Beyond the norm: exploring the uncommon squamous cell carcinoma of the prostate using a Saudi tumor registry

Background: Squamous cell carcinoma (SCC) of the prostate has limited treatment choices and portends a dismal prognosis with an average survival time of ~14-months. This study provides a descriptive overview of SCC of the prostate in Saudi Arabia. Materials and Methods: A retrospective cohort study of patients diagnosed with prostatic SCC between 1 January 2008 and 31 December 2017. Information on demographic and tumor characteristics and the survival of patients was collected from the Saudi Cancer Registry. Survival was depicted through Kaplan–Meier plots. Fisher’s exact test was used to assess the association between categorical variables and death, while a Wilcoxon rank sum test was applied for numerical variables. Results: Out of a larger subset of 3607 patients, 16 patients were diagnosed with prostatic SCC, of which half resided in the Central region (50.0%) and most (81.2%) were aged greater than or equal to 60 years. Most patients (62.6%) had poorly differentiated (grade III, 43.8%) lesions, and 50% of cases were metastatic at diagnosis. 62.5% of patients died, all residing in the Eastern and Central regions. Regional extension (75.0%) and distant metastasis (87.5%) were significantly associated with death compared to localized lesions (0.0%) (P=0.022). The 5-year survival rate in our study was 33%. Conclusion: The present study is the first to describe the characteristics of prostatic SCC in Saudi Arabia. Our results are consistent with prior studies showing that prostatic SCC is often high-grade and metastatic at diagnosis, conferring a poor prognosis.


Background
Prostate cancer stands as the most prevalent cancer in males and constitutes the second-leading cause of cancer-related mortality among men [1] .The majority of prostate cancer cases are adenocarcinomas, whereas a rare and aggressive variant, squamous cell carcinoma (SCC), accounts for 05-1% of prostate cancer cases [2,3] .The literature on primary SCC of the prostate is limited, with fewer than 100 reported cases [4] .
The exact cause of SCC of the prostate remains unknown, with the prostatic urethral urothelium, periurethral ductal epithelium, prostatic acinar epithelium, or radiation-or endocrinetherapy-induced differentiation of adenocarcinoma cells all being implicated as potential origins of the cancer [4][5][6][7][8] .Patients with prostatic SCC often present with obstructive symptoms, such as weak stream, straining, and hesitancy, as well as metastatic symptoms like bone pain from osteolytic metastases, unlike the osteoblastic metastases that are typically a feature of adenocarcinomas [9,10] .
Histological examination of a biopsy or surgical specimen remains the mainstay of diagnosis [11] .Mott proposed the following criteria to identify primary SCC of the prostate: (i) the presence of clearly malignant invasive neoplasm with disordered growth and cellular anaplasia; (ii) definite squamous features of keratinization, squamous pearls and/or numerous distinct

HIGHLIGHTS
• This study provides a comprehensive analysis of 16 cases of squamous cell carcinoma (SCC) of the prostate, an uncommon and aggressive variant of prostate cancer, using data from the Saudi Cancer Registry.(iv) no prior estrogen therapy; and (v) the absence of primary squamous cancer elsewhere, particularly in the bladder [12] .These criteria help distinguish prostatic SCC from non-neoplastic squamous metaplasia possibly secondary to an infarction, acute/ chronic prostatitis, and granulomatous prostatitis due to Bacillus Calmette-Guérin (BCG), estrogen, or radiation therapy [12] .
Due to its aggressive nature and resistance to standard therapies, SCC of the prostate has limited treatment choices and portends a dismal prognosis with an average survival time of ~14-months [13] .Radiation therapy, chemotherapy, and radical prostatectomy have all been tried with limited success [10,14,15] .
This study provides a descriptive overview of SCC of the prostate with a comprehensive analysis of 16 cases retrieved from the Saudi Cancer Registry (SCR) in Saudi Arabia.

Methods
This retrospective cohort study included all patients diagnosed with prostatic SCC between 1 January 2008 and 31 December 2017.Patients with secondary lesions metastasizing to the prostate were excluded.The data was collected from the SCR, a registry that collects tumor data from all private, military, and health ministry hospitals across five regional offices in Saudi Arabia.The data analysis and periodic reporting take place at the main office in Riyadh.This work has been reported in line with the STROCSS criteria [16] .This study has been registered into the research registry [researchregistry9189].

Statistical analysis
All statistical analyses was performed using RStudio (R version 4.2.2.).Categorical variables were expressed as frequencies and percentages, while numerical variables were presented as the median and interquartile range (IQR).Survival analysis was conducted using the Kaplan-Meier method.Due to the large number of variables with zero frequencies and empty rows that could limit the validity of a Cox regression analysis, we opted to employ an inferential test to assess factors associated with cancerrelated mortality.Fisher's exact test was used to assess the association between categorical variables and death, while a Wilcoxon rank sum test was applied for numerical variables.Statistical significance was defined as P <0.05.

