An 88-year-old man with a history of castration-sensitive prostate cancer presented to the emergency department with gross hematuria and urinary incontinence. The patient was diagnosed with prostatic adenocarcinoma five years prior, based on a serum prostate-specific antigen (PSA) of 141 ng/mL. He did not undergo prostate core biopsy and had been on Lupron and/or Casodex (bicalutamide). He had no evidence of soft tissue or bone metastasis. A computed tomography scan of the abdomen and pelvis demonstrated marked bladder wall thickening with small enhancing soft tissue along the posterior wall, resulting in mild bilateral hydroureteronephrosis—likely representing recurrent prostate cancer (Fig. 1). His PSA increased from 2.8 to 11.4 ng/mL in two months. The patient underwent a transurethral resection of prostate.
During the transurethral resection of prostate, he was found to have direct prostate cancer involvement and invasion into the bladder neck and obstructing bilateral ureters. A 22-g, 8.0 × 5.5 × 1.5-cm aggregate of soft tissue and blood clot was submitted. Microscopically, the tumor involved nearly 100% of the prostate chips and was composed of uniform basaloid cells in irregular solid nests with central necrosis (Fig. 2A). The tumor cells had scant eosinophilic cytoplasm and round to oval nuclei, with evenly distributed coarse chromatin and occasional prominent nucleoli (Fig. 2B). Peripheral palisading and mitotic figures were noted (Fig. 2C). The tumor formed focal acinar structures, lined by cuboidal to low columnar cells with apical pale to eosinophilic cytoplasm and contained intraluminal eosinophilic secretions (Fig. 2D). By immunohistochemistry, tumor was focally positive for CK903, GATA-3, synaptophysin, and CD56, with a Ki-67 proliferation index of 70% (Fig. 3). Immunohistochemistry was negative for PSA, prostatic acid phosphatase (PAP) prostate-specific membrane antigen, NKX3.1, AR, chromogranin, and p63.
Based on the clinical history and histomorphology, our initial differential diagnosis included basal cell carcinoma (BCC) of the prostate, small cell neuroendocrine carcinoma, poorly differentiated prostatic carcinoma, and poorly differentiated urothelial carcinoma. Here, we discuss key diagnostic points for selected entities in the differential diagnosis, followed by a discussion of our final diagnosis.
Basal cell carcinoma is very rare and is described as having 2 main patterns: (1) adenoid cystic carcinoma pattern when the morphologic features resemble that of salivary gland–type tumors, or (2) BCC pattern when lacking such features.1–3 The adenoid cystic carcinoma pattern shows nests with cribriform architecture, and the BCC patterns can show small solid nests with peripheral palisading, tubules or cords of cells, or large solid nests of basaloid cells with central necrosis. The basaloid large nest type is the least common and most aggressive variant. In either pattern, PSA/PAP and NKX3.1 are usually negative, and basal cell markers including p63 and high-molecular-weight keratin are positive. Basal cell carcinoma occasionally resembles basal cell hyperplasia. Infiltrative growth pattern, perineural invasion, extraprostatic extension, and necrosis are key diagnostic criteria for malignancy, regardless of pattern.
Small cell carcinoma of the prostate can arise de novo or can occur in response to androgen deprivation therapy (ADT), which results in androgen receptor (AR)–indifferent or –negative prostate cancer.4–7 Small cell carcinoma of the prostate is a distinct subtype of prostate neuroendocrine tumors, distinguished from other subtypes such as carcinoid, atypical carcinoid, or large cell neuroendocrine carcinoma by characteristic morphology and immunophenotypic features. These include findings of a high-grade tumor composed of cells with a high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei lack of prominent nucleoli, nuclear molding, crush artifact, frequent apoptosis and mitosis, and necrosis, among others.5,6 Typically, the tumor has a Ki-67 proliferation index greater than 80% and positive neuroendocrine markers such as synaptophysin and chromogranin. Small cell carcinoma is typically negative for PSA, PAP, NKX3.1, and AR. Mixed neuroendocrine carcinoma–acinar adenocarcinoma is more common and has a usual acinar adenocarcinoma component, which also may develop either de novo or secondary to ADT. Diagnosis of castration-resistant prostate cancer (CRPC) with either pure or a component of small cell carcinoma requires correlation with a clinical history of tumor no longer responding to ADT, as well as histologic evidence of small cell neuroendocrine carcinoma.7
The majority of prostatic adenocarcinoma that progressed following ADT remains to be AR-driven, as evidenced by expression of AR and AR target genes. A subset becomes AR-independent, by either transforming to small cell carcinoma or dedifferentiation to AR-negative (adeno)carcinoma. The emergence of a therapy-induced double-negative prostate cancer (DNPC) phenotype, defined by lack of expression of both AR/AR targets and neuroendocrine markers, has recently been described by Bluemn et al.8 The authors reported that approximately 20% of metastatic CRPC cases in their study had this “double-negative” phenotype and were driven by fibroblast growth factor/mitogen-activated protein kinase signaling.8,9 Moreover, the proportion of DNPC cases in metastatic CRPC samples has increased significantly since the introduction of more potent second-generation ADT agents.8 Nowadays, it is not uncommon for pathologists to encounter AR-negative/neuroendocrine-negative CRPC, particularly when metastatic tumors were biopsied for sequencing analysis to look for actionable targets after the patients failed ADT.
After considering the above differential diagnoses, the final diagnosis for this case is determined to be “poorly differentiated adenocarcinoma, consistent with prostatic origin” with the following comment: “This is compatible with androgen-independent prostatic adenocarcinoma in the appropriate clinical setting.”
Although the striking morphology of solid nests with central necrosis raised the possibility of BCC, the findings were most compatible with poorly differentiated prostatic adenocarcinoma given the clinical history of a prior PSA-secreting prostate cancer, treated with ADT over several years and no longer responding to therapy. Additionally, the findings of focal acinar differentiation and p63 negativity did not support BCC, basaloid large nest variant. There was no strong support for urothelial carcinoma or small cell carcinoma based on negative or focal staining for GATA-3, CK903, p63, and neuroendocrine markers, respectively. The tumor did not have typical morphologic features of small cell carcinoma such as nuclear molding, crush effect, and lack of prominent nucleoli. Given the totality of clinical and histopathologic findings, the best diagnosis was poorly differentiated prostatic adenocarcinoma. The basaloid morphology, negativity for AR, PSA, PAP and NKX3.1, and a high Ki-67 proliferation index of 70% likely indicated tumor transformation toward DNPC under the selection pressure of ADT, which portends a poor prognosis and is therefore important to convey to clinicians and patients. At the time of manuscript preparation, a case follow-up showed that the patient died 5 months after the diagnosis.
Under the selection pressure of intensive androgen deprivation therapy, prostatic adenocarcinoma may transform to poorly differentiated to undifferentiated carcinoma in addition to small cell neuroendocrine carcinoma. Correct diagnosis requires (1) a history of hormonal treatment for at least a year, (2) a recent treatment failure, and (3) exclusion of neuroendocrine carcinoma and other malignancies, particularly bladder carcinoma.
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