Aggressive Squamous Cell Carcinoma of Unknown Primary: Isolated Inguinal Metastasis and Uncommon Progression

Introduction

Carcinoma of unknown primary (CUP) is a rare malignancy, accounting for less than 5% of all cancers [1,2]. Recent studies indicate that the incidence of CUP has decreased to 1–2%, primarily due to advances in screening and molecular techniques [3]. Histologically, the most common subtype is well/ moderately differentiated adenocarcinoma (60%), while squamous cell carcinoma (SCC) is a less frequent subtype, comprising only 5% of CUP cases [4].

Inguinal lymph node (LN) metastasis as an initial and isolated presentation in CUP is rare, and SCC of unknown primary in isolated inguinal LNs is even more uncommon. A database review of 2232 inguinal LN metastasis cases identified only 22 (1%) classified as CUP, with only 6 of those confirmed as SCC [5]. In a larger study, Hemminki et al noted that out of 18 911 CUP cases, only 25 cases (0.1%) presented as SCC with inguinal LN metastasis [6]. This limited data highlights the unusual clinical course and diagnostic complexity of SCC manifesting solely as inguinal LN metastasis, challenging our understanding of CUP’s metastatic patterns and suggesting distinct biological behavior for single-site metastatic CUP cases.

Treatment approaches for single-site metastatic CUP have not significantly changed since the 1980s, and no standard treatment protocol exists [7]. This subset of CUP is often grouped within favorable prognostic categories and may be amenable to local ablative treatments, as per European Society for Medical Oncology (ESMO) guidelines [1]. Local interventions, such as surgery and/or radiotherapy (RT), can offer prospects for long-term remission or even cure [1,2,6,8–12]. Nevertheless, this favorable classification does not fully encompass the aggressive progression observed in some cases, which can result in unexpected metastatic patterns and treatment resistance.

This article presents a case of metastatic SCC in the isolated left inguinal LN without a detectable primary lesion. Despite following current guidelines for favorable CUP management, the patient exhibited aggressive disease progression, ultimately developing breast metastasis – a site not previously documented in the literature for this CUP subtype. This case is of critical importance in illuminating the gaps in the diagnostic and treatment approaches for SCC as a rare presentation of inguinal LN metastasis, understanding of CUP’s metastatic behavior and treatment response, and implications for future therapeutic strategies.

Case Report

A 65-year-old woman presented to the Department of General Surgery at Gaziantep City Hospital with a 2-month history of a mass in her left inguinal region. On examination, she appeared in good general health. Vital signs were within normal limits. The mass was immobile and non-tender. She had no significant medical or surgical history, and there was no family history of cancer. The patient reported no additional symptoms such as weight loss, cough, chest pain, skin lesions, abdominal or pelvic pain, or vaginal bleeding. There were no enlarged LNs in the cervical or supraclavicular areas. A detailed skin examination revealed no suspicious skin lesions. Gynecological, urologic examination, and colonoscopy/endoscopy were unremarkable. Tumor markers were within normal limits. PET-CT showed a hypermetabolic pathological LN measuring 20×14 mm in the left inguinal area, with no additional focal lesions detected (Figure 1). On August 24, 2023, a left inguinal LN dissection was performed.

The pathological examination revealed a LN measuring 2.7×1.8×1.5 cm with intact capsule integrity. For the initial differential diagnoses, the immunohistochemical (IHC) markers recommended by the ESMO guidelines were utilized [1]. The primary markers, CK7 and CK20, were negative, suggesting a differential diagnosis that included renal cell carcinoma, hepatocellular carcinoma, germ cell tumor, prostate cancer, gastric cancer, small cell lung carcinoma (SCLC), adrenal cortical carcinoma, neuroendocrine carcinoma, and SCC. The tumor cells were positive for CK(AE1/AE3), P40, CK5/6 (Figure 2), and p53.

These findings are consistent with a diagnosis of SCC, possibly from a primary SCC in the skin, vulva, vagina, cervix, anus, or distal urethra. P16 was negative, indicating that the tumor was unlikely to be associated with HPV (human papillomavirus) infection. Given the findings, the multidisciplinary tumor board initially recommended close surveillance.

Four months later, on December 26, 2023, the patient returned with a mass lesion in the left inguinal area. On examination, she appeared in good general health, with vital signs within normal limits. Additionally, she reported no other concerns. Re-evaluation did not reveal any additional focal lesions. Colonoscopy/endoscopy, skin examination, and urological and gynecological evaluations were normal. Smear results were negative, and tumor markers were within normal limits. PETCT revealed pathological conglomerated LNs in the left inguinal area, consistent with the initial diagnosis, and showed no additional lesions. Given the unresectable nature of the recurrent disease, the decision was made to proceed with definitive chemoradiotherapy (CRT) according to the multidisciplinary tumor board decision.

