Case Report: The integration of chemoradiotherapy and immunotherapy in a patient with advanced-stage renal squamous cell carcinoma and pulmonary metastases

Renal squamous cell carcinoma (RSCC) is an uncommon malignancy, representing less than 1% of all renal cancers, and is associated with a notably poor prognosis. Surgical intervention is the primary treatment modality for early and intermediate-stage cases; however, the efficacy of combined chemoradiotherapy and immunotherapy in advanced-stage patients remains unclear. In this report, we present a case of RSCC with pulmonary metastases, wherein the patient attained disease remission following a treatment regimen comprising combined chemo-radiotherapy and immunotherapy. The patient demonstrated a progression-free survival (PFS) of 12 months and an overall survival (OS) of 14 months. This case study aims to provide a comprehensive analysis of the treatment approach, potentially serving as a reference for therapeutic strategies in patients with inoperable RSCC.

1 Introduction

Renal squamous cell carcinoma (RSCC), a highly uncommon and aggressive variant of renal cell carcinoma (RCC), accounts for less than 1% of all renal malignancies. This subtype is marked by limited therapeutic options and rapid disease progression, leading to a poor prognosis (1). As a subtype of non-clear cell renal cell carcinoma (nccRCC), RSCC demonstrates significant heterogeneity. Notably, nccRCC is distinguished from clear cell renal cell carcinoma (ccRCC) by its unique molecular characteristics and differential treatment responses (2). The development of RSCC is potentially attributable to distinct carcinogenic pathways. Various etiological factors, such as nephrolithiasis, prior radiotherapy, analgesic misuse, and infections, have been implicated in the pathogenesis of squamous cell carcinoma of the upper urinary tract. These factors induce chronic and persistent urothelial injury, leading to squamous metaplasia and dysplasia, which may progress to squamous cell carcinoma (3, 4). Approximately 50% of patients diagnosed with primary renal squamous cell carcinoma (PRSCC) present with concurrent nephrolithiasis or chronic infections. However, the patient in the present case study reported no history of nephrolithiasis, urinary tract infections, or urinary schistosomiasis, indicating the potential involvement of alternative carcinogenic mechanisms. Currently, there is an absence of studies elucidating the specific molecular mechanisms or oncogenes associated with RSCC, leaving its molecular pathogenesis inadequately understood. RSCC is characterized by rapid progression and a propensity for early distant metastasis, which contributes to a poor clinical prognosis. Among patients with renal malignancies, synchronous lung metastasis is the most prevalent pattern of metastasis, followed by metastasis to the bone, lymph nodes, and liver (5). There is presently a paucity of standardized treatment protocols for metastatic nccRCC, with limited large-scale randomized clinical trials available. Consequently, clinical decision-making predominantly relies on small-scale studies and expert consensus (6–8). As one of the rarest subtypes of nccRCC, RSCC suffers from a particularly limited body of evidence-based medical research, further complicating its treatment (9). In this report, we present the first documented case of RSCC complicated by pulmonary metastases, which was managed with a combination of chemoradiotherapy and immunotherapy.

2 Case report

In September 2022, a 65-year-old male presented with a 2-month history of recurrent flank pain and hematuria. Serum biochemistry was normal, but tumor markers indicated elevated levels: squamous cell carcinoma antigen (SCC) at 2.88 ng/mL (normal 0–1.5 ng/mL), carbohydrate antigen 19-9 (CA 19-9) at 7.13 ng/mL (normal 0–3.4 ng/mL), and cytokeratin 19 fragment (CYFRA 21–1) at 22.9 ng/mL (normal 0–3.3 ng/mL). A contrast-enhanced CT scan showed an irregular hypodense mass (9.4 × 7.9 cm) in the left renal parenchyma, indicating renal carcinoma with intra-abdominal and retroperitoneal lymph node metastases (Figure 1A). Thoracic Computed Tomography (CT) identified multiple bilateral pulmonary nodules, suggesting metastases (Figure 1B). Color Doppler ultrasound detected left renal vein thrombosis. After the first multidisciplinary team (MDT) discussion, due to the high risk of renal biopsy, a CT-guided percutaneous lung biopsy was conducted in October 2022. Histopathological analysis confirmed the presence of squamous cell carcinoma (Figure 2A), with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 55% (Figures 2B–D). Immunohistochemical staining revealed the following profile: TTF-1(SPT24)(-),NapsinA(-), P40(+),ALK(-),CK(P)(+),Vimentin(+),CK7(+),WT-1(-),PAX8(-). Following a second MDT discussion, a comparative analysis of metastatic patterns and clinical manifestations strongly indicated a primary renal malignancy originating in the left kidney, with pulmonary metastases. Additionally, concurrent intra-abdominal and retroperitoneal lymph node metastases were confirmed. A comprehensive evaluation classified the disease as advanced stage, specifically cT3N2M1, stage IV, according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system for renal carcinoma.

Figure 1

Figure 1. Treatment flowchart and imaging changes during therapy: initial diagnosis (September 2022): (A) Contrast-enhanced urological CT: 9.4×7.9 cm irregular low-density mass in left renal parenchyma. (B) Chest CT: multiple small bilateral pulmonary nodules. Lung biopsy (October 2022, due to risk) confirmed SCC. Second MDT diagnosed PRSCC with pulmonary metastases. After radiotherapy combined with two cycles of chemo-immunotherapy, December 2022 CT: (C) left renal lesion stable; (D) bilateral pulmonary nodules significantly decreased. Pre-third chemotherapy, CT re-examination: (E) left renal mass reduced to 8.5 × 7.7 cm; (F) most pulmonary lesions further regressed, lesion marked by yellow arrow (F left panel) resolved. Patient continued q3w immunotherapy and received two additional nab-paclitaxel cycles. September 2023 re-evaluation: PD. Patient succumbed to AKI (November 2023), OS 14 months. MDT, multidisciplinary team; SCC, squamous cell carcinoma; RSCC, renal squamous cell carcinoma; SD, stable disease; PR, partial response; RT, radiotherapy; CT, chemotherapy; IO, immunotherapy; MT, medical treatment; PFS, progression-free survival; OS, overall survival; IMT, Immunological Maintenance Therapy; AKI, acute kidney injury. PD, Progressive Disease.

