding the management and therapies for cisplatin, nivolumab, surgery, or chemoradiotherapy. However, no standardized guidelines have been established, given the rarity of this presentation[19-21]. Surgical resection has been reported to play a role; however, location, age, and morbidity of the surgery can be limiting factors[22]. Since the patient responded well to chemoradiotherapy, surgery was not considered in subsequent follow-up. The limited case reports which have been presented show a positive response to radiotherapy, as in our case.

CONCLUSION

Squamous cell CUP in the pelvis is an exceedingly rare condition with limited literature and no established treatment guidelines. A thorough and systematic diagnostic evaluation is essential. Our case illustrates that chemoradiotherapy may offer an effective and non-invasive treatment option in appropriately selected patients.