Diagnostic utility of Ki-67 proliferation index,PSA,and other immunohistochemical markers in prostatic basal cell carcinoma: A review of 24 cases in the current literature and discussion on current treatment and diagnostics

Abstract

Background

Basal cell carcinoma (BCC) of the prostate is a rare and poorly characterized malignancy distinct from conventional prostatic adenocarcinoma. Due to its rarity, diagnostic challenges arise, often leading to misclassification and delayed management. Immunohistochemical markers such as Ki-67 proliferation index and prostate-specific antigen (PSA) levels may aid in distinguishing BCC from typical adenocarcinoma, but data remain limited.

Methods

This case series review study retrospectively analyzes published case reports and series spanning from 1988 to 2023 to evaluate Ki-67 staining patterns, PSA levels, and other immunohistochemical features to identify distinguishing characteristics of prostatic BCC. Data extracted included patient demographics, PSA levels at presentation, Ki-67 proliferation index values, and results of other immunohistochemical staining (i.e., PSA, P63).

Results

Of the 24 BCC cases included in the final analysis, 20 reported PSA level at first presentation (mean: 2.56 ng/mL, range 0.08-7.3 ng/mL, normal range <4), 15 reported PSA IHC staining, and only 13 reported Ki-67 percentage values obtained through primary tumor biopsy staining (mean: 46.88%, range 0-80%). In comparison, Ki-67 expression numbers from National Comprehensive Cancer Network (NCCN) for prostate adenocarcinoma report varied Ki-67 expressions between risk groups: low-risk patients averaged 5.1% ± 3.8%, intermediate-risk patients averaged 7.4% ± 6.8%, and high-risk patients averaged 12.0% ± 12.4%. Various immunohistochemical staining was also collected yielding positive staining with Ki-67 in 13/13 cases, HMWCK/34βE12 in 14/14 cases, P63 in 14/14 cases, and BCL-2 in 12/13 cases.

Conclusion

This retrospective analysis suggests that prostatic BCC may be characterized by higher Ki-67 proliferation indices and lower PSA levels compared to typical prostatic adenocarcinoma. This review further explores and proposes the potential of combining Ki-67 and PSA assessments along with other biomarkers to aid in distinguishing BCC from conventional prostate cancers, facilitating earlier recognition and appropriate management of this rare malignancy.

Keywords

molecular pathology PSA Ki-67 Biomarker-driven studies basal cell carcinoma

Background

As of 2023, prostate cancer is the most prevalent solid-organ malignancy among men and continues to be the second most common cause of tumor-related death, only second to lung cancer. The five most prevalent subtypes of prostate cancer from most to least prevalent include: Adenocarcinoma (∼95% of cases), Small Cell Carcinoma (∼1%), Squamous Cell Carcinoma (<1%), Transitional Cell (Urothelial) Carcinoma (<1%), and Sarcomas (<0.1%). However, often less studied and significantly rarer, is the basal cell carcinoma (BCC) subtype. This subtype has been estimated to have less than 150 total cases reported in literature to date.

BCCs of the Prostate are defined through histopathology, immunochemistry, and genomic characteristics that separate it from other prostate subtypes. On histopathology, BCC show basal cell differentiation with adenoid cystic-like structures, small solid nests with peripheral palisading patterns, and/or basal cell hyperplasia-like patterns.¹ BCCs can strongly stain cytokeratin 34βE12, BCl-2, and p63 and may show negative PSA staining, which sets it apart from common prostatic adenocarcinomas.^1–3 Clinically, BCC often presents with obstructive and dysuria/hematuria symptomology and normal PSA values.⁴ The presentations BCC demonstrate can vary, from being indolent to aggressive with recurrence/metastases.² The prognosis is typically poor, with Komura et al. showing poor percent survival for those with basal cell carcinoma compared to other subtypes.⁵ The purpose of this case review is to compile, summarize and analyze observations made both clinically and diagnostically in these cases; by analyzing the quantifiable data we hope to establish new diagnostic criteria and/or treatment recommendations.

Methods

Data source and collection method

Cases were identified using PubMed. We used terms such as “BCC of prostate” or “adenoid cystic carcinoma of the prostate” combined with other terms in advanced searches such as “case review” or “case study”. We were aiming to only report cases (and data) directly from the case study involving patient care, and not as referenced in a separate case review. Case studies with multiple patients from the same hospital system were also considered. We analyzed 45 articles in our literature review, and of those, there were 20 articles (24 total cases) that had reported and confirmed cases of BCC of the prostate. No sample size calculation was pursued due to the deference of statistical analyses. After collecting acceptable case study literature, we collected the following data from the studies: year the study was published, symptoms, PSA level at first presentation, metastasis if applicable, treatment/outcome, Ki-67 index, tumor markers tested, age, race, other primary cancers, and Histology/IHC findings. Given the heterogeneity of the collected data, data points were organized descriptively in a table; a systematic review was deferred. None of the studies were excluded for not having any of the parts of the data collected; “Not Specified” or “Unknown” was applied when data was missing. When a specific data variable was not present for all the studies, only studies that had the data variable recorded were considered when tabulating a descriptive summary for that specific variable. We compiled the data in excel sheets and descriptively communicated key qualitative data through distribution charts, circle graphs, and bar graphs. Our institution did not require ethical approval for reporting retrospective individual cases or case series.