Figure 2

Figure 2. Histopathological examination. (A) Hematoxylin and eosin (H&E) staining of a pulmonary metastatic lesion reveals the presence of squamous cell carcinoma. (B) Positive control immunohistochemistry (IHC) of pulmonary metastasis using EnVision two-step method. (C, D) Assessment of PD-L1 expression in pulmonary metastasis employing the EnVision two-step method.

The patient is a practitioner of Chinese medicine with a decade-long history of hypertension, during which his systolic blood pressure reached a peak of 220 mmHg. His hypertension is effectively managed with amlodipine and metoprolol. He also has an 8-year history of type 2 diabetes, currently treated with metformin, although the status of his glycemic control is not documented. Additionally, the patient has a history of coronary artery disease and takes aspirin on an intermittent basis. He has a smoking history spanning over 20 years, during which he smoked 40 cigarettes daily, but he ceased smoking 10 years ago. Furthermore, he has a history of alcohol consumption exceeding 30 years at a rate of 100 ml per day, but he discontinued alcohol use six months ago. The patient denies any history of infectious diseases, including hepatitis and tuberculosis, as well as any history of surgical procedures, trauma, or blood transfusions. He reports no known food or drug allergies and has no family history of cancer. In light of the limited incidence of advanced RSCC cases and the lack of extensive randomized controlled trials, in conjunction with the patient’s comorbid conditions—namely hypertension, diabetes mellitus, and coronary artery disease—which contraindicate surgical intervention, the second MDT consensus meeting devised a treatment plan consistent with the biological characteristics of squamous carcinoma. This plan involved the integration of chemoradiotherapy and immunotherapy. Financial limitations restricted the patient’s access to category I recommended agents as per the Chinese Society of Clinical Oncology (CSCO)/National Comprehensive Cancer Network (NCCN) guidelines (pembrolizumab/nivolumab), leading to the selection of tislelizumab as the immunotherapeutic agent. Concurrently, to manage ongoing flank pain and gross hematuria, the patient received localized radiotherapy (60 Gy over 30 fractions) directed at the primary renal lesion (Figure 3) from October to December 2022. During the course of radiotherapy, the patient was administered two cycles of combination therapy, consisting of nanoparticle albumin-bound paclitaxel (0.3 g intravenously on day 1 every 3 weeks) and tislelizumab (200 mg intravenously on day 1 every 3 weeks). In accordance with the NCCN guidelines, prophylactic administration of granulocyte colony-stimulating factor was implemented for the patient, as the albumin-bound paclitaxel utilized is part of a high-risk chemotherapy regimen. Consequently, no myelosuppression was observed throughout the treatment period. The patient experienced only mild nausea and vomiting, classified as Grade 1, which improved following antiemetic treatment with tropisetron. No adverse reactions related to radiotherapy were noted during this time. Following this therapeutic regimen, a chest CT scan conducted at discharge in December 2022 demonstrated a significant regression of bilateral pulmonary lesions compared to baseline imaging from September 2022 (Figure 1D). Concurrently, an abdominal CT scan revealed stability in the primary renal lesions (Figure 1C). According to RECIST 1.1 criteria, the pulmonary response was classified as a partial response (PR), with systemic disease stabilization (SD).

Figure 3

Figure 3. Delineation of radiation target volume. The axial enhanced CT image at the level of the largest diameter of the renal primary lesion, as planned using the Pinnacle system, shows the following: The Gross Tumor Volume (GTV) is outlined by the red solid line, indicating a 9.4×7.9 cm primary lesion in the left kidney. The Clinical Target Volume (CTV) is delineated by the purple solid line, representing the GTV expanded by 10 mm to include the high-risk retroperitoneal lymph node area. The prescribed dose is 60 Gy to the CTV, delivered in 30 fractions.

In January 2023, a follow-up thoracic CT scan showed further regression of the lesions (Figure 1F), including the complete resolution of select metastases (left panel, Figure 1F). Abdominal imaging indicated a reduction in the size of the left renal mass to 8.5 × 7.7 cm, along with the resolution of hematuria and flank pain. Consequently, the overall response was upgraded to a PR, leading to the continuation of the original regimen: two additional cycles of nanoparticle albumin-bound paclitaxel (0.3 g IV on day 1, every three weeks) in combination with tislelizumab (200 mg IV on day 1, every three weeks). Subsequent maintenance immunotherapy with tislelizumab (200 mg every three weeks) was administered at a local hospital. During the immunotherapy period, there were no observed adverse reactions, including immune nephritis, immune pneumonia, immune hepatitis, hematuria, endocrine disorders, or dermatological issues.

