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Systematic Review

Oncology Reviews ·

Volume 20 - 2026 | https://doi.org/10.3389/or.2026.1801426

Occult squamous cell carcinoma presenting as oligometastatic lymphadenopathy. A systematic review with a case report

  • Łukasz Ważny1,2*corresponding author
  • Jakub Ciesielka3
  • Krzysztof Jakimów1,4
  • Aleksandra Tobiasz1
  • Paulina Kluszczyk1
  • Grzegorz Owczarek5
  • Mateusz Winder6
  • Jerzy T. Chudek3*corresponding author
  1. 1Student Scientific Society, Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
  2. 2Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
  3. 3Department of Internal Medicine and Oncological Chemotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
  4. 4Doctoral School, Institute of Medical Sciences, University of Opole, Opole, Poland
  5. 5Department of Radiotherapy, Professor K. Gibiński University Clinical Centre of Medical University of Silesia in Katowice, Katowice, Poland
  6. 6Department of Oncological Radiology and Nuclear Medicine, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
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Abstract

An occult squamous cell carcinoma (SCC) is a rare subtype of SCC for which standard radiological protocols are often unable to identify the primary tumour. We describe our patient’s history and provide a systematic review of the literature. To review the clinical characteristics, treatment strategies, and outcomes of patients with occult SCC presenting with lymph node (LN) metastases and to report a rare case of a patient with occult SCC metastasizing to the inguinal and iliac LNs. A systematic literature search was conducted in PubMed, Scopus, and Embase, covering the period from 2000 to 2025. The inclusion criteria for eligible studies comprised case reports and case series documenting patients with occult SCC presenting with LN metastases. Data were extracted at the individual-patient level and synthesised descriptively. A 75-year-old man suffering from myelodysplastic syndrome presented with inguinal lymphadenopathy. Pathological analysis of a core needle biopsy revealed metastases of poorly differentiated SCC. Positron emission tomography-computed tomography (18F-fluorodeoxyglucose PET-CT) showed isolated glucose uptake in the iliac LNs without a potential site of primary disease. Consequently, an iliac lymphadenectomy was performed, followed by adjuvant radiotherapy. The patient remained asymptomatic with no signs of cancer for 15 months following treatment; however, follow-up PET-CT imaging revealed retroperitoneal lymphatic recurrence. Metastases to cervical LNs were observed in a significantly higher proportion of males than of females (63.4% vs. 39.5%; p = 0.033). On the contrary, inguinal LN metastases were more frequently observed in females than in males (39.5% vs. 17.1%; p = 0.026). Within the assessed cohort, systemic therapy was administered to 62% of patients, radiotherapy to 68.4%, and surgical intervention to 59.5%. Notably, five patients (6.3%) received immunotherapy. The diversity of therapeutic approaches documented in the literature emphasizes the importance of individualised treatment strategies, including immunotherapy. Genomic profiling may help implement molecular-based therapy; however, no genetic testing has been reported for the patients included in this cohort.

Keywords

1 Introduction

The diagnosis and management of occult squamous cell carcinoma (SCC) constitute a significant challenge since the primary tumour site remains undetermined following the completion of the standard diagnostic work-up (1). Cancers of unknown primary (CUP), also referred to as occult primary cancers, represent a small percentage, specifically 3%–5%, of all cancers (2), while occult SCC comprises 9% of all CUP cases. Multiorgan and liver metastatic diseases are observed in 33% and 25% of all occult SCC cases, respectively, implicating a poor prognosis and a low one-year survival rate of 20% (3). In some cases, challenges with diagnostic techniques or the use of suboptimal diagnostic procedures can impede the identification of the primary tumour site in occult SCC (4).

Immunohistochemistry (IHC) has become an indispensable auxiliary test for narrowing the differential diagnosis and classification of undifferentiated tumours. Ongoing advances in the discovery of IHC markers have improved the accuracy of SCC identification and subtyping, thereby supporting the search for the potential primary site. However, the accuracy of IHC in identifying the primary organ is limited, especially in poorly differentiated carcinomas (1,5).

The overall decline in CUP cases, observed globally over the years, coincides with the development and implementation of more effective detection techniques (1). The biological characteristics of occult SCC remain largely undefined. One suggested pathophysiological mechanism for its development involves the early spread of cancer cells from primary lesions that are undetectable by current diagnostic methods. As these metastatic clones expand across different sites, the primary tumour might be either neutralized by the immune system or reach a state of equilibrium, leading to the dormancy of cancer cells. In contrast, the primary lesion remains radiologically undetectable (1). Of note, when a multiorgan and liver metastatic disease is diagnosed in over half of all occult SCC patients, a lymph node (LN) disease is exhibited only in 7% of all individuals (1,3), leading to insufficient clinical and pathological exploration of this group of patients.