Results

Patients and presenting characteristics

There was a total of 24 cases included in the final analysis. Cases ranged from 1988 to as recent as 2023. The different cases were from a variety of sources including case reviews and systematic analyses. Due to this heterogeneity, the following results are descriptive without statistical inferences between cases.

Of the 24 cases, only 20 cases had reported PSA level at first presentation. PSA values ranged from 0.08 to 7.3 with a median of ∼2.1ng/mL (Figure 1). Of the 20 cases, 15 had normal PSA and only 5 had an abnormal PSA. All of the patients with reported normal PSA were symptomatic at the time of presentation, and only 1/5 of the cases with abnormal PSA were asymptomatic (Table 2, Figure 1). A common presenting feature among the cases was micro or macrohematuria, dysuria, and overflow incontinence (Table 1).

Figure 1.

Box Diagram of Initial PSA values on patient presentation for patients included in this review. The box covers 25th to 75th percentile of the data. The line within the box highlights the median. The whiskers each represent Q1 – 1.5 x Interquantile Range (IQR) and Q3 + 1.5 x IQR.

Table 1.

Summary of age, race/country of origin, symptoms on presentation, physical exam findings, radiographic findings, TNM staging, information of metastases on presentation, and treatment course/final outcome for each patient among the case reports (if the information is not specified in the publication, it is referred to Unknown in the table).