By September 2023, the patient experienced recurrent gross hematuria subsequent to the self-administration of traditional Chinese medicine. Laboratory analyses revealed acute kidney injury, characterized by a serum creatinine level of 567.1 μmol/L (reference range: 44-120 μmol/L), a potassium level of 5.91 mmol/L (reference range: 3.5-5.3 mmol/L), and an elevated SCC of 8 ng/mL. The most recent computed tomography scan conducted at our institution demonstrated sustained pulmonary improvement; however, it also indicated a progressive enlargement of over 20% in the left renal hilar lymph nodes and ipsilateral adrenal nodules, exhibiting heterogeneous enhancement, which met the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) criteria for Progressive Disease (PD). The patient achieved a progression-free survival (PFS) of 12 months. Within 48 hours, the patient deteriorated to anuria accompanied by worsening azotemia (estimated glomerular filtration rate [eGFR] of 8.25 mL/min/1.73 m²; reference range: 80-120), necessitating intensive care unit management and nephrology intervention. The clinical trajectory ultimately resulted in end-stage renal disease (ESRD), requiring dialysis. Two months later, the patient succumbed to multi-organ failure secondary to acute renal failure, resulting in an overall survival (OS) of 14 months. (For a comprehensive overview of the entire treatment course, please consult Table 1).

Table 1

Table 1. Timeline of treatment and clinical outcomes.

3 Discussion

In this study, we present a rare case of squamous cell carcinoma characterized by a space-occupying lesion in the left kidney, accompanied by bilateral lung metastases. The identification of the primary site has been a subject of considerable debate. Imaging findings suggest a primary tumor in the left kidney with venous tumor thrombus; however, histological confirmation could not be obtained due to the risks associated with biopsy. Conversely, the pathologically confirmed lung squamous cell carcinoma raises the possibility of either a primary lung tumor metastasizing to the kidney or a primary renal carcinoma metastasizing to the lungs, without ruling out the potential for dual primary sites. Following a comprehensive MDT evaluation, and based on the principles of monism, imaging characteristics, tumor biological behavior, and analysis of metastatic patterns, the final diagnosis was established as primary renal squamous cell carcinoma with bilateral lung metastases. The primary diagnostic criteria are as follows:

Primary renal squamous cell carcinoma (PRSCC) accounts for less than 1% of urological malignancies and is characterized as a rare and highly aggressive tumor with a poor prognosis. PRSCC predominantly originates from the renal pelvis (10), while its occurrence in the renal parenchyma is relatively uncommon (11). In this case, the renal lesion was situated within the renal parenchyma, which is inconsistent with the typical primary site distribution of renal squamous cell carcinoma. In contrast to the rarity of renal squamous cell carcinoma, lung squamous cell carcinoma (LSCC) is the second most common histological subtype of non-small cell lung cancer, following adenocarcinoma (12, 13). LSCC generally originates in the central regions of the lungs or major airways (14). However, in the present case, pulmonary lesions were predominantly located in peripheral regions, which contradicts the typical primary site preference associated with LSCC. If anatomical localization discrepancies cannot definitively determine the primary origin of squamous cell carcinoma in this instance, can reliance solely on the incidence disparity between LSCC and RSCC suffice to establish the diagnosis? Although LSCC has a significantly higher incidence than RSCC, their metastatic patterns exhibit distinct biological differences. The most common metastatic sites for lung cancer include the brain and bones, whereas solitary renal metastasis from primary pulmonary squamous cell carcinoma is exceedingly rare (15). Moreover, renal metastases typically present as small, multifocal, bilateral, wedge-shaped, endophytic lesions confined within the renal capsule (16). In stark contrast, the renal lesion in this case demonstrated characteristics that were fundamentally different: it was a large (9.4×7.9 cm), solitary, unilateral mass confined within the renal parenchyma, markedly deviating from the typical radiological features associated with metastatic renal involvement. Furthermore, in the cohort of lung cancer patients with renal metastases studied by Adamy et al., only 15% exhibited gross hematuria, with the majority of renal metastatic lesions remaining asymptomatic (17). Notably, the present case displayed prominent symptoms of gross hematuria and flank pain, while completely lacking pulmonary symptoms, thereby further diminishing the likelihood of a primary pulmonary origin. In contrast, the metastatic profile of renal carcinoma closely aligns with the current case. The lung is the most common site for metastasis in renal carcinoma, accounting for 45% of metastatic renal cell carcinoma cases, with pulmonary metastases typically remaining asymptomatic (5). Sas S et al. reported that among 10 incidentally diagnosed cases of RSCC, two exhibited metastatic pulmonary nodules (18). This discrepancy in metastatic patterns, coupled with contrasting clinical presentations, provides critical evidence supporting the diagnostic orientation towards a primary renal origin with pulmonary metastases.