Several reviews have previously addressed occult SCC, although their scope has predominantly been limited to head and neck presentations, particularly cervical LN metastases (6,7). Nieder et al. conducted a systematic review of diagnostic and radiotherapeutic strategies for cervical LN metastases originating from occult SCC (8), while subsequent reviews focused on more specific aspects of occult SCC, including HPV prevalence and p16/HPV status (9–11), PET/CT imaging (12,13), narrow-band imaging (14), palatine tonsillectomy (15), transoral robotic or laser surgery (16,17), tongue-base mucosectomy (18), and diagnostic or prognostic biomarkers (19). These studies have substantially refined the diagnostic and therapeutic framework for occult HNSCC presenting with cervical nodal disease. However, they were not intended to offer a broader case-based clinicopathological synthesis of occult SCC presenting as lymphadenopathy across different nodal regions. Extracervical presentations have been much less frequently analyzed, with abdominal, pelvic, and retroperitoneal occult SCC discussed mainly in limited case-based literature, including the report by El Rassy et al (20). Thus, the available evidence remains fragmented, particularly in relation to patient-level data on the clinical course, diagnostic assessment, pathological features, and therapeutic management of occult SCC with distant or non-cervical nodal disease.

To our knowledge, this study provides the first comprehensive case-based analysis of the clinicopathological profile of occult SCC presenting as isolated lymphadenopathy, based on a literature review and single-center experience. As noted above, most systematic reviews on occult SCC focus on locoregional metastases in the head and neck region, particularly cervical nodal disease, whereas this paper also provides insight into distant metastases.

By examining these less frequently reported presentations, this review expands prior analyses of occult SCC and highlights rare lymphadenopathic patterns despite the fragmented and heterogeneous nature of the evidence base. The choice of a case-based approach, in contrast to cohort-based meta-analyses, enabled the inclusion of detailed patient-level data, which we considered essential for addressing the objectives of this review.

2 Objectives

This study aimed to conduct a systematic review of the clinical characteristics, therapeutic approaches, and outcomes of patients with occult SCC who present with LN metastases, and to report a case study of our patient with occult SCC that metastasized to the inguinal and iliac LNs.

3 Methodology

3.1 Study selection and search strategy

This systematic review was conducted in accordance with the PRISMA guidelines (21). In the course of the literature review conducted from May to August 2025, a systematic search was executed across the PubMed, SCOPUS, and Embase databases utilizing the following search algorithm (((cancer OR carcinoma OR tumor) AND ((unknown AND primary) OR (unknown AND origin) OR occult)) OR CUP) AND ((“squamous cell” AND (carcinoma OR cancer)) OR SCC) AND ((case report OR case OR case series) AND (metastasis AND (lymph node OR lymphadenopathy))). The review exclusively considered scientific publications comprising case reports or case series of occult SCC with LN metastases, published between 2000 and August 2025. Conference abstracts, letters, and unpublished reports were not included in the analysis. The database search was conducted without language restrictions. Nevertheless, records published in languages other than English were excluded during screening. Studies were excluded if the primary tumour was subsequently identified or if the pathological findings were inadequately described. The initial search yielded 839 records (PubMed: n = 226, Scopus: n = 68, Embase: n = 545). All retrieved articles were imported into the Zotero reference management software. Following the removal of duplicates (n = 606), the remaining publications underwent independent screening for eligibility by all team members based on titles and abstracts, followed by a secondary review by one of the authors (Ł.W.). One publication was excluded because the primary tumour site was identified during the patient’s clinical course (22). Ultimately, 51 studies comprising 79 cases were included in the review. The selection process is depicted in a flowchart (see Figure 1). The complete database-specific search strings, including syntax adapted for PubMed, Scopus, and Embase, together with the applied limits, search dates, and numbers of records retrieved, are provided in Supplementary Material S1.

Flow diagram for study selection. Created with [BioRender.com](http://BioRender.com).
Figure 1. Flow diagram for study selection. Created with BioRender.com.

3.2 Data extraction

In the course of analyzing the selected publications, patient-level data were extracted, encompassing variables such as sex, age, LN location of the tumour, tumour stage, presence and sites of distant metastases, type of therapy administered, imaging results, and, when available, key clinical endpoints related to survival outcomes, including progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Data extraction was performed independently by all authors, and the extracted data were subsequently verified by one of the authors (Ł.W.). The collected data were analyzed using Microsoft Excel 2019.

3.3 Quality assessment

All authors evaluated the full case reports and case series for quality assessment, and one author (Ł.W.) subsequently conducted a qualitative review to check adherence to the JBI Critical Appraisal Checklist for Case Reports (23). Quantitative scoring was not applied due to limited data; instead, studies were excluded if they lacked essential data necessary for analysis (see Section 3.2). Critical appraisal results for the included studies, assessed using the JBI Critical Appraisal Checklists for Case Reports and Case Series, are provided in Supplementary Material S2.