Publication	PUB link	Age	Race/Country of origin	Urinary symptoms on presentation \| physical exam findings \| positive imaging findings	Specific TNM staging on presentation	Metastases on presentation	Treatment course \| Final outcome	Other primary cancers?
Hudson et al. (2008) European Journal of Cancer Care⁶	PMID: 18616505	68	Unknown	Dysuria, intermittent frank hematuria, urinary tract infections	Unknown	Yes (bilateral pulmonary metastases, solitary metastatic deposit in the right lobe of the liver)	C (non-responsive) → S (retropubic prostatectomy) → R → experienced symptom relief → metastases worsened → patient passed away 9 months post-prostatectomy	Superficial Transitional Cell Carcinoma of the bladder in remission
Segawa et al. (2008) International Journal of Urology⁷	PMID: 18489650	67	Asian (Japan)	overflow incontinence	T4N1M1a (local invasion of bladder wall and seminal vesicle. Enlarged iliac and paraaortic nodes)	Yes	Bx (5g prostatic tissue) → voiding restored → HR → declined further treatment → liver dysfunction → passed away 8 months after presentation to hospital	Unknown
Shibuya et al. (2018) Molecular and Clinical Oncology⁸	PMID: 30655983	68	Asian (Vietnam)	None	Unknown	No	S → recurrence free for one year post-operation	Bladder Cancer → transurethral resection of the bladder tumor a year prior to presenting
Hennes et al. (2020) IJU Case Reports⁹	PMID: 32743470	69	Unknown	2 years of voiding difficulty and intermittent macroscopic hematuria \| \| enlarged and vascular prostate was observed on flexible cystoscopy	pT2c	No	After a failed trial of med management → robot-assisted radical prostatectomy	Unknown
Tuan et al. (2012) Indian Journal of Urology¹⁰	PMID: 23204663	78	Unknown	lower urinary tract symptoms, nocturia and gross hematuria \| enlarged smooth prostate and normal rectum \| (MRI) confirmed numerous cysts within a markedly enlarged prostate (333 cc) with atypical T1 and T2 signals	T4N1M0 (extended through the prostatic capsule and invaded the obturator-internus and levator-ani muscles. There was a 2-cm lymph node along the left pelvic sidewall)	None	C & R → Died ∼25 months later from unrelated cause	None
Arquimedes Rodriguez-Carlin et al. (2013) Archivos Españoles de Urología¹¹	PMID: 23676544	76	Unknown	IPSS score was 29 (severity of lower urinary tract symptoms (LUTS)	Unknown	Unknown	S (TURP) → S (radical prostatectomy) → 23months of follow-up, no recurrence	Unknown
Bohn et al. (2010) Annals of Diagnostic Pathology¹²	PMID: 20850702	65	Unknown	Dysuria and urinary outlet obstruction	Unknown (perineural invasion was extensively identified)	Unknown	Antibiotics + anti-inflammatories prescribed initially → S (TURP)→ follow-up for 12 months shows persistent low PSA without other treatment	Unknown
Trinh et al. (2023) The Prostate¹³	PMID: 36967482	80	Unknown	Obstructive urinary symptoms, received simple prostatectomy, but developed further voiding dysfunction so received palliative radical prostatectomy	Unknown	Yes (liver, pelvis)	S (simple prostatectomy) → S (palliative radical prostatectomy) → analgesia → C-> \| Died 14 months after diagnosis	Unknown
Dong et al. (2020) Frontiers in Oncology¹⁴	PMID: 32537438	62	Unknown	Intermittent gross hematuria for 1 month	pT2NxMx	Yes (liver)	S (radical prostatectomy) → R → metastasis in lungs → C (ineffective) → C → patient stable upon reporting after 9 months of C	Unknown
Chang et al. (2013) World Journal of Surgical Oncology²	PMID: 23941693 (included 3 cases)	50	Unknown	Acute urinary retention	Unknown	Yes (bone, liver)	S (radical cystectomy + ileal conduit urinary) → R → HR → bone metastasis → palliative R + zoledronic acid → liver metastasis after 6 months → C + S (hepatic intervention) → patient followed for 3 years upon reporting and can perform ADLs independently	Unknown
Chang et al. (2013) World Journal of Surgical Oncology²	PMID: 23941693 (included 3 cases)	62	Unknown	Acute urinary retention	Unknown	Yes (bone)	S (TURP) + R (regional treatment) → 30 months later, metastasis to ischium → R (palliative), then rapidly deteriorating	Unknown
Chang et al. (2013) World Journal of Surgical Oncology²	PMID: 23941693 (included 3 cases)	65	Unknown	Acute urinary retention	Unknown	Yes (lung)	S (TURP) + HR→ passed away 5 months after discharge	Unknown
Wang et al. (2023) Frontiers in Oncology¹⁵	PMID: 36969067	59	Unknown	Progressive dyspareunia and had been treated for recurrent urinary retention 4x in 5 years \| \| MRI of the prostate performed 40 days postoperatively showed a small lamellar long T2 and long T1 signal in the central lobe of the prostate with a slightly high signal on diffusion-weighted imaging (DWI)	Unknown	None	S (TURP) → post-op biopsy revealed BCC diagnosed (previously diagnosed as prostatic hyperplasia) → S (laparoscopic radical prostatectomy) → follow-up to 50 months post-operation: PSA at 0, no recurrence or metastases	Unknown
Ahn et al. (2002) Yonsei Medical Journal⁵	PMID: 1652178	38	Unknown	Nocturia & dysuria of 5 years, acutely worsened in 4 months prior to presenting (nocturia 3-4x per night) \| \| CT showed enlarged prostate gland displacing the urinary bladder to an anterior superior position with signs of invasion into the seminal vesicle	Unknown	None	The prostate gland was malignant, a transurethral prostatectomy resulted in a diagnosis of adenoid cystic carcinoma, a prostatectomy was then performed	Unknown
