Molecular profiling of basal cell carcinoma of the prostate: A case report and literature review

Abstract

Prostate basal cell carcinoma (BCC) is a rare pathologic variant with a poorly understood molecular profile. Here, we describe a case of prostate BCC and compare its genetic alterations to cases in the literature. After presenting with hematuria, our patient underwent definitive radical prostatectomy for his localized biopsy-proven BCC. Somatic and germline testing revealed mutations in PIK3R1, KMT2D, and NOTCH1, and MUTYH, NBN, and MSH3, respectively. Upon literature review, we found that prostate BCC mutations disrupt cell growth, epigenetic regulation, and cell fate determination. With no consensus guidelines available, experimental targeted therapies have shown promise for prostate BCC management.

Highlights

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Basal cell carcinoma (BCC) is a rare form of prostate cancer.
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Prostate-specific antigen may not be a reliable surveillance method for prostate BCC.
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Prostate BCC has genomic alterations that disrupt cell growth and differentiation.
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Targeted therapies may treat prostate BCC cases with actionable molecular targets.

1 Introduction

Prostate cancer is the most common solid malignancy in men, but BCC is a rarer histologic variant than the typical adenocarcinoma. Since reported cases of prostate BCC are limited, its malignant potential remains unclear. Given its heterogenous presentations, treatment approaches are also widely variable. Management options may include chemotherapy, radiation, radical prostatectomy (RP), androgen deprivation therapy (ADT), and/or targeted therapies, but there remain no consensus treatment recommendations for prostate BCC. With the advent of targeted therapies and emphasis on precision medicine in modern molecular oncology, molecular profiling of a patient’s cancer can enable design of a personalized treatment regimen. Here, we offer a report on the clinical history of a patient with prostate BCC and a survey of its genomic profile.

2 Case presentation

In January 2019, a 61-year-old man first presented with hematuria. The patient had a family history of prostate cancer of unknown pathology in his grandfather. Cystoscopy demonstrated benign prostate hyperplasia with trilobar hypertrophy and intravesical extension. He was monitored with serial prostate-specific antigen (PSA) measurements, and his PSA rose from 3.3 in November 2018 to 4.6 in November 2020. After this PSA increase, he underwent a transrectal ultrasound-guided prostate biopsy, which demonstrated atypical small acinar proliferation. Subsequent multiparametric magnetic resonance imaging (mpMRI) revealed a 1.1× 1.5-cm PI-RADS (Prostate Imaging Reporting and Data System) 3 lesion in the left posterior peripheral zone ( Fig. 1 A). Apparent diffusion coefficient and high B-value diffusion weighted imaging demonstrated mild restricted diffusion ( Fig. 1 B and C). PSA density based on volume of 136 cc was 0.03ng/mL/mL. Based on these radiographic findings and the atypia on original biopsy, the patient elected for repeat prostate biopsy, which demonstrated BCC. He initially postponed definitive treatment for social reasons and opted for cystolithalopaxy to treat his lower urinary tract symptoms secondary to cystolithiasis. With no indications of metastatic disease, radical prostatectomy was recommended for definitive treatment, which he underwent in December 2022.

Final pathology was consistent with his original diagnosis of BCC, stage pT2N0MxR0. The tumor had variably sized nests of cells with peripheral palisading of basaloid cells, irregular anastomosing sheets of basaloid neoplastic cells, nests with prominent cribriform architecture (adenoid cystic carcinoma-like pattern) and cytoarchitectural atypia, infiltrating between normal prostate acini ( Fig. 2 A–D). The tumor cells were diffusely BCL-2+ and negative for PSA, HER-2, GATA-3, AMACR, chromogranin, and synaptophysin ( Fig. 3 A). High molecular weight cytokeratin and p63 highlighted the outermost layer and CK7 labeling adluminal layer within the tumor cells ( Fig. 3 B). Ki-67 proliferation index was high (>20 %) ( Fig. 3 C), potentially indicating a more aggressive malignancy.