3.4 Statistical analysis

All statistical analyses were performed using Jamovi (version 2.3, 2022). Continuous variables were expressed as mean (±SD) or median (Q1 – Q3) when appropriate. Categorical data were expressed as a number and a percentage. The normality of the variables was assessed using the Shapiro-Wilk test. Variance homogeneity analysis was performed using Levene’s test. Data with a normal distribution were compared using a t-test. The analysis of continuous, non-normally distributed data was performed using the Mann–Whitney U test. The associations between categorical variables were analyzed using the chi-square test or the chi-square test with Yates’ continuity correction when appropriate. Statistical significance was determined as p < 0.05.

4 Case report

This case is presented as an illustrative example of an uncommon extracervical manifestation of occult SCC, in which inguinal and iliac lymphadenopathy remained the only detectable disease sites despite extensive diagnostic imaging. Within the context of this review, the case illustrates the diagnostic challenge of occult primary tumour detection, the individualized nature of treatment selection, and the potential for delayed lymphatic recurrence in rare non-cervical nodal presentations.

A 75-year-old male patient with a medical history of myelodysplastic syndrome presented with a two-week history of pain localised to the costal arch region. Myelodysplastic syndrome had been diagnosed during a previous haematological hospitalization for pancytopenia in May 2023 (Figure 2), during which peripheral blood tests showed decreased red blood cell count, reduced haemoglobin concentration, marked leukopenia with moderate neutropenia, and mild thrombocytopenia. The diagnosis was confirmed by pathological examination of a bone marrow trephine biopsy. At the time of the current evaluation, the patient reported weakness, slightly reduced exercise tolerance, and easy bruising after minor trauma. His performance status was WHO/ECOG 0, and laboratory tests showed only mild thrombocytopenia, with no leukopenia or neutropenia. In response to the observed inguinal lymphadenopathy, a core needle biopsy was performed. Histopathological examination revealed metastases of poorly differentiated SCC, with markers CK+, CK7+, CK5/6+, p63+, p40+, and GATA3+/−. 18F fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) failed to identify a potential primary site (Figure 3). Further imaging, including magnetic resonance imaging, revealed iliac lymphadenopathy measuring up to 19 mm in the short-axis (Figure 4). Assessment of HPV and EBV status, PD-L1 (programmed death receptor 1) expression, and next-generation sequencing (NGS)-based molecular profiling was not performed. The ambiguous GATA3 result necessitates careful interpretation, as the diagnostic utility of GATA3 is enhanced when evaluated alongside staining intensity and distribution patterns. Strong and diffuse expression of GATA3 may indicate a urothelial or breast origin, whereas weak or focal staining has been observed in SCC and is insufficient for determining the primary site (24,25). Consequently, in the current case, the GATA3+/− finding was deemed non-definitive and was interpreted solely within the context of the complete immunohistochemical panel.

Timeline of the diagnostic and treatment procedures. Created with [BioRender.com](http://BioRender.com).
Figure 2. Timeline of the diagnostic and treatment procedures. Created with BioRender.com.
The frontal cross-section of an abdominal 18F fluorodeoxyglucose PET-CT scan reveals increased FDG uptake in the right inguinal LN **(A)** and the right iliac LN **(B)**. Panel **(C)** presents the corresponding CT images, with arrows indicating both metastatic sites. No primary tumour site was identified.
Figure 3. The frontal cross-section of an abdominal 18F fluorodeoxyglucose PET-CT scan reveals increased FDG uptake in the right inguinal LN (A) and the right iliac LN (B). Panel (C) presents the corresponding CT images, with arrows indicating both metastatic sites. No primary tumour site was identified.
Transverse 18F fluorodeoxyglucose PET-CT images of the pelvis reveal increased FDG uptake indicative of metastatic involvement in the right inguinal LN **(A)** and the right iliac LN **(C)**. Panels **(B)** and **(D)** display the corresponding CT images at the same anatomical levels, with both metastatic sites clearly visualised. These findings demonstrate the localisation of nodal metastases in the absence of a detectable primary tumour.
Figure 4. Transverse 18F fluorodeoxyglucose PET-CT images of the pelvis reveal increased FDG uptake indicative of metastatic involvement in the right inguinal LN (A) and the right iliac LN (C). Panels (B) and (D) display the corresponding CT images at the same anatomical levels, with both metastatic sites clearly visualised. These findings demonstrate the localisation of nodal metastases in the absence of a detectable primary tumour.

Given the isolated nodal disease amenable to radical local treatment, surgery followed by consolidative radiotherapy was selected as the preferred local treatment strategy. As a result, an iliac lymphadenectomy was performed, followed by adjuvant radiotherapy at a dose of 45 Gy in 15 fractions. Post-radiotherapy, the patient reported experiencing urinary urgency, dysuria, and erythema at the site of irradiation. During the follow-up period, the patient’s overall clinical condition has remained stable since the last hospitalization. However, PET-CT imaging performed on 15 October 2025 revealed disease recurrence with metabolically active retroperitoneal LNs (three lesions, each about 1 cm). Close monitoring and further management have been recommended as part of ongoing post-treatment surveillance.

