Tislelizumab Combination With Chemotherapy Successfully Converted Unresectable Advanced Penile Cancer Into Complete Surgical Excision: a Case Report and Literature Review

Background: Locally advanced Penile squamous cell carcinoma (PSCC) with unresectable inguinal lymph nodes has a poor prognosis, and benets from surgical treatment alone. Effective conversion therapy regimens are urgently needed. Case Presentation: We report a locally advanced PSCC patient with bulky, xed inguinal lymph node metastasis complicated within genial skin ulcers, who completed inguinal lymph node dissection and achieved pathologically complete response via conversion therapy by immunotherapy plus chemotherapy. Conclusion: For unresectable locally advanced PSCC, neoadjuvant immunotherapy combined with chemotherapy is a potential treatment approach. Biomarkers of immune ecacy need to be explored. At the same time, clinical trials are needed to test the notions.


Background
Penile carcinoma is a rare tumor in the male genitourinary system and the main histopathological type is squamous cell carcinoma. For locally advanced penile squamous cell carcinoma (PSCC) patients with bulky, xed, bilateral inguinal lymph node metastases and extra-nodal extension, it is di cult to bene t from surgery alone and the prognosis is very poor [1][2][3]. The use of multiple strategies reducing pathological staging, even convert to operability can improve prognosis and increase survival rate.
Neoadjuvant chemotherapy is the usual treatment for this kind of patients [4], but multiple small size cohort studies have demonstrated that nearly half of patients do not bene t from neoadjuvant chemotherapy alone, which made it urgent to nd new and effective treatments.
In recent years, immune checkpoint inhibitors (ICIs) have become a hot topic in oncology treat and even became the standard of care for tumors such as melanoma and lung cancer. By inhibiting the Programmed death-1receptor (PD-1) or PD-1 ligand (PD-L1), ICIs block the inhibition of CD8 + effector T cells and reverse the suppressive tumor microenvironment, which may improve the prognosis for patients resistant to other treatment modalities (e.g.chemotherapy/radiotherapy). For some unresectable tumors, neoadjuvant immunotherapy offers a potential solution by mediating tumor regression to make them operability or even curable. Currently, evidence has accumulated in lung and breast cancers demonstrated that neoadjuvant immunotherapy increases the rate of pathological response and improves overall survival. However, immunotherapy combined with chemotherapy for patients with unresectable locally advanced PSCC has rarely been reported.

Case Presentation
Here, we present a 58-year-old male patient who was admitted to the local hospital for sub-preputial mass and xed lymphadenopathy in the left inguinal region. Distal penectomy and biopsy of the left inguinal lymph node were done subsequently. The postoperative pathological biopsy showed high-/medium-differentiated squamous carcinoma of the penis invading the penile corpus cavernosum, with no involvement of the uroepithelium. Pathological biopsy of the left inguinal lymph node present loss of normal lymph node structure and multifocal cancerous in ltration of brous tissue. Also, the nal pathological staging was IV (pT3N3M0). 21 days after surgery, the patient was admitted to the West China Hospital of Sichuan University, where an enhanced CT of the pelvis showed multiple enlarged lymph nodes in the left inguinal region, and the largest lymph node section was 4.0 x 2.5 cm ( Fig. 2A). After multidisciplinary collaboration consultation, it was di cult to perform a complete inguinal lymph node dissection. The patient was enrolled in a clinical trial on EGFR monoclonal antibodies. However, a larger inguinal lesion was developed after 6 cycles of EGFR monoclonal antibodies. And the lesion was evaluated as progressive disease by CT scanning (Fig. 2B). Next, the patient received paclitaxel 240mgD1 plus cisplatin 40mgD1-3 chemotherapy after withdrawing from the clinical trial. After the 1st cycle of chemotherapy, no change of tumor mass was found (Fig. 2C).