The clinical diagnosis and management of PRSCC continue to present significant challenges, as no standardized guidelines or treatment protocols have been established to date. Radical surgery remains the primary therapeutic option for early- and intermediate-stage PRSCC (19). Given that the majority of renal squamous cell carcinomas are diagnosed at advanced stages (20), characterized pathologically by moderately to poorly differentiated histology, the prognosis remains poor, with 5-year survival rates below 10% (21). This underscores the urgent need to explore novel therapeutic strategies. In recent years, immune checkpoint inhibitors (ICIs) have made groundbreaking advancements in the treatment of renal cell carcinoma (RCC). The KEYNOTE-564 trial has shown that adjuvant pembrolizumab significantly extends disease-free survival in patients with high-risk clear cell RCC (ccRCC) (22) Regrettably, there remains an absence of standardized treatment protocols for RSCC. At present, there are no documented cases of immunotherapy application for PRSCC, and the available evidence is confined to small-scale investigations concentrating on non-clear cell renal cell carcinoma (nccRCC) subtypes (23). Among the most extensive prospective trials conducted thus far is Cohort B of the KEYNOTE-427 trial. This multicenter, non-randomized phase II study involved 165 patients with advanced nccRCC who received pembrolizumab monotherapy as a first-line treatment, resulting in an objective response rate (ORR) of 26.7% in the overall population and a median progression-free survival (mPFS) of 4.2 months (24). Similarly, the CheckMate 374 trial demonstrated that nivolumab monotherapy achieved favorable anti-tumor efficacy in patients with advanced nccRCC, with an ORR of 23% and an mPFS of 4.0 months (25). Furthermore, a meta-analysis conducted by the Petrelli group, which encompassed 23 studies on first-line immunotherapy for various nccRCC subtypes, corroborated the efficacy of ICIs, reporting a pooled ORR of 26.6% and a median PFS of 6.59 months (26). Nonetheless, Nevertheless, none of these studies specifically incorporated the RSCC subtype in their analyses. Concurrently, other research indicates that patients with nccRCC may experience less favorable survival outcomes from immune checkpoint inhibitor (ICI) monotherapy compared to those with ccRCC (25, 27–30). A study conducted by Bimbatti et al. further corroborated the significant variations in treatment efficacy among nccRCC subtypes. They categorized nccRCC into papillary renal cell carcinoma (pRCC), renal cell carcinoma not otherwise specified (NOS-RCC), and other histological types, discovering that the mPFS following ICI treatment was 9.7 months for pRCC patients, whereas it was merely 3.0 months for other nccRCC subtypes (31). These disparate findings suggest that the effectiveness of ICIs in treating nccRCC is highly contingent upon the tumor’s histological subtype and inherent heterogeneity. Nevertheless, current evidence suggests that patients with nccRCC may experience a relatively high ORR with first-line ICI therapy (28, 29). Furthermore, research has demonstrated that patients exhibiting positive programmed death-ligand 1 (PD-L1) expression derive significantly greater benefit from ICI treatment compared to those with negative PD-L1 expression (32–34). This correlation has been substantiated by large-scale studies; for instance, in a cohort of 8,887 patients analyzed by Christopher et al., the degree of therapeutic benefit was markedly higher in individuals with elevated PD-L1 expression (P = 0.006) (35). Consequently, PD-L1-positive patients may achieve the greatest survival advantage from adjuvant immunotherapy (36, 37), thereby providing a theoretical foundation for the use of ICIs in PRCC. However, clinical decision-making must holistically consider factors such as tumor histological subtype, patient physical status, comorbidities, and clinical manifestations (27).

This case involves a 65-year-old male patient diagnosed with renal squamous cell carcinoma (cT3N2M1, stage IV), which is complicated by lung metastasis and a tumor thrombus in the left renal vein. The patient’s Eastern Cooperative Oncology Group (ECOG) performance status is 1, and he has a medical history that includes hypertension, diabetes, and coronary atherosclerotic heart disease, rendering him inoperable. Currently, there is no established systemic treatment protocol for metastatic renal squamous cell carcinoma. In light of the rarity of such cases, Sas S et al. have proposed a treatment regimen consisting of cisplatin-based chemotherapy combined with palliative radiotherapy for similar advanced cases (18), which aligns with our initial treatment strategy. However, the survival benefit associated with this regimen remains uncertain, as none of the participants in their study elected to undergo chemotherapy. In light of the absence of standardized systemic treatment protocols for nccRCC, encompassing RSCC, combined with the patient’s surgical contraindications, an individualized treatment strategy was developed after thorough deliberations by a MDT. Given the patient’s compromised general health and multiple comorbidities, which could potentially lead to intolerance of cisplatin chemotherapy’s side effects, single-agent albumin-bound paclitaxel was selected. Concurrently, palliative radiotherapy targeting the renal lesion was incorporated to alleviate hematuria and mitigate the risk of tumor thrombus detachment. Genetic testing revealed a PD-L1 tumor proportion score (TPS) of 55%, indicating a potential benefit from immunotherapy. Although pembrolizumab was initially recommended, tislelizumab was ultimately selected due to the patient’s financial limitations. Following two cycles of combined chemo-immunotherapy and radiotherapy, subsequent chest CT scans demonstrated significant regression of pulmonary lesions (Figure 1D). Continued triweekly immunotherapy over two months resulted in further reduction, including complete resolution of certain lesions (left panel, Figure 1F). The overall response was classified as a PR according to the RECIST v1.1 criteria.

Following radiotherapy, the primary renal lesion exhibited resolution of hematuria and flank pain; however, the extent of tumor reduction did not satisfy the criteria for PR. This outcome contrasts sharply with the significant regression observed in pulmonary metastatic lesions, a discrepancy that may be attributed to the inherent radioresistance of RCC to conventional fractionated radiotherapy (38). Funayama et al. reported that even with the application of stereotactic body radiation therapy (SBRT), which is known for its potent cytotoxic effects, renal tumor responses were notably slow. Among 13 RCC patients studied, the majority achieved PR, but only after a gradual reduction in tumor volume over extended periods, with a median time to confirmed PR of 22.6 months for partial or complete responders (39). In the present case, the primary renal lesion demonstrated a 14.3% reduction in volume (from 9.4×7.9 cm to 8.5×7.7 cm) within 4 months, aligning with the criteria for Grade II radiosensitivity classification.

The notable regression of pulmonary metastatic lesions may result from the synergistic interactions of multiple mechanisms. The primary focus is the radiation-induced abscopal effect, a biological phenomenon first described by Mole in 1953, characterized by the spontaneous regression of unirradiated distant metastases following localized radiotherapy (40). The incidence of the abscopal effect varies considerably across different tumor types. A meta-analysis conducted by Steven et al. revealed that approximately two-thirds of reported abscopal effects were concentrated in specific malignancies, such as renal carcinoma, non-small cell lung cancer, and melanoma (41). Of greater clinical significance is the systematic review by Abuodeh et al., which examined globally reported cases from 1969 to 2014. Among the 46 cases of the abscopal effect, three patients with RCC exhibited pulmonary metastatic regression following irradiation of the primary renal tumor (42), a pattern that closely resembles the clinical course observed in the present case.