Rebhan et al. (2022) Current Opinion in Urology¹⁶	PMID: 35749783	55	White	Painless macrohematuria \| \| CT of thorax/abdomen/pelvis scan with a urographic phase as well as mpMRI of the prostate. MRI revealed a PIRADS-5 lesion in the left transition zone elevating the bladder floor	Unknown	None @ first presentation mets 7 mo post-op	S (open radical prostatectomy combined with standard bilateral lymph node dissection and en-bloc dissection of the bladder neck)→ 7mo later (PSA-0) CT confirmed suspect lymph nodes in the proximal lymph nodes of the pelvis → lymph node dissection up to the inferior mesenteric artery → metastatic lymph node involvement in three out of eleven lymph nodes with formations resembling the primum → vismodegib → following 5 months later: novel hepatic lesions but no other signs of cancer with a PSA of → experimental treatment with the FGFR-inhibitor pemigatinib → currently (1.5 years post-operation), the patient is continuing pemigatinib (almost complete morph regression and absolute functional regression of the hepatic lesion) and radiation therapy planned	Unknown
Ahuja et al. (2011) Pathology, Research and Practice¹⁷	PMID: 21440997	62	Unknown	3 months of obstructive urinary symptoms \| \| enlarged hard nodular prostate on exam	Unknown	Unknown	After diagnosis, due to clinical stage and surgical inoperability max → AR blockade in the form of S (bilateral orchiectomy) and bicalutamide (50 mg OD) → no progression of disease during the 6 months of follow up, then was lost to follow up	Unknown
Young et al. (1998) American Journal of Clinical Pathology¹⁸	PMID: 2827457 (includes 2 cases)	60	Unknown	Symptoms of urinary tract obstruction \| enlarged prostate gland \| \|	Unknown	Unknown	S (radical prostatectomy) was performed → the patient was well six years after the prostatectomy	Unknown
Young et al. (1998) American Journal of Clinical Pathology¹⁸	PMID: 2827457 (includes 2 cases)	68	Unknown	Symptoms of urinary retention, nocturia, increased frequency, and hesitancy \| prostate gland was enlarged on digital rectal exam \| \|	Unknown	Unknown	S (TURP) + R → 8 months follow up shows no evidence of disease	Unknown
Toesca et al. (2023) Advances in Radiation Oncology¹⁹	PMID: 38778823	77	Unknown	Worsening lower urinary obstruction for past year \| \| MRI of the prostate/pelvis with and without contrast was notable for predominance of multinodular transitional zone, and a calculated Prostate Imaging Reporting & Data System, version 2.1 scoring of 2 or lower	Unknown	Unknown	Holmium laser enucleation of the prostate (HoLEP) with tissue morcellation. Diagnosed with BCC of the prostate with disease involvement into the corpus spongiosum; demonstrated a complete radiographic response after treatment with definitive chemoradiation.	None
Minei et al. (2001) International Journal of Urology²⁰	PMID: 11555019	43	Unknown	Urinary outlet obstruction, digital rectal examination revealed an elastic hard prostate \| \| the findings of transrectal ultrasound sonography (TRUS) were normal, s/p subscapular prostatectomy, MRI revealed an irregularly thickened bladder wall, which suggested that the lesion had extended to the urinary bladder	Unknown	Unknown	Initially diagnosed as BPH → treated with oral medications → one year later, underwent S (subcapsular prostatectomy) → diagnosed as adenoid cystic carcinoma of the prostate	Unknown
Ryan et al. (2022) Urology Case Reports²¹	PMID: 35530540	72	Unknown	New lower urinary tract symptoms \| an abnormal feeling prostate on digital examination \| flexible cystoscopy revealed no mucosal abnormality of the urethra and an obstructive prostate with intravesical protrusion, MRI revealed a 4.3× 4 cm soft tissue mass on the posterior corpus spongiosum encasing the bulbar urethra superiorly with tumor abutting the apex of the prostate, cross-sectional imaging was arranged for staging of the disease which revealed multiple pulmonary metastases.	Unknown	Yes (lungs)	S (transperineal (TP) biopsies) with histology confirming adenoid cystic carcinoma → then underwent treatment with sunitinib	Unknown
Tulunay et al. (2004) International Urology and Nephrology²²	PMID: 15338674	74	Unknown	Urinary tract obstruction and gross hematuria \| on digital examination, the prostatic gland was minimally enlarged and hard, raising the suspicion of a prostate cancer \| transrectal ultrasonography showed a 23 gram. prostate and hypoechoic lesions in peripheral zone	Unknown	Unknown	Had undergone S (TURP) → 15 years prior to presenting for benign prostate hyperplasia-> Underwent repeat S (Turp) after Transrectal ultrasound suggested concerning pathology	Unknown
Taskovska et al. (2023) Research and Reports in Urology²³	PMID: 37324807	56	Unknown	weight loss, nausea and vomiting \| \| six days after admission, contrast-enhanced CT urography and contrast-enhanced CT of the thorax were completed	Unknown	Yes	S (transurethral resection of bladder tumor) → S (radical cystectoprostatectomy) → 6 months later, enlarged lymph nodes, iliac pain → no biopsy/chemotherapy → died from metastasis 17 months after presentation with symptoms	Unknown
Montironi et al. (2005)Journal of Clinical Pathology²⁴	PMID: 15735163	71		1 year of increasing urinary obstructive symptoms \| \| diffuse enlargement of prostate by transrectal ultrasonography and digital rectal exam	Unknown	Unknown	Suprapubic (simple) prostatectomy, diagnosed as benign prostate hyperplasia with diffuse basal cell hyperplasia at the time → 4 years later presented with urinary symptoms → S (TURP) with normal voiding after, diagnosed as urothelial cancer at the time → S (2nd TURP) 1 year later, new pathology confirmed BCC → local recurrence (20cm across causing obstructive symptoms) → no additional treatment given → patient passed of unrelated heart failure 3 years later	Unknown