The CRT plan included a primary dose of 45 Gy to cover potential primary sites (vulva, vagina, cervix, distal urethra, and anal regions) and nodal areas (bilateral inguinal, obturator, internal and external iliac, and mesorectal regions) as part of the clinical target volume (CTV). This was followed by a boost dose of 59.4 Gy specifically targeting the left inguinal lymph nodes, marked as gross tumor volume (GTV), with a 1-cm margin for the planning target volume (PTV). The entire treatment was planned with 1.8 Gy per fraction. The RT plan is illustrated in Figure 3. Concurrent chemotherapy with cisplatin at 40 mg/m2 was administered for a total of 5 cycles. During CRT, the patient developed a perforation in the left inguinal lymph node, necessitating an adaptive treatment approach mid-course. This adaptation involved modifying the radiation plan to ensure accurate dose coverage despite the anatomical change in the affected area. To prevent infection in the left inguinal region, local antibiotic treatment was administered throughout CRT. Additionally, antibiotic therapy was initiated due to the development of cystitis in the fourth week of treatment. The other mild adverse effects observed during chemoradiotherapy such as nausea and diarrhea were effectively managed with supportive care, enabling the patient to continue with the treatment. CRT was administered from January 22, 2024, to March 11, 2024. The pre- and post-RT images of the left inguinal area are presented in Figure 4.

At the 1.5-month follow-up after definitive CRT, on April 22, 2024, she was experiencing tenderness in the pubic area and pain in the left inguinal region; however, there were no additional concerns. The left inguinal area showed slight signs of improvement on physical examination (Figure 5). No additional focal lesions were detected in the pelvic region according to pelvic MRI; however, a subcutaneous nodule in the pubic area was shown as a new sign (Figure 6). Additionally, a whole-body CT scan revealed widespread multiple lung metastases. She subsequently received 4 cycles of cisplatin and 5-flourasil on days 1–4 of a 28-day cycle.

After 4 cycles of chemotherapy, on August 26, 2024, she reported having tenderness in the pubic area and pain in the left inguinal region, as well as swelling extending from the left thigh to the inguinal area. Follow-up imaging showed progression in lung metastases and a subcutaneous nodule in the pubic area, with the emergence of 2 nodules in the upper inner and lower inner quadrants of the right breast (Figure 7). Meanwhile, a surgical approach was considered for the open tumoral lesion in the left inguinal region, but it was deemed too risky due to hemorrhagic complications. Although a biopsy of the right breast was planned, the patient died on September 2, 2024, 12 months after diagnosis, due to lung infection and respiratory distress.

Discussion

Isolated inguinal LN metastasis from SCC of unknown primary is a rare clinical condition, leading to limited data available in the literature. The existing data are generally derived from series that included all CUP cases. A common finding across these studies is that this entity tends to be classified as having a favorable prognosis [2,6,8–12], unlike our case. According to Hemminki et al’s [6] large series that examined all CUP cases, survival varies significantly based on the histology, location, and nodal status of the disease. The location of LN metastasis has a major impact on survival outcomes. Among nodal tumors, SCC histology was associated with the best prognosis. Specifically, SCC in the inguinal region had the lowest hazard ratio when considering all regions and histological types. In their study, the 1-year survival rate for 25 cases of inguinal LN metastasis from SCC of unknown primary was 83%, with a median survival time of 14 months. Long-term follow-up showed that the 10-year survival rate for patients with SCC metastasis in the head and neck or inguinal regions exceeded 50%, which was higher than that for patients with other affected LNs. A long-term study by Zaren et al [5] found the overall survival of patients with unknown primary inguinal LN metastasis was 55%, although the specific histology was not detailed. Similarly, another study reported the highest survival rates as approximately 30% in SCC cases over a 10-year follow-up period, with patients having LN metastasis showing significantly better survival compared to those with metastases at other sites, but the study did not specify the number or location of the LNs involved [13]. Our patient had a survival time of 12 months, suggesting a poor prognosis relative to these findings.

Currently, there is insufficient evidence to determine the most appropriate treatment modality – surgery vs definitive RT, surgery vs surgery + adjuvant RT, (neo)adjuvant chemotherapy, or immunotherapy. Thus, there is no clear consensus on treatment approaches. However, nearly all studies recommend surgery ±RT, with chemotherapy not being routinely advised [1,2,8,12,14]. Local ablative treatment is initially recommended, with surgery being the primary option. For unresectable cases, RT is considered the first-line treatment. The recent the Spanish Society of Medical Oncology (SEOM) guideline has also recommended tumor resection as the first-line treatment, but if the solitary lesion is eligible, definitive radiation should be proposed [2]. In ESMO guidelines, Kramer et al [1] classify cases of SCC inguinal LN metastasis of unknown primary as “a single metastatic lesion or oligometastatic disease suitable for local ablative treatment such as surgery and/or radiotherapy (single region and/or oligometastatic CUP)”. Local recurrences are frequently suitable for local ablative treatment. Adjuvant chemotherapy is considered a reasonable option in certain cases, particularly for patients with poorly differentiated carcinomas or when a specific tumor is suspected [2]. Therefore, we evaluated our patient primarily from a surgical perspective in light of this literature, both at the time of diagnosis and in the event of recurrence. The decision for definitive CRT was planned according to guidelines after being assessed as unresectable and aggressive disease following recurrence. However, this case showed significant differences in treatment outcomes compared to cases in the existing literature.