At the mechanistic level, radiotherapy induces immunogenic cell death (ICD) in tumor cells, leading to the release of tumor-associated antigens (TAAs) and the activation of inflammatory signaling pathways, which collectively initiate systemic anti-tumor immune responses. Nevertheless, the incidence of abscopal effects resulting from radiotherapy alone remains below 5%. An increasing body of research suggests that the combination of radiotherapy with immunotherapy markedly enhances abscopal responses (40). Specifically, PD-1/PD-L1 blockade reverses T-cell exhaustion and amplifies radiation-induced systemic immunity. This synergistic approach facilitates the migration of tumor-reactive T cells to non-irradiated sites, thereby inducing regression of secondary tumors beyond the radiation field and achieving effective control of distant metastases (43, 44). In the current case, the concurrent administration of the PD-1 inhibitor tislelizumab during radiotherapy likely mediated the observed abscopal effect through these mechanisms. While radiation and immunotherapy may have predominantly contributed to the regression of pulmonary metastases, the synergistic impact of nab-paclitaxel should not be underestimated. As a classic chemotherapeutic agent, the paclitaxel family is extensively employed in cancer treatment due to its strong microtubule-stabilizing properties (45). In comparison to conventional paclitaxel formulations, nab-paclitaxel utilizes the enhanced permeability and retention (EPR) effect to achieve greater tumor-targeted accumulation. This not only augments antitumor efficacy but also significantly enhances drug safety and tolerability (46). Therefore, the pronounced response of pulmonary lesions observed in this case is likely attributable to the integrated mechanisms of radiotherapy, immunotherapy, and chemotherapy.

The patient experienced acute kidney injury (AKI) 12 months following the administration of combined chemoradiotherapy and ICI therapy, subsequently succumbing to the condition 2 months thereafter. A comprehensive analysis of the etiology of AKI in this case necessitates consideration of several multidimensional factors. Firstly, a large-scale meta-analysis conducted by Amisha et al., encompassing 48 clinical studies with a total of 11,482 participants, reported an overall incidence of AKI following PD-1 inhibitor therapy at merely 2.2% (47). The median onset of ICI-related AKI (ICPi-AKI) was identified at 16 weeks post-treatment (IQR 8–32 weeks). In this particular case, AKI manifested 48 weeks (12 months) after the initiation of treatment, representing a delay of 32 weeks beyond the typical onset period, thereby attenuating the causal link to ICPi-AKI. Secondly, from a pathological perspective, acute interstitial nephritis (AIN) is the predominant histological manifestation of ICI-related toxicity (48). However, this patient lacked renal biopsy histopathological evidence or key indicators such as eosinophilic infiltration, making it difficult to directly attribute AKI to immune toxicity. Merza’s study identified a history of hypertension as an independent risk factor for AKI (OR 4.3; 95% CI 1.8–6.1; p<0.001). Notably, AKI was found to be independent of the type of ICI drug or cancer type (49). This particular patient had a 10-year history of hypertension, coronary artery disease, and diabetes, suggesting that the underlying renal injury due to chronic hemodynamic alterations should not be overlooked. Furthermore, the patient consistently self-administered complex traditional Chinese medicine formulations during treatment, which may have contained nephrotoxic components that exacerbated renal dysfunction through drug-drug interactions. Additionally, the concurrent progression of the primary renal lesion at the onset of AKI raises the possibility of tumor infiltration or factors related to paraneoplastic syndrome. In conclusion, the etiology of AKI in this patient is likely attributable to multifactorial interactions among preexisting comorbidities, pharmacological toxicity, and tumor progression.

In light of the fact that the majority of RSCC cases documented in the current literature have been treated surgically, and there is a paucity of directly comparable cases involving combined chemoradiotherapy with immunotherapy or immunotherapy alone (50, 51), this study employed an indirect comparison approach. Sas et al. documented 14 RSCC patients who underwent surgical treatment without immunotherapy, reporting a median OS of merely 5 months (18). In contrast, the patient with advanced-stage RSCC in this study received combined chemoradiotherapy with immunotherapy, resulting in an OS of 14 months, which is nearly threefold longer than that associated with the conventional treatment approach. Furthermore, when compared to other rare subtypes of nccRCC, Li et al. described a case involving a 60-year-old male patient with collecting duct carcinoma (CDC, with an incidence of approximately 1%), who exhibited PD within 1 month and achieved an OS of less than 2 months following treatment with chemotherapy, camrelizumab immunotherapy, and sorafenib targeted therapy (52). In conclusion, this case illustrates that the integration of the radiotherapy-induced abscopal effect with the synergistic impact of chemotherapy-immunomodulation substantially extended the survival of patients with advanced RSCC, suggesting a promising new treatment paradigm for inoperable cases. Nevertheless, the findings of this study are derived from the treatment experience of a single patient; thus, the generalizability and long-term efficacy of these results require further validation through cohort studies with larger sample sizes.

4 Conclusion

In conclusion, renal squamous cell carcinoma (RSCC) is an uncommon malignancy. For patients who are not candidates for surgical intervention, the combination of chemoradiotherapy and PD-1 inhibitors has shown promising efficacy, potentially extending survival and improving prognosis to a certain degree. This approach may serve as a valuable reference for the comprehensive management of advanced RSCC, although vigilant monitoring for nephrotoxicity is essential.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

Ethics statement

The studies involving humans were approved by Institutional Review Board of Taihe Hospital, affiliated hospital of Hubei University of Medicine. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

YN: Writing – original draft, Writing – review & editing. SW: Writing – review & editing, Data curation. XD: Writing – review & editing. ML: Writing – review & editing. JC: Writing – review & editing. ZL: Writing – review & editing.