5 Results

Given the rarity of occult SCC presenting with lymphadenopathy, with documentation primarily limited to isolated case reports or small case series, the present review was undertaken to consolidate scattered patient-level evidence and provide a descriptive overview of this undercharacterized clinical presentation.

The analysis included 79 patients, comprising 38 women (48.1%) and 41 men (51.9%), aged 32–80 years. The mean age of the cohort was 57.6 ± 10.9 years. The age values did not differ significantly between males and females (58.5 ± 9.33 vs. 56.7 ± 12.4 years, p = 0.48).

Data regarding the presence or absence of a relevant oncological history were available for 38 of the 79 patients (48.1%). Among these, eight patients (21%) had a documented history of significant oncological disease. Before diagnosis, cancer-related symptoms were observed in 58 patients (73.4%), absent in 7 patients (8.9%), and could not be determined for the remaining 14 patients (17.7%). Among patients presenting with current oncological symptoms, the majority (51 patients; 81.9%) reported a mass. Additional reported symptoms included pain, cough, and dysphagia. The patients exhibited metastases to LNs in various anatomical regions. The median maximum lesion diameter was 47.5 mm (IQR, 30.5–62.5) across the entire cohort. The maximum lesion diameter was comparable between males and females: 47.5 mm (IQR, 38–60) vs. 45 mm (IQR, 28.8–68.8), p = 0.92. Metastases were most frequently observed in the cervical nodes (n = 41, 51.9%), followed by the inguinal nodes (n = 22, 27.8%), mediastinal nodes (n = 9, 11.4%), pelvic nodes (n = 7, 8.9%), supraclavicular nodes (n = 6, 7.6%), and retroperitoneal nodes (n = 5, 6.3%). They were less commonly identified in the abdominal nodes (n = 4, 5.1%), axillary nodes (n = 2, 2.5%), iliac nodes (n = 2, 2.5%), presacral nodes (n = 1, 1.3%), and other LN locations (n = 2, 2.5%) (see Figure 5).

Lymph nodes metastasis sites in occult SCC. Created with [BioRender.com](http://BioRender.com).
Figure 5. Lymph nodes metastasis sites in occult SCC. Created with BioRender.com.

Stratified by sex, metastases to cervical LNs were revealed in a significantly higher proportion of men compared to women (63.4% vs. 39.5%; p = 0.033). In contrast, a substantially higher incidence of inguinal LN metastases was observed in females than in males (39.5% vs. 17.1%; p = 0.026). No significant sex-related differences were observed in abdominal, iliac, pelvic, presacral, retroperitoneal, and LN metastases (21.1% vs. 9.8%; p = 0.28). Similarly, no significant difference was found between males and females in the incidence of supraclavicular, mediastinal, or axillary LN metastases (18.4% vs. 14.6%; p = 0.65). The comparison of metastasis frequencies across nodal localizations, stratified by sex, is presented in Table 1. Overall, 32.9% of patients had metastatic disease involving distant organs (see Figure 5). This difference was not significant between males and females (34.1% vs. 31.6%; p = 0.81). Among these, the most frequently involved sites included the bones, lungs, skin, and other anatomical locations (see Figure 6).

TABLE 1. The comparison of metastasis frequencies in nodal localisation stratified by sex.

Nodal localisationMetastasesSexχ2dfp
Male: n; %Female; %
Supraclavicular, mediastinal, axillary-35; 44.3%31; 39.2%0.20610.65
+6; 7.6%7; 8.9%
Cervical-15; 19%23; 29.1%4.5310.033
+26; 32.9%15; 19%
Abdominal, iliac, pelvic, presacral, retroperitoneal, and other-37; 46.8%30; 38%1.18 #10.28
+4; 5.1%8; 10.1%
Inguinal-34; 43%23; 29.1%4.9310.026
+7; 8.9%15; 19%

χ2 continuity correction.

Sites of distant metastases in patients with occult SCC. Created with [BioRender.com](http://BioRender.com).
Figure 6. Sites of distant metastases in patients with occult SCC. Created with BioRender.com.

All Patients underwent various anticancer treatments. A significant proportion of patients received systemic therapy (n = 49, 62%) and radiotherapy (n = 54, 68.4%). Surgical procedures were conducted in 47 patients (59.5%). Five patients received immunotherapy (6.3%), including two who received chemoimmunotherapy (2.5%) and three who received a combination of chemoradiotherapy and immunotherapy (3.8%). Additionally, adjuvant therapy was administered to 23 patients (29.1%), and neoadjuvant therapy to 2 patients (2.5%). Palliative anticancer therapy was administered to 12 patients (15.2%). Among the case reports included in this study, 15 (19%) deaths had been reported by the time of publication. Data on PFS, DFS, and OS were frequently unavailable or incomplete, precluding a reliable analysis of these outcomes. Comprehensive details regarding the patients included in the analysis are presented in Table 2.

TABLE 2. Characteristics of patients regarding their treatment type.