TURP – transurethral resection of the prostate, C – chemotherapy, R – radiation therapy, S – surgery, BPH – benign prostatic hyperplasia, BCC – basal cell carcinoma of prostate, FGFR – fibroblast growth factor receptor, PSA – prostate-specific antigen, ADL – activities of daily living, HR – hormone therapy, AR – androgen receptor.

Tumor pathology

The tumor pathology observed was very similar to previously reported patterns. Histologically, the two growth patterns that have been commonly observed in literature up to this point have been the adenoid cystic/cribriform and the basaloid patterns. The adenoid cystic pattern is composed of nests of tumor cells arranged in cribriform architecture; eosinophilic basement membrane-like material or basophilic mucinous secretions can be present within punched out spaces. In the basaloid pattern, there are variably sized solid nests, cords, or trabeculae with peripheral palisading that can be seen with extensive comedonecrosis (Table 2).

Table 2.

Summary of Prostate-specific antigen (PSA), Ki-67 staining (%), other markers, U/S (ultrasound) prostate volume, and histology/immunohistochemistry (IHC) descriptions for each patient among the case reports (if the information is not specified in the publication, it is referred to Unknown in the table).

Publication	PSA on presentation (ng/ml)	Ki-67 staining (%)	Other markers	U/S prostate volume (cc/mL)	Histology/IHC description
Hudson et al. (2008) European Journal of Cancer Care⁶	3.6	Positive	(+): HMWCK 34BE12, BCl-2 elevated, s100, SMA, p63, calponin	165	Microscopically malignant epithelial tumor forming solid large-sized sheets of basaloid cells, with central necrosis, cribriform differentiation and peripheral palisading. Focal areas of smaller nests and basaloid tubules with an adenoid cystic-like pattern. Basal cell hyperplasia with and without atypia
Segawa et al. (2008) International Journal of Urology⁷	0.08	70% Ki-67 (+) cells	(+): AE1/AE3, p63, HMWCK 34βE12, CK5/6, (AR), weak/focal PAP, c-erB2 onco, BCL-2 focally (+) (-): CK7, CK20, ER/PgR, SMA, S-100, CEA, PSA, P504S, Chromogranin A, D2-40	Unknown	Histologically, the tumor was composed of solid nests of small, round cells with scant cytoplasm, arrayed in a basaloid growth pattern. The tumor showed extensive vascular and perineural invasion. Postmortem biopsy: extensive vascular and perineural invasion. Transition from the normal epithelium to tumor cells within a single prostatic gland was seen
Shibuya et al. (2018) Molecular and Clinical Oncology⁸	5.61	Unknown	(+): p63 (-): PSA	61	Tumor cells with a high nucleus-to-cytoplasm ratio forming a small nest-like basaloid cell carcinoma – retropubic radical prostatectomy with extended lymph node dissection: coexistence of a predominant basaloid component and an adenoid cystic-like tumor with cribriform appearance, negative margins or lymph node metastases
Hennes et al. (2020) IJU Case Reports⁹	5.67 & 0.09-- dec. to <0.03 3wks post-rad prostatectomy	Ki-97 immunostaining index was 50–90 in these areas.	(+): p63, Cytokeratin 5/6, strong Bcl2 staining, Luminal stain w/Cytokeratin 7 (-): alpha methlacyl-CoA	Unknown	Basaloid lesion with a spectrum of changes, including multiple foci of basal cell carcinoma. Final histopathology of the resected specimen showed basal cell carcinoma in both lobes, involving approximately 4% of the gland, without extra capsular extension, lymphovascular invasion, or seminal vesicle involvement. Concomitant acinar adenocarcinoma (Gleason 3 + 3) was also identified, involving less than 1% of the gland, with one focus of perineural invasion
Tuan et al. (2012) Indian Journal of Urology¹⁰	0.8	Unknown	(+): LP34, CK 7 (-): PSA, TTF-1, CK 20, chromogranin A	333	Histopathology revealed basal cell carcinoma of the prostate with no evidence of conventional prostatic adenocarcinoma. Malignant sheets of basaloid cells with small islands of keratinizing squamous epithelium extensively infiltrated all six biopsy cores. The tumor cells showed mitosis but not necrosis
Arquimedes Rodriguez-Carlin et al. (2013) Archivos Españoles de Urología¹¹	0.924	Unknown	(+): specific monoclonal antibodies anti-cytokeratin 34βE12, (+) p63 and (+) BCL-2 (-): PSA, stained	Unknown	Basal cell carcinoma with adenoid cystic growth pattern, perineural infiltration and focal involvement of the left seminal vesicle
Bohn et al. (2010) Annals of Diagnostic Pathology¹²	2.9	20	(+): CK7, CK34bE12 and p63; focal immunoreaction for S100, CD117 and Bcl-2 (-): CK20, HER2 (erbB2), PSA, calponin, SMA, and AMACR	Unknown	Microscopic examination revealed a malignant tumor composed of basaloid cells with round nuclei and scant cytoplasm, showing peripheral palisading and forming solid nests, with focal central necrosis, mixed with areas of adenoid-cystic pattern; 8/10 mitoses per high-power field were seen in solid areas, and perineural invasion was extensively identified. Atypical basal hyperplasia and benign prostate hyperplasia were also identified admixed with the malignant component
Trinh et al. (2023) The Prostate¹³	Negative	Not Explicitly	(+): Bcl-2 +, High Molecular Weight Cytokeratin +, p63 +, PD-L1 score - 7% (-): PSA, Synaptophysin, chromogranin A -	Unknown	Tumor displayed an ill-defined focal cribriform pattern with an extensive solid nested pattern with basaloid cells and areas of comedonecrosis
Dong et al. (2020) Frontiers in Oncology¹⁴	2.42 ng/mL	Tumor Bx: 1, Lung Nodules: 20	(+): HMWCK 34βE12, p40, CK5/6, LMWCK (-): PSA, chromogranin A, synaptophysin, androgen receptor, TTF-1, CD117, CD30, and OCT4	3.4 × 4.6 × 3.3 cm (51.612 cm^3)	The pathology report indicated local invasion of the nerve and thrombosis of tumor vessels; however, the margin and seminal vesicles were negative.
Chang et al. (2013) World Journal of Surgical Oncology²	0.29 ng/mL	70	(+): p63, p53, HMWCK 34βE12, Bcl-2, Ki67 (-): PSA, cytokeratins 7 and 20	Not explicitly stated; DRE revealed fixed nodular prostate	Large pleomorphic nuclei and scant cytoplasm, showing peripheral palisading and forming solid nests
Chang et al. (2013) World Journal of Surgical Oncology²	1.36 ng/mL	50	(+): p63, HMWCK 34βE12, Bcl-2, Ki67	Unknown	Not Specified
Chang et al. (2013) World Journal of Surgical Oncology²	1.35 ng/mL	60	(+): p63, HMWCK 34βE12, Bcl-2, Ki67	Unknown	Not Specified
Wang et al. (2023) Frontiers in Oncology¹⁵	1.29 (tPSA)	Unknown	(+): P63 and 34βE12 (-): P504s and NKX3.1	5.1 cm4 cm3.8 cm (77.52 cm^3)	Microscopic examination revealed a predominantly adenoid cystic carcinoma structure with a basal cell mass of variable size containing numerous small round or ovoid window pores in the form of sieve pores with eosinophilic material. postoperative. Histopathological examination showed a small amount of residual cancer with negative margins and no involvement of the seminal vesicles and vas deferens.