Funding

The author(s) declare financial support was received for the research and/or publication of this article. This work was funded by the Central Guidance on Local Science and Technology Development Fund of Hubei Province (Grant No.2022BGE270), the Natural Science Foundation of Hubei Province (2024AFB335, 2024AFB352, 2024AFD434, 2023AFB180).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Moch H, Cubilla AL, Humphrey PA, Reuter VE, and Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs—part a: Renal, penile, and testicular tumours. Eur Urol. (2016) 70:93–105. doi: 10.1016/j.eururo.2016.02.029

PubMed Abstract | Crossref Full Text | Google Scholar

2. Drobner J, Portal D, Runcie K, Yang Y, and Singer EA. Systemic treatment for advanced and metastatic non-clear cell renal cell carcinoma: Examining modern therapeutic strategies for a notoriously challenging Malignancy. J Kidney Cancer VHL. (2023) 10:37–60. doi: 10.15586/jkcvhl.v10i3.295

PubMed Abstract | Crossref Full Text | Google Scholar

3. Busby JE, Brown GA, Tamboli P, Kamat AM, Dinney CPN, Grossman HB, et al. Upper urinary tract tumors with nontransitional histology: a single-center experience. Urology. (2006) 67:518–23. doi: 10.1016/j.urology.2005.09.010

PubMed Abstract | Crossref Full Text | Google Scholar

4. Tyagi N, Sharma S, Tyagi SP, Maheshwari V, Nath P, Ashraf SM, et al. A histomorphologic and ultrastructural study of the Malignant tumours of the renal pelvis. J Postgrad Med. (1993) 39:197–201.

PubMed Abstract | Google Scholar

5. Vig SV, Zan E, and Kang SK. Imaging for metastatic renal cell carcinoma. Urol Clin North Am. (2020) 47:281–91. doi: 10.1016/j.ucl.2020.04.005

PubMed Abstract | Crossref Full Text | Google Scholar

6. Motzer RJ, Jonasch E, Agarwal N, Alva A, Baine M, Beckermann K, et al. Kidney cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw: JNCCN. (2022) 20:71–90. doi: 10.6004/jnccn.2022.0001

PubMed Abstract | Crossref Full Text | Google Scholar

7. John A, Spain L, and Hamid AA. Navigating the current landscape of non-clear cell renal cell carcinoma: A review of the literature. Curr Oncol. (2023) 30:923–37. doi: 10.3390/curroncol30010070

PubMed Abstract | Crossref Full Text | Google Scholar

8. Sepe P, Ottini A, Pircher CC, Franza A, Claps M, Guadalupi V, et al. Characteristics and treatment challenges of non-clear cell renal cell carcinoma. Cancers. (2021) 13:3807. doi: 10.3390/cancers13153807

PubMed Abstract | Crossref Full Text | Google Scholar

9. Rini BI, Battle D, Figlin RA, George DJ, Hammers H, Hutson T, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J immunotherapy Cancer. (2019) 7:354. doi: 10.1186/s40425-019-0813-8

PubMed Abstract | Crossref Full Text | Google Scholar

10. Ghosh P and Saha K. Primary intraparenchymal squamous cell carcinoma of the kidney: a rare and unique entity. Case Rep Pathol. (2014) 2014:1–3. doi: 10.1155/2014/256813

PubMed Abstract | Crossref Full Text | Google Scholar

11. Xiao J, Lei J, He L, and Yin G. Renal calculus complicated with squamous cell carcinoma of renal pelvis: Report of two cases. Can Urol Assoc J. (2015) 9:310. doi: 10.5489/cuaj.2441

PubMed Abstract | Crossref Full Text | Google Scholar

12. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, and Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2018) 68:394–424. doi: 10.3322/caac.21492

PubMed Abstract | Crossref Full Text | Google Scholar

13. Pan Y, Han H, Labbe KE, Zhang H, and Wong K-K. Recent advances in preclinical models for lung squamous cell carcinoma. Oncogene. (2021) 40:2817–29. doi: 10.1038/s41388-021-01723-7

PubMed Abstract | Crossref Full Text | Google Scholar

14. Sabbula BR, Gasalberti DP, Mukkamalla SKR, and Anjum F. Squamous cell lung cancer. In: StatPearls. StatPearls Publishing, Treasure Island (FL (2025).

PubMed Abstract | Google Scholar

15. Wang J, Wang L, Long L, Tao Q, Xu F, and Luo F. Solitary renal metastasis from squamous cell carcinoma of the lung: a case report. Med (Baltimore). (2019) 98:e14310. doi: 10.1097/MD.0000000000014310

PubMed Abstract | Crossref Full Text | Google Scholar

16. Wu M-Z, Pan H-J, Zhou A-A, and Tian J-Q. Renal metastasis from lung squamous-cell carcinoma: a case report. Asian J Surg. (2023) 46:2261–2. doi: 10.1016/j.asjsur.2022.11.132

PubMed Abstract | Crossref Full Text | Google Scholar

17. Adamy A, Von Bodman C, Ghoneim T, Favaretto RL, Bernstein M, and Russo P. Solitary, isolated metastatic disease to the kidney: memorial sloan-kettering cancer center experience. BJU Int. (2011) 108:338–42. doi: 10.1111/j.1464-410X.2010.09771.x

PubMed Abstract | Crossref Full Text | Google Scholar

18. Sas S, Na M, Hh Q, M H, G S, R M, et al. Squamous cell carcinoma of the kidney: A large case series. Oncol (willist Park NY). (2023) 37:246–249. doi: 10.46883/2023.25920997.