​Sex (age)Nodal locationLocalisation of distant metastasesTherapyDeath (0 = no; 1 = yes)Year of publicationSource
Surgical treatment
1Woman (59)Right inguinal​Surgerynd2023(26)
2Women (73)Cervical, supraclavicular, mediastinalBones, pleuraSurgery02019(27)
3Man (63)Cervical​Surgery02016(28)
4Men (59)Subtracheal​Surgery12011(29)
5Women (50)Cervical​Surgery02009(30)
6Men (56)Hilar​Surgery02008(31)
7Men (80)Cervical​Surgery12008(32)
8Women (65)Cervical​Surgery02008(32)
9Women (78)Inguinal​Surgery02006(33)
Radiotherapy
10Men (70)CervicalThe abdominal cavityRTnd2022(34)
11Men (75)Cervical​RT02019(35)
12Women (59)CervicalHard palateRT02009(36)
Chemiotherapy
13Women (78)Inguinal, mediastinal, abdominal, PelvicLungsCTH (CBDCA + GEM + lenalidomide)02013(37)
Combination therapies
14Men (65)Left cervicalSkinCIT (NIVO, PTX + CET)12025(38)
15Women (32)PelvicCervicalLiver, lungs, bonesCIT (PEMBRO + 5-FU + CDDP)nd2023(39)
16Women (33)Inguinal​CRT + IO (CDDP + RT, PAX + CBDCA, NIVO)nd2023(40)
17Women (42)Cervical, supraclavicular, abdominal, inguinalBonesCRT + IO (5-FU + CDDP/CBDCA + CET + DTX)02021(41)
18Men (60)Inguinal​CRT (PTX/CBDCA + RT)02021(42)
19Men (63)MediastinalVertebra (L3)CRT12018(43)
20Men (74)Pretracheal​CRT (CBDCA + PTX)02017(44)
21Women (69)Retroperitoneal and pelvic​CRT (VMAT, CDDP)02016(45)
22Women (68)Inguinal​CRT (CDDP + 5-FU)02014(46)
23Women (53)Inguinal​CRT (CDDP + 5-FU)02014(46)
24Women (60)Inguinal​CRT (mitomicin C + 5-FU)02014(46)
25Women (61)Inguinal​CRT (CDDP + 5-FU)02014(46)
26Women (59)Inguinal​CRT (CDDP + 5-FU)02014(46)
27Women (56)Inguinal​CRT (CDDP + 5-FU)02014(46)
28Men (74)Inguinal​CRT (CDDP + 5-FU)02014(46)
29Men (59)Inguinal​CRT (CDDP + 5-FU)02014(46)
30Men (68)Inguinal​CRT (CDDP + 5-FU)02014(46)
31Women (40)Inguinal​CRT (CDDP + CPM)02014(47)
32Men (40)CervicalVertebral columnCRTnd2014(48)
33Women (45)Supraclavicular​CRT (CDDP, PTX)02009(49)
34Women (65)Left inguinalLungs, skinSurgery + CRT (CDDP + 5-FU)12025(50)
35Men (52)Cervical​Surgery + CRT (CDDP)nd2022(51)
36Men (58)Cervical​Surgery + CRT02020(52)
37Women (58)Retroperitoneal mass extending to the left pelvic side wall​Surgery + CRT (CDDP + RT)02016(45)
38Men (48)CervicalTonsilSurgery + CRT02010(53)
39Men (51)Cervical​Surgery + CRTnd2010(54)
40Women (65)Axillary, supraclavicularBonesSurgery + CRT (CDDP)nd2000(55)
41Women (43)Pelvic, iliac, abdominal aortic, inguinal, and presacralPeritoneum, surrounding both ovariesSurgery + CTX (PTX + CDGP)02023(56)
42Men (67)Cervical, mediastinal, axillaryThyroidSurgery + CTH (LEN, CBDCA + PTX)02018(57)
43Men (59)Intrathoracic​Surgery + CTH (CDDP + VNR + RT)02015(58)
44Women (50)RetroperitonealSkinSurgery + CTH (CBDCA + GEM)12014(59)
45Men (59)Lesser curvature of the stomachStomachSurgery + CTH02014(60)
46Men (50)Cervical​Surgery + CTH12008(32)
47Men (50)Cervical​Surgery + CTH02008(32)
48Men (51)Cervical​Surgery + CTH (CDDP, 5-FU)02003(61)
49Men (63)CervicalLeft lungSurgery + CTH (CDDP)02002(62)
50Men (50)MediastinalLiverCIT (CAM + VIN + END) + CRT + IO (CDDP + VNR/PTX/CBDCA, ANL, TIS + PTX)12023(63)
51Men (44)Cervical​Surgery + RTnd2022(64)
52Women (37)Cervical​Surgery + RT02020(65)
53Men (57)Cervical​Surgery + RT02014(66)
54Men (60)Cervical​Surgery + RT02008(32)
55Men (52)Cervical​Surgery + RT02008(32)
56Women (57)Cervical​Surgery + RT12008(32)
57Women (50)Cervical​Surgery + RT02008(32)
58Men (64)Cervical​Surgery + RT02008(32)
59Men (51)Cervical​Surgery + RT02008(32)
60Women (42)Cervical​Surgery + RT12008(32)
61Men (59)Cervical​Surgery + RT02008(32)
62Women (70)Cervical​Surgery + RT02008(32)
63Men (52)Cervical​Surgery + RT02008(32)
64Women (70)Iliac​Surgery + RT02006(67)
65Men (43)Cervical​Surgery + RT02003(68)
66Men (44)CervicalLungsSurgery + RT12003(68)
67Women (48)Cervical​Surgery + RT02003(68)
68Men (55)Cervical​Surgery + RT02001(69)
69Men (70)Cervical​Surgery + RT02001(69)
70Men (61)Cervical​Surgery + RT02001(69)
71Women (71)Cervical​Surgery + RT02001(69)
72Women (49)Supraclavicular, upper mediastinal, and hilarBrainRT + CTH (CBDCA, PTX)12004(70)
Without therapy, or no data available
73Women (47)Retroperitoneal, and pelvic​Without therapy12016(45)
74Men (65)Supraclavicular, mediastinalRight atrium, right ventricle, liverWithout therapy12014(71)
75Women (∼60)Inguinal​nd02022(72)
76Women (56)CervicalLungs, interventricular septum, bonesndnd2013(73)
77Men (56)CervicalSpinal cordndnd2012(74)
78Women (58)MediastinalMediastinumnd12012(75)
79Women (75)Cervical​ndnd2011(76)