Discussion And Conclusion
Chemotherapy is commonly used as a translational therapy strategy for patients with locally advanced unresectable PSCC. However, despite the meaningful response to systemic chemotherapy, long-term survival rates were disappointing, with 2-year progression-free survival (PFS) and disease-speci c survival (DSS) probabilities of 12% and 28%, respectively. Moreover, patient resistance to chemotherapy have a worse prognosis. Therefore, there is a urgent need to nd new translational therapeutic strategies with higher e cacy and low toxicity pro le. Referring to the experience with advanced non-small cell lung cancer and melanoma, PD-(L)1 blockade plus chemotherapy may be a promising option.
Theoretically, in the primary tumor, PD-(L)1 blockade relieves the suppressive immune microenvironment, restores the activity of exhausted cytotoxic T cells, and mediates tumor regression. Simultaneously, chemotherapy causes tumor cell necrosis and releases more tumor antigens. In the presence of ICIs, dendritic cells can present antigens to T cells more e ciently, initiating tumor-speci c T cell proliferation and activation. Activated T cells leave the tumor-draining lymph nodes into the bloodstream and migrate to tumor sites and distant micro-metastases, shrinking the primary lesion and reducing postoperative distant recurrence [6]. In addition, the preoperatively induced systemic immune response generates longterm immune memory and prevents tumor recurrence [7].These suggest that immunotherapy combined with chemotherapy is a promising translational treatment strategy.
Numerous factors are involved in the effectiveness of immunotherapy. To explore the treatment options, we performed immunohistochemistry and next generation sequencing (NGS) analysis on our patient. PD-L1 expression in tumor tissues is validated companion diagnostic test for predicting e cacy of treatment with ICIs. Several studies have shown that 40-60% of PSCC patients express PD-L1 (PD-L1 positivity de ned by > 5% tumor expression), and high PD-L1 expression positive associated with worse staging and prognosis [8]. It is also associated with lower numbers of Tumor-in ltrating lymphocytes (TILs) in tumor tissue. The PD-L1 expression of our patient was 40%(Tumor Proportion Score, TPS), and these ndings provide a rationale for the use of ICIs as a treatment option for patients with PSCC. Tumor mutation burden (TMB) is also a promising immunotherapeutic marker in many cancer types. However, the TMB cut-off values are not the same in different cancers. In our case, the patient had a TMB of 5.0 mutations per mega base (Muts/Mb), slightly higher than the median value (4.5 Muts/Mb) in PSCC, and a recent report suggests that mutations in select genes may be a better predictor than TMB. Microsatellite instability high (MSI-H) is another valid marker of sensitivity to ICIs. Our case was microsatellite stable (MSS), the literature reports a low incidence of MSI-H in PSCC [9].
More interesting, patient's laboratory testing got human papillomavirus (HPV) 16 DNA. Patients with HPV + PSCC have a better prognosis than those with HPV − . The possible mechanism is that the virus increases the production of neo-antigens, while increasing the number of in ltrating CD8 + T cells in the tumor microenvironment [10]. Does this mean that the HPV virus could be a meaningful biomarker for immunotherapy? Considering the impact of HPV on the tumor, several clinical trials of combinatorial immunotherapy augmented with HPV-targeted vaccines have been conducted in HPV-associated malignancies. Current results regarding the association between the status of HPV and the expression of PD-L1 are con icting and need to be con rmed by more studies. However, the differences in TMB between HPV − and HPV + PSCC patients are minimal [8].
In addition, patient in current case had high expression of epidermal growth factor receptor (EGFR) by immunohistochemistry and was treated experimentally with EGFR monoclonal antibody. Several studies have shown that high EGFR expression detected by IHC is frequently seen in PSCC [11]. High expression of EGFR may be associated with poor prognosis, implying better effects by targeting EGFR. Retrospective studies [12] have shown that the use of Cetuximab or dacomitinib (a pan-HER tyrosine kinase inhibitor) provide bene t to only a small number of patients. Our patient had disease progression after attempting EGFR monoclonal antibodies. NGS of this case showed a mutation in PIK3CA p.E453K. In colon cancer, PIK3CA mutations are signi cantly associated with clinical resistance to EGFR monoclonal antibodies [13].
In conclusion, current case present with HPV + locally advanced inoperable PSCC that responded well to ICI plus chemotherapy, converted to operable, and underwent inguinal lymph node dissection, which was pathologically con rmed to achieve a complete response. Postoperative disease-free survival (DFS) exceeded 12 months and continued the trend of prolongation. For this group, immunotherapy combined with chemotherapy is a promising translational treatment option. However, more clinical trials are needed to validate this notion and effective biomarkers need to be further explored.  The time pipeline of treatment procedure