PubMed Abstract | Crossref Full Text | Google Scholar

19. Ni S, Tao W, Chen Q, Liu L, Jiang H, Hu H, et al. Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. Eur Urol. (2012) 61:1142–53. doi: 10.1016/j.eururo.2012.02.019

PubMed Abstract | Crossref Full Text | Google Scholar

20. Holmäng S, Lele SM, and Johansson SL. Squamous cell carcinoma of the renal pelvis and ureter: Incidence, symptoms, treatment and outcome. J Urol. (2007) 178:51–6. doi: 10.1016/j.juro.2007.03.033

PubMed Abstract | Crossref Full Text | Google Scholar

21. Bhaijee F. Squamous cell carcinoma of the renal pelvis. Ann Diagn Pathol. (2012) 16:124–7. doi: 10.1016/j.anndiagpath.2011.08.009

PubMed Abstract | Crossref Full Text | Google Scholar

22. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. (2024) 390:1359–71. doi: 10.1056/NEJMoa2312695

PubMed Abstract | Crossref Full Text | Google Scholar

23. Hinata N, Yonese J, Masui S, Nakai Y, Shirotake S, Tatsugami K, et al. A multicenter retrospective study of nivolumab monotherapy in previously treated metastatic renal cell carcinoma patients: Interim analysis of Japanese real-world data. Int J Clin Oncol. (2020) 25:1533–42. doi: 10.1007/s10147-020-01692-z

PubMed Abstract | Crossref Full Text | Google Scholar

24. McDermott DF, Lee J-L, Ziobro M, Suarez C, Langiewicz P, Matveev VB, et al. Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol. (2021) 39:1029–39. doi: 10.1200/JCO.20.02365

PubMed Abstract | Crossref Full Text | Google Scholar

25. Vogelzang NJ, Olsen MR, McFarlane JJ, Arrowsmith E, Bauer TM, Jain RK, et al. Safety and efficacy of nivolumab in patients with advanced non-clear cell renal cell carcinoma: Results from the phase IIIb/IV CheckMate 374 study. Clin Genitourin Cancer. (2020) 18:461–468.e3. doi: 10.1016/j.clgc.2020.05.006

PubMed Abstract | Crossref Full Text | Google Scholar

26. Petrelli F, Verri E, Ghidini A, Vavassori I, Lonati V, Nolè F, et al. First-line therapy for advanced non–clear cell renal cell carcinoma: A systematic review and meta-analysis. JAMA Oncol. (2025) e251891. doi: 10.1001/jamaoncol.2025.1891

PubMed Abstract | Crossref Full Text | Google Scholar

27. Palma Dos Reis AF, Simão D, Odeny T, Rodrigues C, Fontes-Sousa M, da Luz R, et al. A systematic review of immune checkpoint inhibitors in non-clear-cell renal cancer. Kidney Cancer (clifton Va). (2022) 6:115–27. doi: 10.3233/KCA-210012

PubMed Abstract | Crossref Full Text | Google Scholar

28. McKay RR, Bossé D, Xie W, Wankowicz SAM, Flaifel A, Brandao R, et al. The clinical activity of PD-1/PD-L1 inhibitors in metastatic non-clear cell renal cell carcinoma. Cancer Immunol Res. (2018) 6:758–65. doi: 10.1158/2326-6066.CIR-17-0475

PubMed Abstract | Crossref Full Text | Google Scholar

29. Chahoud J, Msaouel P, Campbell MT, Bathala T, Xiao L, and Gao J. Nivolumab for the treatment of patients with metastatic non-clear cell renal cell carcinoma (nccRCC): A single-institutional experience and literature meta-analysis. Oncologist. (2020) 25:252–258. doi: 10.1634/theoncologist.2019-0372

PubMed Abstract | Crossref Full Text | Google Scholar

30. Barata P, Hatton W, Desai A, Koshkin V, Jaeger E, Manogue C, et al. Outcomes with first-line PD-1/PD-L1 inhibitor monotherapy for metastatic renal cell carcinoma (mRCC): A multi-institutional cohort. Front Oncol. (2020) 10:581189. doi: 10.3389/fonc.2020.581189

PubMed Abstract | Crossref Full Text | Google Scholar

31. Bimbatti D, Pierantoni F, Lai E, Ballestrin M, Cavasin N, Erbetta E, et al. Advanced non-clear cell renal cell carcinoma treatments and survival: A real-world single-centre experience. Cancers. (2023) 15:4353. doi: 10.3390/cancers15174353

PubMed Abstract | Crossref Full Text | Google Scholar

32. Shen X and Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ (clin Res Ed). (2018) 362:k3529. doi: 10.1136/bmj.k3529

PubMed Abstract | Crossref Full Text | Google Scholar

33. Zhang Y, Chen J, Wang X, Wang H, Chen X, Hong J, et al. Effectiveness of systemic treatments for advanced non-clear cell renal cell carcinoma: A systematic review and meta-analysis. Front Oncol. (2024) 14:1478245. doi: 10.3389/fonc.2024.1478245

PubMed Abstract | Crossref Full Text | Google Scholar

34. Yi L, Wang X, Fu S, Yan Z, Ma T, Li S, et al. Association between response to anti-PD-1 treatment and blood soluble PD-L1 and IL-8 changes in patients with NSCLC. Discov Oncol. (2023) 14:35. doi: 10.1007/s12672-023-00641-2