Demographic characteristics
In this study, we focused on a subset of a larger dataset of 3607 patients with four types of cancers: acinar adenocarcinoma (n = 3374, 93.5%), ductal adenocarcinoma (n = 209, 5.8%), embryonal rhabdomyosarcoma (n = 8, 0.2%) and SCC (n = 16, 0.4%).Our analysis specifically examined 16 patients with SCC of the prostate and compared their survival rates to those with other types of cancer.Among patients with SCC, half of them resided in the Central region (50.0%), and most (81.2%) were aged greater than or equal to 60 years.Detailed demographic characteristics are presented in Table 1.The majority of our patients (n = 7, 43.8%) were diagnosed with the disease in 2018 (Fig. 1).The median (IQR) interval between diagnosis and last contact or death was 4.0 years (2.0-10.2) (Fig. 2).

Tumor characteristics
Only one patient (6.2%) had a grade I tumor, whereas grades II (five patients, 31.2%),III (seven patients, 43.8%), and IV (three patients, 18.8%) tumors were more prevalent.Localized tumors were detected in 25.0% of patients, whereas distant metastasis was reported among 50.0% of cases.The diagnosis was based on histological testing of the primary lesion in most patients (87.5%) and the histology of metastases in 12.5% of cases.Further details on tumor characteristics can be found in Table 2.

Analysis of mortality and associated factors
Among patients with SCC of the prostate, death occurred in 10 patients (62.5%).Residing in the Eastern and Central regions was significantly associated with death (100.0 and 75.0%, respectively) compared to other provinces (0% in all) (P = 0.018).This phenomenon could be attributed to the fact that the most challenging cases are generally referred to these regions owing to the presence of the largest hospitals.Additionally, the waiting lists are very long in these hospitals.Regional extension (75.0%) and distant metastasis (87.5%) were also significantly associated with death compared to localized lesions (0.0%) (P = 0.022).The time interval between diagnosis and last contact or death was significantly shorter among dead patients (median = 3.0 years, IQR = 2.0 to 4.0) compared to alive patients (median = 12.5 years, IQR = 10.2-14.0,P = 0.031, Table 3).

Discussion
Our study provides a descriptive overview and survival analysis of 16 cases of SCC of the prostate from the SCR in Saudi Arabia.Consistent with prior studies, our studies indicate that SCC predominantly affects males above 60 years old [17] .Most of our patients presented with high-grade lesions ( ≥grade III) and distant metastasis were common (50%) compared to localized tumors (25% of patients), which is also in agreement with prior studies where this type of tumor was found to be high-grade at presentation and metastasize most frequently to regional lymph nodes and bone, with the lungs, liver, and brain being less common sites [17,18] .Histological examination was the primary mode of diagnosing the primary lesions (87.5%), similar to prior case studies [4,19,20] .
Our study revealed a high mortality rate in SCC patients (62.5%), with place of residence and tumor extent being the strongest predictors of mortality.Encouragingly, the 5-year survival rate for the individuals in our study was 33%, which is significantly higher than most studies as per a meta-analysis that showed the 1-year survival of prostatic SCC to be 32% and a 3year survival of only 9% [17] .Treatment options for SCC of the prostate are limited, with the contemporary literature reporting a mix of chemotherapy, radiotherapy, and prostatectomy use, either in combinations or alone, all with limited success [17,21] .However, long-term survival has recently been reported in recent independent case reports with a combination of radiotherapy to the whole pelvis and prostate along with a chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil [4,22,23] .
There are several limitations to our study, most notably the small sample size.A more comprehensive retrospective study with a larger sample size would provide a better understanding of the demographic and clinical characteristics, mortality rates, management, and prognosis of prostatic SCC among Saudi citizens.Furthermore, issues such as underreporting, lack of data on clinical characteristics, incomplete data representation in the TNM classification, distant metastasis, and failure to include crucial factors like specific treatment strategy are limitations in our study that should be addressed by future studies.Lastly, we could not compare differences in demographic and clinical characteristics between different geographical regions to the further our findings of region-specific mortality.

Conclusion
Our findings are in agreement with prior research showing that prostatic SCC is associated with a high-grade and metastasis at diagnosis.Place of residence, particularly in the Eastern and Central regions of Saudi Arabia, was a significant predictor of mortality.Further research is needed to identify the optimal treatment regimen of these patients.

Figure 2 .
Figure 2. A Kaplan-Meier curve for the overall survival of patients with squamous cell carcinoma.

Table 1
Demographic characteristics Figure 1.The frequencies of patients with squamous cell carcinoma who had been diagnosed at different time points.

Table 2
Characteristics of the tumors

Table 3
Factors associated with death among patients with squamous cell carcinoma Figure 3.A Kaplan-Meier curve for the survival of patients with four types of cancer, including acinar adenocarcinoma, ductal adenocarcinoma, embryonal rhabdomyosarcoma and squamous cell carcinoma.