The diagnostic dilemma of squamous differentiation in prostate cancer: A case report

Abstract

Squamous differentiation in prostate cancer is rare, presenting unique diagnostic and therapeutic challenges. We report a case of high-grade prostatic adenocarcinoma with focal squamous differentiation in a 73-year-old man without prior radiation or androgen deprivation. Immunohistochemistry confirmed the squamous component arose from the adenocarcinoma, not a separate malignancy. This case highlights the importance of morphological assessment and strategic immunohistochemical evaluation to distinguish prostate cancer variants. A biopsy capturing only the squamous component could have led to misdiagnosis and inappropriate treatment. To improve diagnostic accuracy and management, we propose the term ‘adenocarcinoma with focal squamous differentiation’ over adenosquamous carcinoma.

Highlights

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Squamous features in prostate cancer can complicate diagnosis and treatment.
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Standard biopsy may miss rare cancer variants within the prostate.
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Careful tissue analysis helps avoid misdiagnosis and guide proper care.
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Current terminology may not reflect the full range of tumor variations.
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Clearer classification can support more accurate diagnosis and management.

1 Introduction

Prostate cancer (PCa) is the second-leading cause of cancer-related death among U.S. men, with a mortality rate of 19 deaths per 100,000 men annually. ^, While approximately 95 % of PCa cases are classified as adenocarcinomas, the disease is known for its heterogeneity due to its variable molecular profiles and clinical behaviors. ^, The remaining 5 % include rare histological variants that develop either independently from distinct cellular origins or via transdifferentiating from prior prostatic adenocarcinoma.

Among these variants, squamous differentiation in PCa refers to the pathological process whereby prostate cells, typically of adenocarcinoma origin, acquire squamous cell morphology and characteristics. Proposed etiologies for this change include metaplastic transformation of adenocarcinoma cells, a collision-type tumor with the emergence of squamous elements from metaplastic foci, or differentiation driven by pluripotent stem cells. Regardless of etiology, squamous differentiation in PCa is classified into two primary categories: adenosquamous carcinoma (ASC) and pure squamous cell carcinoma (SCC). The coexistence of squamous differentiation with adenocarcinoma is pathognomonic for ASC, while pure SCC is characterized by squamous differentiation without any glandular components.

Pure SCC is rare, constituting 0.6–1 % of all prostatic malignancies. Approximately half of these cases follow prior radiation or hormonal therapy for adenocarcinoma, while others arise de novo. Diagnosing pure SCC relies on Mott’s five criteria, which include clearly malignant traits (disorganized growth, cellular anaplasia, invasion), evidence of squamous differentiation (keratinization, squamous pearls, intercellular bridges), absence of glandular/acinar components, no prior estrogen therapy, and exclusion of primary squamous cancer elsewhere.

ASC, however, is distinguished by the coexistence of both glandular and squamous components. Based on incidence rates of ASC and all PCa cases over the same period, the estimated prevalence of ASC is approximately 0.002 % (or about 2 cases per 100,000 PCa diagnoses). ^, However, this is thought to be an underestimation due to diagnostic challenges. Unlike pure SCC, ASC exhibits significant variability in the extent of squamous differentiation, ranging from as little as 5 % to as much as 95 %, with an average of approximately 40 %. This variability extends to its spatial distribution within the prostate as well. Though ASC is described as the coexistence of glandular and squamous components, it can take different forms, including focal areas of differentiation or more complex patterns. Some reports note that the two often intermingle, which can make interpretations difficult to decipher.

The variability in both histological composition and clinical behavior can make ASC feel like a catch-all category that encompasses a wide spectrum of cases. However, not all cases of PCa fit neatly into the existing terminology, highlighting the need for a more nuanced approach. This is a case report of a 73-year-old male with high-grade prostate adenocarcinoma that underwent squamous differentiation in a localized area, notably without any prior history of hormonal or radiation therapy. Considering the unusual focal histologic transdifferentiation of this patient, we propose that there be a distinct classification for a type of ASC called “adenocarcinoma with focal squamous differentiation”. This distinction is important because many of these cases may be missed, as a needle biopsy may catch only a squamous or adenocarcinoma component.

2 Case presentation

A 73-year-old Caucasian male with a past medical history of smoking, hypertension, hyperlipidemia, and benign prostatic hyperplasia presented to the urology clinic with lower urinary tract symptoms (LUTS) and an elevated serum PSA at 12.79 ng/mL (reference range based on age: 0–6.5 ng/mL). Digital rectal examination revealed an enlarged prostate with a firm right lobe and median groove. Magnetic resonance imaging (MRI) of the prostate identified a 12 mm × 7 mm x 19 mm lesion in the peripheral zone, extending from the apex to the mid gland with possible capsular involvement, and was assigned a PI-RADS score of 5. An additional pedunculated mass, measuring 17 mm × 19 mm x 14 mm, was found in the bladder adjacent to the left ureterovesical junction, suspicious for a primary bladder tumor.

One month later, the patient underwent a transurethral resection of the bladder tumor and an ultrasound-guided prostate biopsy. The bladder tumor was confirmed to be a high grade non-invasive papillary urothelial carcinoma. The pathology report for the prostate biopsy revealed Gleason score 3 + 4 = 7 (grade group 2) adenocarcinoma, involving seven of twelve cores collected bilaterally. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) showed a high level of PSMA uptake in the prostate bilaterally, correlating with the biopsy-proven adenocarcinoma.

Two months after the initial biopsy, the patient underwent a robot-assisted radical prostatectomy and pelvic lymph node dissection. Histologic sections of the prostate showed multiple, spatially distinct foci of prostatic adenocarcinoma. The index (dominant) nodule measured 30 mm and involved the left midgland and base, with extensive extraprostatic extension by carcinoma at the left posterolateral neurovascular bundle, including perineural invasion. The cancer was of the usual acinar type and assigned Gleason Score 4 + 5 = 9 (Grade Group 5; 10 % pattern 5, 70 %pattern 4, 20 % pattern 3; Fig. 1 ), with pattern 4 seen as cribriform architecture and pattern 5 as solid sheets of carcinoma. The seminal vesicles and surgical margins were negative for involvement by carcinoma.