PubMed Abstract | Crossref Full Text | Google Scholar

35. Wallis CJD, Lawson K, Butaney M, Satkunasivam R, Parikh J, Freedland SJ, et al. Association between PD-L1 status and immune checkpoint inhibitor response in advanced Malignancies: a systematic review and meta-analysis of overall survival data. Jpn J Clin Oncol. (2020) 50:800–9. doi: 10.1093/jjco/hyaa021

PubMed Abstract | Crossref Full Text | Google Scholar

36. Riveros C, Huang E, Ranganathan S, Klaassen Z, Rini B, Wallis CJD, et al. Adjuvant immunotherapy in renal cell carcinoma: A systematic review and meta-analysis. BJU Int. (2023) 131:553–61. doi: 10.1111/bju.15981

PubMed Abstract | Crossref Full Text | Google Scholar

37. McGregor BA, McKay RR, Braun DA, Werner L, Gray K, Flaifel A, et al. Results of a multicenter phase II study of atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features. J Clin Oncol: Off J Am Soc Clin Oncol. (2020) 38:63–70. doi: 10.1200/JCO.19.01882

PubMed Abstract | Crossref Full Text | Google Scholar

38. Cai L, Chen K, Pan Q, Zhang X, Liu R, Liu Y, et al. Response evaluation and tumor shrinkage pattern post-SBRT for renal cell carcinoma. Radiother Oncol: J Eur Soc Ther Radiol Oncol. (2025) 206:110802. doi: 10.1016/j.radonc.2025.110802

PubMed Abstract | Crossref Full Text | Google Scholar

39. Funayama S, Onishi H, Kuriyama K, Komiyama T, Marino K, Araya M, et al. Renal cancer is not radioresistant: Slowly but continuing shrinkage of the tumor after stereotactic body radiation therapy. Technol Cancer Res Treat. (2019) 18:1533033818822329. doi: 10.1177/1533033818822329

PubMed Abstract | Crossref Full Text | Google Scholar

40. Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, and Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. (2018) 18:313–22. doi: 10.1038/nrc.2018.6

PubMed Abstract | Crossref Full Text | Google Scholar

41. Hatten SJ, Lehrer EJ, Liao J, Sha CM, Trifiletti DM, Siva S, et al. A patient-level data meta-analysis of the abscopal effect. Adv Radiat Oncol. (2022) 7:100909. doi: 10.1016/j.adro.2022.100909

PubMed Abstract | Crossref Full Text | Google Scholar

42. Abuodeh Y, Venkat P, and Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. (2016) 40:25–37. doi: 10.1016/j.currproblcancer.2015.10.001

PubMed Abstract | Crossref Full Text | Google Scholar

43. Mollica V, Santoni M, Di Nunno V, Cimadamore A, Cheng L, Lopez-Beltran A, et al. Immunotherapy and radiation therapy in renal cell carcinoma. Curr Drug Targets. (2020) 21:1463–75. doi: 10.2174/1389450121666200311121540

PubMed Abstract | Crossref Full Text | Google Scholar

44. Ding L, Dong HY, Zhou TR, Wang YH, Yan T, Li JC, et al. PD-1/PD-L1 inhibitors-based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies. Cancer Med. (2021) 10:6384–401. doi: 10.1002/cam4.4190

PubMed Abstract | Crossref Full Text | Google Scholar

45. Viúdez A, Ramírez N, Hernández-García I, Carvalho FL, Vera R, and Hidalgo M. Nab-paclitaxel: A flattering facelift. Crit Rev Oncol Hematol. (2014) 92:166–80. doi: 10.1016/j.critrevonc.2014.06.001

PubMed Abstract | Crossref Full Text | Google Scholar

46. Yardley DA. nab-paclitaxel mechanisms of action and delivery. J Controlled Release. (2013) 170:365–72. doi: 10.1016/j.jconrel.2013.05.041

PubMed Abstract | Crossref Full Text | Google Scholar

47. Jaiswal A, Shergill K, Boppana K, Almansouri NE, Bakkannavar S, Faheem Y, et al. Nephrological detrimental impacts resulting from novel immunotherapy drugs used in the treatment of cancer: A systematic review. Cureus. (2024) 16:e54487. doi: 10.7759/cureus.54487

PubMed Abstract | Crossref Full Text | Google Scholar

48. Gupta S, Short SAP, Sise ME, Prosek JM, Madhavan SM, Soler MJ, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer. (2021) 9:e003467. doi: 10.1136/jitc-2021-003467

PubMed Abstract | Crossref Full Text | Google Scholar

49. Meraz-Muñoz A, Amir E, Ng P, Avila-Casado C, Ragobar C, Chan C, et al. Acute kidney injury associated with immune checkpoint inhibitor therapy: Incidence, risk factors and outcomes. J Immunother Cancer. (2020) 8:e000467. doi: 10.1136/jitc-2019-000467

PubMed Abstract | Crossref Full Text | Google Scholar

50. Zheng Z-H, Shao B, Xu C-M, Wang K, Wen J-Z, Luo L-K, et al. Primary parenchymal squamous cell carcinoma of the kidney: A case report. World J Clin cases. (2025) 13:100037. doi: 10.12998/wjcc.v13.i4.100037

PubMed Abstract | Crossref Full Text | Google Scholar

51. Liang K, Yuan Y, Lv B, and Ke Z. Primary squamous cell carcinoma of renal parenchyma: a case report and literature review. Front Oncol. (2023) 13:1037156. doi: 10.3389/fonc.2023.1037156

PubMed Abstract | Crossref Full Text | Google Scholar

52. Li X, Shen Z, Han Y, and Duan Q. Full of twists and turns: Collecting duct carcinoma presenting as persistent cough. Urol Case Rep. (2022) 45:102283. doi: 10.1016/j.eucr.2022.102283

PubMed Abstract | Crossref Full Text | Google Scholar