Gleason Score 3+3=6 (Grade Group 1) Acinar Adenocarcinoma of the Prostate Arising in the Setting of Benign Prostatic Hyperplasia: A Needle Core Biopsy and Immunohistochemical Study.

Background: Prostate adenocarcinoma is one of the most common malignancies in aging males. Differentiating well-differentiated low-grade prostate adenocarcinoma from benign mimickers such as adenosis (atypical adenomatous hyperplasia) and basal cell hyperplasia in needle core biopsies can be exceptionally challenging, frequently necessitating targeted immunohistochemistry. Case Presentation: A 67-year-old male evaluated for suspected prostate cancer presented with a serum PSA of 18.5 ng/mL and a smooth, grade 1 digital rectal examination. Systematic sextant prostate needle core biopsies (right and left apex, mid-zone, and base) were performed. Histologic evaluation revealed widespread fibroadenomatous hyperplasia (benign prostatic hyperplasia) across all sites; however, the left mid-zone and left base cores demonstrated focal proliferation of small-to-medium-sized crowded glands exhibiting mild cytologic atypia. Confirmatory immunohistochemical staining using the PIN4 cocktail (p63, 34betaE12, and AMACR/P504S) demonstrated the definitive absence of basal cell layers in the atypical glands coupled with aberrant AMACR expression, establishing the diagnosis of conventional Acinar Adenocarcinoma, Grade Group 1 (Gleason Score 3+3=6). Conclusion: The coexistence of benign prostatic hyperplasia and low-grade prostatic adenocarcinoma requires rigorous microscopic evaluation and basal/AMACR marker panels to avoid diagnostic misinterpretation and ensure appropriate patient stratification. Keywords Prostate Adenocarcinoma, Gleason Score 3+3, Grade Group 1, Benign Prostatic Hyperplasia, PIN4 Cocktail, AMACR, Prostate Needle Core Biopsy, Uropathology. Introduction Carcinoma of the prostate is a leading cause of cancer morbidity and mortality worldwide among men. While advanced tumors are readily identifiable, well-differentiated acinar adenocarcinomas (Gleason score 6 / Grade Group 1) can closely mimic benign mimickers of prostate cancer—such as partial atrophy, adenosis, and hyperplastic glands—in limited needle core biopsy material. Elevated serum prostate-specific antigen (PSA) levels prompt systematic transrectal or transperineal core biopsies. When subtle architectural crowding and minimal cytologic atypia are encountered within nodules of benign prostatic hyperplasia (BPH), ancillary immunohistochemical testing utilizing basal cell markers (p63, high-molecular-weight cytokeratins like 34betaE12) and a-methylacyl-CoA racemase (AMACR/P504S) is essential to provide definitive diagnostic clarity. Case Presentation Clinical History and Preoperative Findings A 67-year-old male presented for prostate cancer investigation. Preoperative evaluation revealed a serum PSA level of 18.5 ng/mL. Digital rectal examination (DRE) demonstrated a grade 1, smooth, firm prostate without palpable discrete nodules. Systematic transrectal needle core biopsies were obtained from six distinct anatomic regions: right apex, right mid-zone, right base, left apex, left mid-zone, and left base. Macroscopic Examination Specimens consisted of multiple off-white, cylindrical tissue cores measuring approximately 1.0 × 0.1 × 0.1 cm per container, which were entirely submitted for microscopic analysis. Histopathology Microscopic evaluation via Hematoxylin and Eosin (H&E) demonstrated: Right Apex, Right Mid-Zone, Right Base, and Left Apex: Prostatic tissue cylinders consistently exhibited features of prominent fibroadenomatous hyperplasia (BPH), characterized by variably sized glands lined by a bland double epithelial-basal cell layer with preserved polarity and inconspicuous nucleoli, set within a hypertrophic fibromuscular stroma. Mild focal chronic inflammation was noted in the left apex. No high-grade prostatic intraepithelial neoplasia (PIN) or malignancy was identified in these quadrants. Left Mid-Zone & Left Base: Alongside background BPH, sections revealed interspersed foci of small-to-medium-sized crowded glands lined by a single layer of cells exhibiting mild cytologic atypia (enlarged nuclei, subtle nuclear irregularities, and occasional nucleoli), raising clinical and morphological suspicion for an invasive well-differentiated prostatic adenocarcinoma (Figure 1, Figure 2). Immunohistochemical Confirmation To resolve the suspicious foci in the left mid-zone and base, immunohistochemical staining using a PIN4 cocktail (p63, 34betaE12, and AMACR) was performed on the paraffin-embedded blocks: Basal Cell Markers (p63 and 34betaE12): Demonstrated complete absence of the basal cell layer in the suspect crowded glands, confirming architectural infiltration. AMACR (P504S): Showed diffuse and robust cytoplasmic positivity within the atypical glands. The combined immunophenotypic profile confirmed Conventional Acinar Adenocarcinoma, Grade Group 1 (Gleason Score 3+3=6), involving approximately 6–10% of the examined left mid-zone core tissue. Discussion The diagnosis of low-grade prostate adenocarcinoma (Gleason score 3+3=6) in needle core biopsies requires meticulous morphologic evaluation, particularly when tumors arise in the background of extensive nodular benign prostatic hyperplasia (BPH). Glands in BPH can frequently appear crowded or distorted due to stromal compression, simulating malignant architectural arrangements. When minimal architectural atypia or focal glandular crowding is identified without unequivocal features of malignancy (such as perineural invasion, stromal mucin, or nested glomeruloid structures), immunohistochemistry serves as the definitive gold standard. The PIN4 cocktail combines high-molecular-weight cytokeratins (34betaE12) and p63 to stain benign basal epithelial cells (which are absent in invasive carcinoma) coupled with AMACR, a cytoplasmic enzyme upregulated in prostatic adenocarcinoma. In this patient, despite a moderately elevated PSA (18.5 ng/mL) and a smooth DRE, targeted biopsy sampling combined with expert immunohistochemical workup successfully unmasked a localized, low-grade acinar adenocarcinoma, facilitating timely and appropriate clinical staging and therapeutic management. Conclusions Well-differentiated acinar adenocarcinoma of the prostate (Gleason 3+3=6) can be occult or subtle in needle core biopsies, frequently intermixed with or masked by benign fibroadenomatous hyperplasia (BPH). Focal glandular crowding with minimal cytologic atypia warrants ancillary immunohistochemical evaluation utilizing basal cell markers and AMACR. The PIN4 cocktail is an indispensable diagnostic tool that reliably confirms malignancy by demonstrating basal cell layer loss and aberrant AMACR expression in ambiguous prostatic foci. Figure Captions Figure 1 (Microfotografía - H&E, Low Power): Low-power histological view of the prostatic needle core biopsy demonstrating fibroadenomatous hyperplasia alongside subtle focal glandular crowding and architectural complexity (H&E, 40x). Figure 2 (Microfotografía - H&E, High Power): High-power magnification highlighting small-to-medium-sized crowded glands with enlarged nuclei, subtle nuclear irregularities, and conspicuous nucleoli characteristic of well-differentiated acinar adenocarcinoma (H&E, 200x). References Epstein JI, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Grading of Prostatic Carcinoma. Am J Surg Pathol. 2016;40(2):244-252. Humphrey PA. Histological variants of prostatic carcinoma and their significance. 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