Concerning the single-modality treatment approach, case reports in the literature generally show that isolated inguinal LN metastasis from SCC of unknown primary cases have a good prognosis when treated with surgery alone, with examples of disease-free follow-up, but there are limited data on this. Chen et al [15] reported a case of SCC of unknown primary origin with metastasis to the right inguinal LN. The patient remained recurrence-free for 7 years after undergoing inguinal LN surgery, without the need for additional treatment. In Sugimoto et al’s [16] case, no recurrence was detected 2 years after inguinal LN dissection. However, Sinha et al [17] reported that the case, which was later identified as penile cancer, recurred in the opposite inguinal region 2 years 9 months after isolated left inguinal LN dissection. In our patient, surgical excision was initially performed on the left inguinal region with total excision, and the patient was placed under follow-up. This decision was made due to the recommendations of current guidelines [1,2] and the positive survival outcomes with surgery alone reported in case studies. However, our patient experienced a recurrence in the same area 4 months later. This duration is quite short and unexpected compared to what is reported in previous series. This could be explained a complex and variable disease course in isolated inguinal LN metastasis from SCC of unknown primary cases, with outcomes highly dependent on individual tumor behavior. The identification of molecular and histopathological features will be essential in determining individual prognosis. In current practice, amid this uncertainty and limited data about identifying aggressive cases, there is controversy regarding the use of a combined-modality approach with adjuvant RT and/or chemotherapy after surgery. The case report by Lee et al [18] serves as a good example regarding this approach. A patient with the inguinal LN metastasis from SCC of an unknown primary, accompanied by carcinoma in situ of the cervix and a benign ovarian tumor, underwent RT with concurrent weekly cisplatin following surgical LN dissection. The patient has remained recurrence-free for 22 months after completing treatment in this report. Ray et al [14] emphasized that adjuvant RT should be used in cases of extensive nodal involvement and/ or extranodal tumor spread, similar to SCC with a known primary site. Pouyiourou et al [19] also found that surgical treatment (including adjuvant RT and/or chemotherapy in 21 and 6 cases, respectively) was associated with prolonged OS compared to definitive RT or CRT. However, this publication included mixed regions and histological subtypes; not only SCC cases were analyzed. Regarding definitive CRT, Joseph et al [20] performed definitive CRT of all 9 cases of SCC inguinal LN metastasis of unknown primary over a 10-year period following LN biopsy (2 patients had inguinal LN core biopsy and 7 patients had excisional biopsy). No deaths or local or distant recurrences were reported during the follow-up period.

Based on previous data, although the SEOM [2] and ESMO [1] guidelines do not directly emphasize adjuvant RT after surgery, and Ray et al [14] highlight the importance of adjuvant RT for certain high-risk groups, we believe that RT with concurrent chemotherapy should be considered as part of the primary treatment approach with surgery, to eradicate local and distant microscopic disease. Although we cannot ascertain the primary site, this entity is essentially an oligometastatic disease. The combined use of surgery plus RT and chemotherapy is the most rational approach at the time of diagnosis. In our case, if CRT had been applied at the initial diagnosis after surgery, a better prognosis might have been achieved. It is possible that our patient could have developed resistance after a recurrence, as the tumor biology may differ from that of the initial tumor structure. Therefore, a combined-modality approach should be considered as the initial strategy for isolated inguinal LN metastasis from SCC of unknown primary cases.

Defining the RT volume remains a challenging issue. While the pelvic box with pelvic 3D-CRT was commonly used in older cases [20], defining the RT volume has become increasingly important with the advent of IMRT. Publications on volume definition often lack detail. The most common primary tumor sites for inguinal LN metastasis include the skin of the lower extremities, genitals, distal urethra, and anus. These areas should be carefully evaluated when considering treatment. Hammer-Hansen et al [21] described the RT volume dose as targeting the inguinal, pelvic, and anal regions, with a total dose of 64 Gy delivered in 32 fractions. This was combined with 6 cycles of concomitant cisplatin in a male patient diagnosed with poorly differentiated CUP, presenting with right inguinal LN metastasis. In our case, RT volume and dose details were carefully assessed. Despite being classified as a favorable subtype, our case demonstrated a more aggressive course compared to other examples in the literature. The rapid development of lung metastasis in our patient further highlights the crucial role of chemotherapy in controlling microscopic disease. During follow-up, 2 nodular lesions were also detected in the right breast and were identified as metastases. To the best of our knowledge, this finding has not been previously reported. Regrettably, because the patient died, biopsy confirmation could not be obtained.

Conclusions

This case of isolated inguinal LN metastasis from SCC of an unknown primary underscores the unpredictable nature of CUP, even in favorable subtypes. Despite guideline-directed treatment, rapid progression and unique metastatic patterns were observed. These findings suggest that more aggressive first-line treatments, such as adjuvant CRT following surgery, may be necessary to address potential microscopic disease. Reevaluating standard protocols and conducting further research are essential to improve outcomes for similar cases.