Abbreviations: 5-FU, 5-fluorouracil; ANL, Anlotinib; CAM, Camrelizumab; CBDCA, Carboplatin; CDDP, Cisplatin; CDGP, Nadeplatin; CET, Cetuximab; CIT, Chemoimmunotherapy; CTH, Chemotherapy; CMP, Cyclophosphamide; CRT, Chemoradiotherapy; DTX, Docetaxel; END, Endostar (recombinant human endostatin); GEM, Gemcitabine; IO, Immuno-oncology; LEN, Lenvatinib; LN, Lymph nodes; NIVO, Nivolumab; PEMBRO, Pembrolizumab; PTX, Paclitaxel; RT, Radiotherapy; TIS, Tislelizumab; VMAT, Volumetric Modulated Arc Therapy; VNR, Vinorelbine; nd, no data.

6 Discussion

In this analysis, we observed a predominant percentage of occult SCC metastases in cervical (51.9%), followed by inguinal (27.8%) and mediastinal (11.4%) LNs. The highest rate of metastases to cervical LNs in this analysis may be attributed to the high prevalence of SCC in the cervical region, as SCC is the dominant histotype, accounting for over 90% of head and neck cancers (77,78). The other lymphatic localizations are correlated with genitourinary SCC, followed by lung SCC, aligning generally with the prevalence of these SCC subtypes. Statistical analysis of the patient cohort included in this systematic review revealed a higher incidence of cervical LNs metastases in men than in women (63.4% vs. 39.5%; p = 0.033). This observation aligns with previously published data on occult SCC metastasizing to cervical LNs (79–81) as well as with the general trend of CUP being more prevalent in men (2). Furthermore, except for rare cases of distant primary tumours, cervical LNs are predominantly the site of metastases from head and neck SCC (HNSCC) (82). The risk of developing this malignancy is greater in men across nearly all anatomical subsites within the head and neck region (83). This phenomenon may be partially attributed to the higher prevalence of tobacco smoking and alcohol consumption among men; however, even after adjusting for these factors, men who are not exposed to these carcinogens still exhibit a significantly higher incidence of HNSCC (particularly oropharyngeal, hypopharyngeal, and laryngeal SCC) than women (83). In this context, the increased proportion of men observed in the analyzed cohort with cervical LN metastases may reflect an occult primary tumour originating from the head and neck region in a substantial number of cases.

An inverse correlation was identified concerning metastases to the inguinal LNs in the absence of a discernible primary site. The frequency of inguinal LN metastases was significantly higher among females than among males. The existing literature on this subject is notably sparse; however, it is plausible to hypothesise that this observation may be partially attributable to cases of CUP potentially originating from female genital organs, such as cervical or vulvar SCC.

The therapeutic approach for occult SCC does not differ from the strategies utilised in HNSCC. Surgery or radiation alone can be facilitated in selected cases with early-stage disease (84). In our cohort, this approach was feasible in only a limited number of patients. In the advanced stages of the disease, typical treatment consists of platinum-based chemotherapy and radiation (84). A similar management approach was observed in the retrieved cases. Many patients received treatment based on a combination of these techniques. Ultimately, the approach depends on the disease stage, the lesion site, whether it is deemed resectable or unresectable, and whether other metastases are present. In our patient, the initial radical treatment strategy of lymphadenectomy followed by adjuvant radiotherapy achieved temporary disease control. However, lymphatic recurrence was observed after 15 months of follow-up period. The follow-up PET-CT scan conducted on 15 October 2025 identified metabolically active retroperitoneal LNs. These findings suggest the possibility of neoplastic dissemination, necessitating vigilant clinical and radiological surveillance.