Ahn et al. (2002) Yonsei Medical Journal⁵	Not Specified	Unknown	Unknown	Unknown	Gross finding: Relatively well demarcated from the surrounding tissue, irregularly oval in shape, light yellowish brown in color and stony hard in consistency. The cut surface revealed several lobules separated by fibrous septa with discrete areas of hemorrhage, necrosis and cystic change. Micro find: The tumor was not encapsulated with malignant cells invading the normal prostate tissue forming nodular growth. Variable patterns--glandular, trabecular, cribriform and solid areas--were seen and within the lumen of the cribriform gland, eosinophilic amorphous material was found. The malignant cells had hyperchromatic nuclei with a few vacuoles within the cytoplasm that resembled myoepithelial cells, and frequent perineural invasion was observed
Rebhan et al. (2022) Current Opinion in Urology¹⁶	1.54	80	(+): p63, Her2, and Bcl2, (+) expression of PD-L1 in 40% of tumor cells in metastasis (-): PSA, Gata3, CD-X2, cytokeratin 7, 5/6, 20, synaptophysin, and chromogranin A	Unknown	Histology work-up: showed features indicating malignancy, such as invasive growth patterns, comedonecrosis, and increased proliferative activity. In H&E staining the tumor exhibited tall basal cells forming infiltrative nests and tubules between normal prostate glands and a cribriform architecture
Ahuja et al. (2011) Pathology, Research and Practice¹⁷	3.9	Unknown	(+): CK, SMA, her2nue, Bcl2, AR (-): PSA, CD117	Unknown	Bx showed bilateral, mid, and base regions showed smaller monomorphic tumor cells arranged in a solid basaloid pattern, as well as focally in a cribriform pattern floating in a pool of extracellular mucin. Focally, the glands were infiltrating prostatic fibromuscular tissue. Perineural invasion was also identified in the sections examined
Young et al. (1998) American Journal of Clinical Pathology¹⁸	Not Specified	Unknown	(+): PAS, PAP (prim. in areas where lumina were present), Keratin, S-100 (-): mucicarmine	Unknown	2 major patterns that merged: The first consisted of round-to oval foci with cribriform spaces that usually contained watery basophilic material but occasionally contained hyalinized, eosinophilic material. The second pattern consisted of solid nests of small basaloid-appearing cells. Most of the cells had scant cytoplasm, but in a few areas some cells had appreciable eosinophilic cytoplasm. Only mild cytologic atypia, and rare mitotic figures were identified. No perineural invasion was observed
Young et al. (1998) American Journal of Clinical Pathology¹⁸	Not Specified	Unknown	(+): S-100, CK [-/+], weakly mucicarmine, strongly PAS, PSA, PAP	Unknown	The tumor consisted of small nests, elongated tubules, and cribriform foci that were usually surrounded by a prominent myxoid stroma. Cells that were located centrally in the nests and those that lined the lumina of tubules often had more conspicuous eosinophilic cytoplasm. Some foci within the lesion were indistinguishable from basal cell hyperplasia. Myxoid stromal material lacked staining with PAS and mucicarmine but stained strongly with colloidal iron
Toesca et al. (2023) Advances in Radiation Oncology¹⁹	7	30	(+): PIN multiplex, Bcl2, NKX3.1 (rare + cells). (-): synaptophysin and chromogranin	189	Pathology/microscopy: infiltrative basal cell neoplasm with a predominant adenoid-cystic pattern, cribriform architecture, intraluminal eosinophilic material, and myxoid stroma. Some fragments demonstrated smooth muscle and loose fibroconnective tissue, suggesting extension into periprostatic tissue. One fragment showed urothelium, suspicious for bladder neck involvement
Minei et al. (2001) International Journal of Urology²⁰	2.1	Unknown	(+): epithelial cells in benign prostatic hyperplasia areas were positive for PSA antigen mRNA (-): tumor cells were neg for PAP, PSA antigen mRNA neg in epithelial cells in adenoid cystic carcinoma	Unknown	Histopathologic examination, the tumor cells consisted of basaloid and cribriform glandular patterns that surrounded mucinous lakes, and the tumor infiltrated the prostatic fibromuscular tissue. IHC: Studied the expression of PSA protein and PSA mRNA by means of IHC and an in-situ hybridization technique
Ryan et al. (2022) Urology Case Reports²¹	1.2	Unknown	(+): tumor cells are positive for CAM5-2, CKIT, CK7 (luminal cells), BCL2, p16 (large number of cells) (-): CK20, CDX-2, and TTF-1. Staining for PSA was negative	Unknown	Histology presented from the transperineal biopsy is described as cores of fibrous tissue diffusely infiltrated by a basaloid epithelial tumor with a nested solid growth pattern and areas with a cribriform pattern
Tulunay et al. (2004) International Urology and Nephrology²²	7.3	Unknown	(+): Basal cell proliferations positive for HMWCK in a patchy pattern. Prostatic adenocarcinoma foci showed PAP and PSAP positivity in tumor cells--HMWCK staining was absent in those foci but was positive in glands showing PIN features (-): Basal cell proliferations were negative for PSA, PSAP, CEA, LMWCK	Unknown	Typical benign adenomatous and fibromuscular hyperplasia of the prostate were present. In addition, there were multiple foci of neoplasm, with features of prostatic acinar adenocarcinoma, with a differentiation of Gleason grade 4. were few glands among atypical acini with high grade PIN features and yet there were multiple nodules of BCH that consisted of collections of small, usually solid nests of uniform small cells with uniform small hyperchromatic nuclei which appeared round or oval. There was a distinctive feature seen in some foci was peripheral palisading of cells within each nest, very similar to that seen in basal proliferations of the skin Histologic features of some of these nodules were similar to those occurring in ACC of the salivary glands with evidence of acinar differentiation with central lumen formation surrounded by a layer of cuboidal cells
Taskovska et al. (2023) Research and Reports in Urology²³	Not Specified	40	(+): CK34βE12, CK7, CK 5/6, p63, GATA3 (-): PSA, NKX3.1, AMACR, CK20, Bcl2, and neuroendocrine markers	Unknown	Histopathological examination of TURB-T specimens with extensive cautery artifacts showed poorly differentiated carcinoma. Small tumor cells with hyperchromatic nuclei and scant cytoplasm, arranged in irregular nests or as single cells were invading the lamina propria and muscularis propria
Montironi et al. (2005) Journal of Clinical Pathology²⁴	2.5	35%	(+): 34βE12, p63, and Bcl-2, cells were negative for CK7, CK20, AE1/AE3, PSA. Luminal Cells: positive for AE1/AE3 and CK7. both alcian blue positive acid mucin and periodic acid Schiff positive neutral mucin (pattern occupied approximately 20% of the specimen) (+): S100, α smooth muscle actin, anti-c-erbB-2	Unknown	10% of the specimen showed the appearance of benign prostatic hyperplasia (BPH). The remaining 90% showed diffuse alteration of the prostatic architecture and structure by a composite nodular lesion, with three distinct patterns

