Researcher Highlights Need for Improved Understanding of Prostate Basal Cell Carcinoma

Michael C. Haffner, MD, PhD

Basal cell carcinoma (BCC) of the prostate is a rare variant of prostate cancer so uncommon that few physicians will ever treat the disease in their careers. Only 100 or so patients have been identified in the literature compared with more than 1 million diagnoses every year for adenocarcinoma.

There has been a long controversy around the name BCC, Michael C. Haffner, MD, PhD, assistant professor in the Human Biology Division and an assistant professor in the Clinical Research Division at Fred Hutchinson Cancer Center, said in an interview with OncLive^®. The disease was originally called adenoid cyst carcinoma (ACC) of the prostate when it was first identified in 1974, and the World Health Organization reclassified ACC as a spectrum of BCC in 2004.¹

“From a very basic standpoint, we can see that the benign prostate has 2 different cell types, a luminal cell layer and the basal cell layer,” Haffner said. “The basal layer is thought to be more the regenerative cell portion, whereas the luminal cells are the ones that produce the prostatic secretion—they are the business end of the prostate gland.”

Although it is related in some ways to the more common AAC, BCC displays distinctive histopathological and biological features. Most ACCs that arise in the prostate have a phenotype that looks very similar to a luminal cell, he added. BCCs, in contrast, show different pathology features and growth patterns and immunohistochemical markers can be used to differentiate between adenocarcinomas and BCCs.

“Diagnostically, even though some cases might be challenging, it is possible [to] establish the diagnosis of basal cell carcinoma by integrating morphology and immunohistochemistry,” Haffner said.

Typically, the disease “possesses a lower malignancy potential,” according to findings published in Frontiers in Oncology in 2020. However, there have been incidents of aggressive BBC resulting in metastasis and recurrence.²

Up to 10% of patients experience metastasis and more than 40% experience disease recurrence following initial therapy. BCC-derived metastases also tend to land in the liver, lungs, and bowels.³ ACCs, in contrast, tend to metastasize into bone. In a clinicopathologic study of 19 patients with BCC, investigators observed metastases in 4 patients (21%). In 15 patients followed between 0.3 and 11.8 years, 2 patients died, 3 were alive with cancer, and 10 had no evidence of disease.4 Patient age ranged from 43 to 83 years in the findings from Iczkowski et al.⁴

Prostate adenocarcinoma is always monitored by elevated prostate-specific antigen (PSA) level, but serum PSA level is usually within the normal range in patients with BCC. In most cases, physicians diagnose prostatic BCCs with elevated PSA at baseline concurrently with prostate adenocarcinoma.⁵

Because it is rare and difficult to diagnose, Haffner said BCC is an understudied disease. One of the largest studies published to date includes 29 patients, and many publications are case studies of a handful of patients.

In November 2022, Haffner and his colleagues published findings from a study seeking to uncover the genetic drivers of BCC.

“In contrast to the extensive literature on genomic alterations in adenocarcinoma of the prostate, the genomic drivers of BCC are unknown,” Haffner said. “This motivated us to study the genomic makeup of prostatic basal cell carcinoma.”

Haffner and his team performed whole-genome sequencing on archival formalin-fixed, paraffin-embedded specimens of 2 patients with BCC. They determined that prostatic BCCs are characterized by an overall low copy number and mutational burden, as well as recurrent copy number loss of chromosome 16.⁶

Furthermore, BCC is associated with putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD. The investigators further confirmed the mechanistic role of the CYLD protein in prostatic basal cells in vitro by demonstrating that CYLD loss leads to increased cellular proliferation. They ultimately concluded that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.

“Overall, the genomes of BCC show a relatively small number of alterations; that includes both copy number changes and structural rearrangement, as well as mutations,” Haffner said. “What was striking to us is none of the classical genomic alterations that we find in adenocarcinoma of the prostate were present in these 2 cases. And, we started to see a recurrence of copy number alterations involving chromosome 16. Even though chromosome 16 is a chromosome that is also affected by copy number changes in other tumor types, this is potentially a differentiating factor for the genomic architecture of these tumors.”

Most men who develop BCCs receive standard prostate cancer treatment, including surgical removal, but more extensive disease might necessitate radiation or chemotherapy. Haffner said most patients respond well to local therapy, “but there are different ‘flavors’ of these basal cell carcinomas, and some cases show a more aggressive behavior.”

“What has been noted in the literature is that some tumors that show a higher rate of necrosis and a higher rate of cell proliferation, tend to be more aggressive in their clinical behavior. These cases are also enriched for the development of metastases,” he added. “So, even though the criteria are not very well established, based on histomorphology and very simple molecular assessment, one can risk start to risk-stratify basal cell carcinoma of the prostate.”

References

1. He L, Metter C, Margulis V, Kapur P. A review leveraging a rare and unusual case of basal cell carcinoma of the prostate. Case Rep Pathol. 2021;2021:5520581. doi:10.1155/2021/5520581
2. Dong S, Liu Q, Xu Z, Wang H. An unusual case of metastatic basal cell carcinoma of the prostate: a case report and literature review. Front Oncol. 2020;10:859. doi:10.3389/fonc.2020.00859
3. Identification of potential driver mutations in rare prostate cancer subtype. News release. Fred Hutch Cancer Center. November 21, 2022. Accessed January 30, 2023. https://bit.ly/3jcfKmn
4. Iczkowski KA, Ferguson KL, Grier DD, et al. Adenoid cystic/basal cell carcinoma of the prostate: clinicopathologic findings in 19 cases. Am J Surg Pathol. 2003;27(12):1523-1529. doi:10.1097/00000478-200312000-00004
5. Chang K, Dai B, Kong Y, et al. Basal cell carcinoma of the prostate: clinicopathologic analysis of three cases and a review of the literature. World J Surg Oncol. 2013;11(1):193. doi:10.1186/1477-7819-11-193
6. Low JY, Ko M, Hanratty B, et al. Genomic characterization of prostatic basal cell carcinoma. Am J Pathol. 2023;193(1):4-10. doi:10.1016/j.ajpath.2022.09.010