6.1 Future directions

The molecular pathogenesis, genetic profile, and therapeutic targets implicated in occult SCC remain poorly understood. In the study by Robinson et al. (85), a targetable PIK3CA mutation was identified in 27.3% of all occult SCC, exceeding the rates reported for HNSCC, where the PIK3CA mutations are estimated to occur in 9.5%–17.4% of cases (86). Results from the phase 2b study combining ipatasertib, a PI3K-AKT-mTOR inhibitor, with pembrolizumab in SCC are currently awaited (87). Of note, the significantly increased frequency of PIK3CA mutations in occult SCC may correlate with more aggressive tumour biology, implicating poorer outcomes; however, studies examining their role in other SCC subtypes yielded divergent results (86,88,89,91). Additionally, in the same genomic landscape study, PTEN mutations were detected in 15.1% of occult SCC cases, a lower proportion than that reported for lung and oral SCCs, where the corresponding rates reach up to 64% and 56.6%, respectively (92,93). KRAS mutations were observed at a slightly higher frequency of 10.4% in all occult SCC samples, compared to lung SCC, where this mutation frequency ranges from 1.3% to 7.4%. However, no clinical studies have examined the administration of KRAS inhibitors in SCC (94).

More importantly, in the same genomic study, the authors revealed that a tumour mutational burden (TMB) ≥10 mutations/Mb is prevalent in 33.9% of occult SCC cases, but is rare in HNSCC (3.75%). It is expected that high TMB in occult SCC tumours may lead to an aggravated immune response, resulting in partial or complete regression. Considering the high but comparable prevalence of TP53 and CDKN2A mutations in occult SCC malignancies −62% and 37%, respectively—these tumours exhibit early epithelial-to-mesenchymal transition and metastases, even when the primary lesion completely regresses due to an aggravated immune response (85).

The significantly higher TMB in these malignancies also underscores the urgent need to evaluate the impact of immunotherapy on patients with occult SCC, as this subgroup may exhibit a better therapeutic response compared to HNSCC. In one of the latest studies, assessing the combination of nivolumab and ipilimumab in recurrent or refractory CUP after platinum-based chemotherapy, the authors reported a significantly higher OS and PFS in patients with a TMB ≥12 mutations/Mb: 18.3 vs. 2.4 months for OS, and 18.3 vs. 3.6 months for PFS, respectively (95). Although the authors incorporated various HNSCC histotypes, it is reasonable to consider evaluating TMB in selected patients with occult SCC after progression on platinum-based chemotherapy (95).

The ESMO Guidelines (2) for CUP recommend assessing PD-L1 in patients with distant metastases, relapsed disease, or progression, as higher levels are associated with better PFS and longer OS in patients treated with nivolumab; however, these differences remain statistically insignificant. PD-L1 assessment should be provided with either the tumour proportion score or the combined positive score (96). A second-line approach with immune checkpoint inhibitors appears appropriate when high PD-L1 expression is present, and no alternative therapeutic strategy is available, especially when cancer cells resemble those of a known primary cancer for which immunotherapy is an established treatment (2). Immunochemotherapy should also be considered, as it may significantly improve OS. This view is supported by the results of the KEYNOTE-048 study, where pembrolizumab with chemotherapy led to longer OS than cetuximab with chemotherapy (13.0 months vs. 10.7 months), while PFS and objective response rates remained similar. Pembrolizumab alone also showed promising results in selected patients (97). Therefore, pembrolizumab was approved for use as first-line treatment in HNSCCs with PD-L1 expression. If this option is not available, cetuximab with chemotherapy can be administered (96). Nevertheless, further studies are needed to assess the effects of this treatment, primarily since the treatment of occult SCC is not fully described in the literature (74,75); however, this option appears promising (98,99). Given immunotherapy and immunochemotherapy as potential therapeutic interventions, PD-L1 expression should be the standard assessment in these cases, in the absence of a chance of radical surgery or radiotherapy.