TURB-T – transurethral resection of bladder tumor, H&E – hematoxylin & eosin, PAS – periodic acid-schiff.

In our case review, there were 2 out of 24 cases that had no information on growth patterns. Of the 22 cases with histological growth information, 17 cases demonstrated an adenoid cystic growth pattern, 13 cases showed a basaloid pattern and 10 cases were associated with both growth patterns. However, out of the total 24 cases, there were 13 cases that had local extra-prostatic extension, 10 cases with perineural invasion, and 9 cases with distant metastases (Table 2).

Microscopy and IHC w/analysis

There were a number of markers tested on immunohistochemical testing between all of the studies including Ki-67, high molecular weight cytokeratin (34βE12/HMWCK), BCL-2, S-100, CK5, CK6, CK7, CK20, SMA, PAS, PAP, PSA, C-erb2 (HER2Nue) Synaptophysin, Chromogranin-A, Calponin, TTF-1 (NKX2-1) Alpha-methyl acyl-CoA/P504S, Low molecular weight cytokeratin (LMWCK/CAM5.2), CD117/CDKIT, and AE1/AE3. Some studies tested only a handful of these markers in various combinations. We listed positivity for tested markers and omitted any of the previously listed markers in studies where they were not tested for. There was only one study that had no information on marker testing in the case described by Ahn SK et al. (Table 2).

Ki-67 was found to be positive in all of the cases testing for the marker (13/13). HMWCK/34βE12 was positive in 14 out of 14 cases. We found P63 (14/14) and BCL-2 (12/13) to be positive in the set of cases tested for these markers. S100 was positive in five of the six cases tested with one negative case. CK5 and six were positive in 6/7 of cases tested as well. CK7 was positive in six out of nine cases (Table 2).

The following were the positivity for the less frequently tested markers: CK20 positive in 0/8 cases (0%), C-erb2 (HERNUE) positive in 4/5 cases, SMA positive in 3/5 cases. PAS positive in 3/3 cases, PAP positive in 4/5 cases, PSA positive in 3/16 cases, synaptophysin positive 0/5 cases, Chromogranin-A positive in 0/8 cases, Calponin positive in one of two cases, TTF-1 (NKX2-1) in 0/3 cases, AR in one of two cases, Alpha-Methyl acyl-CoA//P504S was positive in 0/4 cases, Low molecular weight cytokeratin (LMWCK/CAM5.2) in 3 of 4 cases, CD117 in 2/3 cases, and AE1/AE3 in 2/2 cases (Figure 2).

Figure 2.

Number of positive and negative staining among all initial biopsies collected of all patients for each patient.

Treatment and longterm survival

The median follow-up time for the cases was 1.5 years. Of the 24 cases, 13 underwent prostatectomy. Among the 13 prostatectomy patients, six were symptom-free during follow-up (with 9 months, 1 year, 2 years, 3 years, 4 years, and six years of follow-up), three had very limited or no follow-up information, and three died with cause relating to BCC diagnosis, with an additional patient deceased 3 years post-diagnosis due to heart failure. Among the 11 non-prostatectomy patients, one patient received orchiectomy with hormonal meds before losing follow up after six months, and six patients received a TURP-T (three of which died, 2 had no evidence of disease at 8 and 23 months post-op, and one had no follow-up data). a Of the remaining four non-prostatectomy patients, one died after 25 months post-chemoradiation therapy, one received HoLEP (Holmium Laser Enucleation of the Prostate) followed by chemoradiation and showed complete radiologic resolution 6 months post treatment, and one was undergoing chemo treatment at the time of publication. The final patient received a radical cystectomy followed by radiation, HR, and zoledronic acid; at 3 year follow-up, the patient was able to independently complete ADL's with an ECOG score of 1. To reiterate, thirteen patients received definitive therapy in prostatectomy with four total deaths among the 10 with adequate follow-up (>6 months), and eleven patients did not receive definitive therapy, amongst which four patients also died (Table 1).