To guide clinical decision-making, TEMPUS genetic testing panels were utilized on his prostate biopsy specimens. Somatic tissue testing (TEMPUS xT) revealed two frameshift mutations and one stop gain mutation in PIK3R1, a frameshift mutation in KMT2D, and a missense (G34C) mutation in NOTCH1. Tumor mutational burden was in the 19th percentile without microsatellite instability. Germline saliva testing (TEMPUS xG) revealed that the patient was heterozygous for MUTYH, NBN, and MSH3. Despite these insights, additional experimental targeted therapies were not indicated after prostatectomy due to the localized nature of his disease. Starting at 3 months after surgery, he has been undergoing surveillance with serial PSA measurements, although the optimal strategy for post-treatment surveillance in prostate BCC remains unclear.

3 Discussion

While serum PSA remains standard for long-term monitoring of most forms of prostate cancer, optimal surveillance strategies for prostate BCC are currently unknown. Exemplified by our patient, prostate BCC often stains negative for PSA, bringing into question the clinical utility of PSA for surveillance. As BCC often arises in the transition zone, studies have demonstrated limited associations of BCC with elevated PSA, concluding that prostate BCC may be best monitored with MRI, PSA density, or the 4K score. ^, ^, Radiographic surveillance with both computed tomography and MRI has been effectively employed in both localized and metastatic cases of prostate BCC. ^, Until a more sensitive surveillance tool is developed, an effective observation plan for prostate BCC will depend on overall disease burden and key histologic features of the patient’s tumor.

In these cases, Ki-67 staining had also been reported to be a reliable indicator of tumor proliferation. The presence of local invasion or necrosis on histology and an elevated Ki-67 index allows for distinction between malignant BCC and benign basal cell hyperplasia. While it is accepted that Ki-67 is a proliferation marker, other literature has speculated that high Ki-67 staining could indicate distant BCC metastasis. However, given the low incidence of BCC, more cases must be examined for a definitive answer. In prostate adenocarcinoma, the literature is more conclusive that Ki-67 correlates with malignant lesions and Gleason grade, a proven predictor of overall prognosis.

Next generation sequencing of malignant tissue informs us of the specific molecular mechanisms that drive oncogenesis, which is especially important when characterizing rarer neoplasms such as prostate BCC. Growth signaling aberrations, epigenetic dysregulation, and disruption of cell fate determination define the somatic mutational profile of our patient’s tumor, which includes mutations in PIK3R1, KMT2D, and NOTCH1. PIK3R1 is a tumor suppressor gene involved in growth signaling pathways that is mutated in up to 6 % of prostate cancers. KMT2D is a component of a histone methyltransferase complex that has also been implicated as a putative driver gene in another prostate BCC case. Meanwhile, NOTCH1, classified as a “Variant of Uncertain Significance”, may be involved in cell fate determination, potentially suppressing tumorigenesis by impeding prostate cancer invasion.

Examining germline changes can also help elucidate underlying molecular mechanisms and inheritance patterns of disease, which is critical when performing genetic counseling with patients. Our patient’s germline mutations of MUTYH, NBN, and MSH3 may contribute to dysfunctional DNA damage repair mechanisms, potentially leading to oncogenesis. Although NBN and MSH3 are both considered “Variants of Uncertain Significance”, MUTYH is mutated in a form of hereditary polyposis that increases a patient’s risk of genitourinary and gastrointestinal cancers. While much remains unknown behind the genetic mechanisms of prostate BCC development, germline mutation screening can help patients stratify risk within their families to optimize cancer prevention strategies.

Key prostate BCC mutations from the literature, in addition to the mutations in our patient, are summarized in Table 1 . These genes have many functions but can be generally classified into three broad categories: chromatin remodeling, DNA damage repair, and cell development. One case of prostate BCC reported mutations in SMARCB and ATM. SMARCB regulates transcription through chromatin remodeling, and ATM is a DNA damage repair enzyme altered in up to 10 % of metastatic prostate cancer cases. MYB-NFIB, a fusion protein frequently implicated in prostate BCC according to fluorescence in situ hybridization analyses, consists of gene products that also regulate stem cells and promote chromatin accessibility. Another fusion protein identified in BCC is MSMB-NCOA4, which is associated with an increased risk of prostate cancer.

Table 1

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