It is worth noting that next-generation sequencing in occult SCC may be valuable for determining the primary site of origin. The CDKN2A and FAT1 mutations are more commonly found in HNSCC, whereas tumours harbouring the TMPRSS2 mutation are more likely to be of prostatic origin (85). The diagnosis of occult SCC remains challenging, as currently available serum biomarkers, including SCC-Ag and CYFRA 21–1, exhibit poor diagnostic accuracy, with low sensitivities of 53% for lung SCC and 34% for HNSCC and false-positive rates ranging from 7% to 11% (100). Although the CYFRA 21–1 antigen may exhibit acceptable diagnostic accuracy in determining lung cancer histotype, in HNSCC, its sensitivity and specificity did not exceed 53% and 97%, respectively (101). In a recent meta-analysis, the authors evaluated the diagnostic predictive ability of novel salivary biomarkers for early occult SCC and HNSCC. In early occult SCC, chemerin and MMP-9 were identified as the most accurate salivary biomarkers, with 94% sensitivity and 93% specificity. In HNSCC, actin showed the highest diagnostic accuracy, with a sensitivity of 91%, specificity of 67%, and an overall accuracy of 79% (102). This finding may be valuable in occult SCC diagnosis, where, similarly to early SCC tumours, occult SCC present with a limited extent, evading the standard diagnostic protocols. However, we lack biomarkers for micrometastasis in certain SCCs, such as lip SCC, which may lead to suboptimal treatment in some patients (103). Considering the high diagnostic accuracy of MMP-9 and chemerin in early oral SCC detection, and a high percentage of 51.9% of cervical lymphadenopathy in this analysis, these markers may help determine the primary site of life-threatening cervical lymphadenopathy, where urgent emergency systemic treatment is needed, and the diagnostic differentiation toward lymphoproliferative diseases remains inconclusive.

6.2 Limitations

Several limitations may apply to this systematic review, including biases arising from the differing complexity of data derived from case reports. Systematic reviews of case reports and case series are intrinsically limited by the absence of comparative control groups, potential selection and reporting bias, confounding factors, and restricted generalizability (104). The results may be influenced by publication bias, which is an unavoidable concern in case reports and often leads to the preference for reporting unusual or favourable outcomes. We are aware that this approach may lead to statistical overinterpretation, especially regarding sex differences, due to heterogeneity of available data and the aforementioned publication bias. Nevertheless, systematic reviews of case reports and case series may be justified in rare and heterogeneous clinical conditions for which higher-level evidence is often unavailable.

To mitigate these limitations and enhance the reliability of the findings, we applied a predefined PRISMA-based methodology, clearly defined inclusion and exclusion criteria, independent screening, comprehensive patient-level data extraction, and a JBI-based quality appraisal. These methodological measures were intended to strengthen the descriptive value of the available evidence, while acknowledging the inherent limitations of case-based data. In this context, this analysis provides the first insight into the clinical and therapeutic profile of occult SCC presenting as lymphadenopathy. A relatively large cohort size, given the disease’s rarity, is a significant strength of the study, enhancing its representativeness. Regrettably, the statistical analysis of disease progression or survival could not be performed due to limited or incomplete data.

A significant limitation was the absence of extractable data concerning the expression of relevant tumour markers and the genetic or molecular profiles of the tumours in the majority of the analysed publications. The current literature on CUP cases often lacks comprehensive data on PD-L1 expression and genetic testing. Incorporating these elements into the standard diagnostic evaluation for CUP patients is crucial and should be a primary focus of future diagnostic advancements.

7 Conclusion

In this systematic review, cervical and inguinal LN metastases were the most frequently reported presentations of occult SCC, which may suggest possible head and neck or genitourinary origins. The diversity of therapeutic approaches documented in the literature emphasises the importance of individualised treatment strategies, including immunotherapy. It also reflects the heterogeneity of clinical management and the lack of standardized treatment strategies, supporting the need for individualised clinical decision-making. However, given the limited quality of the available evidence, which is mainly derived from case reports and case series, these findings should be interpreted with caution and regarded as hypothesis-generating. Genomic profiling may help implement molecular-based therapy, potentially ensuring better outcomes for patients.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/or.2026.1801426/full#supplementary-material

Supplementary material Supplementary material at the source

Supplementary material Supplementary material at the source

Footnotes

Edited by: Nikolas Hendrik Stoecklein, University Hospital Düsseldorf, Germany

Reviewed by: Supriya Peshin MD, Norton Community Hospital, United States

Danijela Veljkovic Vujaklija, Clinical Hospital Centre Rijeka, Croatia

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was received for this work and/or its publication. The authors declared that received funds from Medical University of Silesia to cover the publication fee.

Data availability

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Author contributions

ŁW: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing. JaC: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing. KJ: Conceptualization, Data curation, Formal Analysis, Investigation, Writing – original draft, Writing – review and editing, Methodology. AT: Data curation, Writing – original draft, Writing – review and editing, Investigation. PK: Data curation, Writing – original draft, Writing – review and editing, Investigation. GO: Data curation, Writing – original draft, Writing – review and editing, Resources. MW: Data curation, Writing – original draft, Writing – review and editing, Resources. JeC: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision, Writing – original draft, Writing – review and editing.

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Citation

Ważny, Ł., et al. (2026). Occult squamous cell carcinoma presenting as oligometastatic lymphadenopathy. A systematic review with a case report. Oncology Reviews, Volume 20. https://doi.org/
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20 - 2026

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Copyright © 2026 Ważny, Ciesielka, Jakimów, Tobiasz, Kluszczyk, Owczarek, Winder and Chudek.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Łukasz Ważny; Jerzy T. Chudek

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