Discussion

In our study, we set out to establish potential markers and trends in diagnosing BCC of the prostate. Ki-67 protein is a widely used marker among solid tumors used to ascertain tumor proliferation rates based on the cellular expression of the protein during the phases of the cell cycle.²⁵ When analyzed in a retrospective meta-analysis of general cases of localized prostate cancer (n=5,419), there was a highly statistically significant association between high Ki-67 and decreased survival outcomes as well as distant metastasis. The mean Ki-67 in the pooled patients was 6.14%.²⁵ While our case series is limited by the heterogeneity and small sample size, it may be worth noting that the median Ki-67 in our pool of patients with defined Ki-67 positivity (n = 13) was ∼43% as shown in Figure 3.

Figure 3.

Box Diagram of Ki-67 staining percentages on biopsies early on in treatment course for patients included in this review. The box covers 25th to 75th percentile of the data. The line within the box highlights the median. The whiskers each represent Q1 – 1.5 x Interquantile Range (IQR) and Q3 + 1.5 x IQR.

We know that prostatic basal cell carcinoma is not typically associated with elevated PSA or PAP unless accompanied by acinar adenocarcinoma.¹ Interestingly, there have been few cases where BCC was incidentally diagnosed by needle biopsy because of elevated PSA from a concomitant acinar adenocarcinoma.¹ In our study, we observed a few patients with PSA levels >4 and very few positive PSA staining, which is not expected in immunohistochemistry of bcc. Moreover, the positive GATA 3 and AE1/AE3, which are usually positive in other luminal cancers, in a small number of cases in our study cannot be explained plainly, especially given this is not a commonly seen phenomenon in prostatic BCC. However, taking these odd occurrences out of isolation and into greater context may reveal a larger picture we haven’t entirely visualized yet.

In 2007, a clinicopathology study of 29 cases by Ali & Epstein from John Hopkins detailed findings from consultations collected over a course of 20 years.¹ In their study, they describe similar findings that we have found in our review; Ali & Epstein found BCL-2 to be positive in 22/24 cases and Ki-67 positive in 24/24 cases with 13 cases having greater than 20% positivity (mean=23%).¹ Moreover, they found AMACR to be positive in 6/22 cases (27%) vs our study that found positivity in 0/5 cases.

A previous study explored the utility of BCL-2 and Ki-67 in differentiating benign basal cell lesions from malignant ones and stipulated they could be used as ancillary tools in diagnosis of proliferative basal cell lesions of the prostate after finding all six of the Basal Carcinoma (BC) cases were BCL-2 and Ki-67 positive compared to low reactivity/positivity in the basal cell hyperplasia cases.²⁶ Preliminary empirical evidence gathered from our case series review suggest that Ki-67 and BCL-2 may be included as the primary IHC markers used in diagnosis alongside HWMCK and P63.

Early identification and understanding of the histological and cytological characteristics of a patient’s tumor biopsy is imperative in this malignancy. For a long time, we have primarily considered cell morphology in the grading system of prostate cancer as it does not consider proliferation rate.²⁷ Considering the diagnostic overlap between in cytology that can be seen with BCH and the diagnostic confusion that has been seen with BCC and urological cancers as described in Taskovsa et al.,²³ it would be advantageous to establish stronger objective diagnostic criteria that can be consistently relied upon.

Concerning potential diagnostic criteria in other immunohistochemical markers that we collected, there were intriguing results but nothing consistent or revealing quantitatively. The 80% positivity of ERB-2 tested cases in our review conflicts with a separate study that found positive ERB-2 testing in 1/9 cases while exploring potential clinical treatment targets.²⁸ However, the authors acknowledged conflicting existing evidence concerning the association of erb-2 in BCC cases. Additionally, it is important to note the context of the time that this study was done. This means considering the time-period and interventions available as well as the treatments being done for BPH and adenocarcinoma.

Limitations to this case series review include the heterogeneity and limited sample sizes of the sources. While this may be the case for rarer tumors/tumor presentations, further steps could be taken to account for these differences (e.g. systematic review) to draw inferential conclusions.²⁹

Conclusion

As mentioned in a previous multi-case review of prostatic BCC cases, there can be serious diagnostic challenges when trying to manage patients without a nuanced sense of inquiry.¹ While challenging current diagnostic criteria to establish new ones, it is important to take a step back to view the broader perspective of the subject in question.

Footnotes

Acknowledgements

All individuals who contributed to this work are listed as authors.

ORCID iD

Lister DeBinya

Author contributions

All authors listed on the title page contributed to the study design, analysis and interpretation of the data, and the composition of this manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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