Metastatic prostate cancer diagnosed by fine-needle aspiration: Contemporary cytopathologic and biomarker assessment with clinical correlates

Abstract

Introduction: The diagnosis of metastatic prostatic cancer (MPC) by fine needle aspiration (FNA) can usually be rendered by typical cytomorphologic and immunohistochemical (IHC) features. However, MPC diagnosis may be complicated by transformation to atypical phenotypes such as small cell carcinoma, typically under pressure from androgen deprivation therapy (ADT). Predictive and prognostic biomarkers can also be assessed by IHC. This study illustrates how careful assessment of cytologic and biomarker features may provide therapeutic and prognostic information in MPC.

Design: We reviewed our anatomic pathology archives for MPC diagnosed by FNA from January 2014 to June 2021. Clinical histories, cytology slides, and cell blocks were reviewed. Extensive IHC biomarker workup was performed, including markers of prostate lineage, cell-cycle dysfunction, Ki-67, neuroendocrine markers, PDL1, and androgen receptor splice variant 7. Cases were reclassified into three categories: conventional type, intermediary type, and high-grade neuroendocrine carcinoma (HGNC).

Results: Eighteen patients were identified. Twelve had conventional MPC, including six of six ADT-naive patients. Six of twelve (50%) with prior ADT were reclassified as intermediary or HGNC. Four intermediary cases included two with squamous differentiation and two with pro-proliferative features. Two HGNC cases had typical small cell carcinoma cytomorphology. Expression of PDL1 was identified in two cases and ARv7 in three cases. Five of five intermediary and HGNC patients died of disease versus six of eleven with with conventional type.

Conclusions: Aggressive cytomorphologic variants were commonly identified in patients with prior ADT. Identification of nonconventional cytomorphology and increased proliferation can provide important prognostic information. Recognition of these changes is important for an accurate diagnosis, and the identification of high-grade variants can affect therapeutic decision-making. Clinically actionable biomarkers such as PDL1 and ARv7 can be assessed by IHC.

Keywords: androgen receptor (AR); cytopathology; fine needle aspiration; neuroendocrine; prostate cancer; small cell carcinoma; transdifferentiation.

FIGURE 1

Schematic of prostate cancer progression. Conventional prostate cancer exhibits acinar architecture with canonical androgen receptor signaling and prostate lineage marker expression. However, prostate cancer can undergo progression to pro‐proliferative or transdifferentiated (neuroendocrine and/or squamous) states, under therapeutic pressure or de novo, and then exhibit reduced prostate lineage marker expression, reduced dependence on androgen signaling, and increased proliferation. Prostate cancer can ultimately develop full progression to high‐grade neuroendocrine carcinoma, with elevated proliferation and neuroendocrine markers, a dysfunctional AR pathway, and loss of RB and Cyclin D1. AR indicates androgen receptor; RB, retinoblastoma

FIGURE 2

Conventional acinar prostatic adenocarcinoma metastatic to the sacrum in a therapy‐naive patient (patient 2). Adenocarcinoma is present in cohesive acinar arrangements (A and B, smear slides, DiffQuik‐stained 100× and Papanicolaou‐stained, 200×). NKX3.1 (C) and PSMA (D) are diffusely expressed by immunohistochemical stain. PSMA indicates prostate‐specific membrane antigen

FIGURE 3

Conventional acinar prostatic adenocarcinoma metastatic to mediastinal lymph node in a patient who had received prior anti‐androgen therapy (patient 12). The adenocarcinoma retains the conventional acinar morphology and prominent nucleoli typical of prostatic adenocarcinoma (A and B, smear slides, DiffQuik‐stained 100× and Papanicolaou‐stained, 200×). As in untreated cases, tumor cells retained expression of NKX3.1 (C) and PSMA (D). PSMA indicates prostate‐specific membrane antigen

FIGURE 4

Squamous cell carcinoma differentiation in prostatic cancer metastatic to the femur (patient 13). Carcinoma is present as solid sheets with keratinization (A, cell block, hematoxylin and eosin, 200×) and as clusters with markedly pleomorphic forms (B, ThinPrep, Papanicolaou‐stained, 400×). Patchy retained expression of PSMA (C) was present, whereas NKX3.1 (D) was negative. PSMA indicates prostate‐specific membrane antigen

FIGURE 5

Squamous cell carcinoma differentiation in metastatic prostatic cancer to the mediastinal lymph node (patient 14). Solid sheets of large tumor cells are present with necrosis (A, smear slide, Papanicolaou‐stained, 200×), including prominent keratinization (B, cell block, hematoxylin and eosin, 400×). Prostate lineage marker expression, such as NXK3.1 (C) was retained. Ki‐67 labeling index was elevated (D)

FIGURE 6

Pro‐proliferative features in prostatic cancer metastatic to the subcarina (patient 15). Tumor is present in solid sheets and poorly formed acinar arrangements (A and B, smear slide, Papanicolaou stained, 400× and cell block, hematoxylin and eosin, 200×). NKX3.1 expression is retained (C), but Ki‐67 labeling index is >50% (D)

FIGURE 7

Neuroendocrine transdifferentiation in metastatic prostatic cancer with retained acinar features in a mediastinal lymph node (patient 16). Smear slides show clear acinar formations (A, smear slide, DiffQuik‐stained, 200×), but in other areas tumor cells are present as single cells and in loose sheets, with fine chromatin lacking nucleoli (B, smear slide, Papanicolaou stained, 400×). NKX3.1 expression was retained (C), but moderate expression of synaptophysin (D) was also noted

FIGURE 8

Small cell carcinoma (high‐grade neuroendocrine) in prostatic cancer metastatic to a left cervical lymph node (patient 17). Tumor is present exclusively in loose sheets of cells exhibiting typical small cell features, including high nuclear to cytoplasmic ratios, fine chromatin, nuclear molding, and absent nucleoli (A and B, smear slides, DiffQuik stained, 200× and 400×). Acinar morphology is absent. Ki‐67 labeling index is elevated over 50% (C), and Rb (D) expression is lost

FIGURE 9

Small cell carcinoma (high‐grade neuroendocrine) in prostatic cancer metastatic to a left cervical lymph node (patient 18). Like patient 17, typical features of small cell carcinoma are noted, such as loss of cohesion, fine chromatin, and nuclear molding. (A and B, smear slides, Papanicolaou‐stained, 200× and DiffQuik stained, 400×). NKX3.1 (C) expression was retained, but diffuse synaptophysin (D) expression was also present

FIGURE 10

Biomarker immunohistochemistry in metastatic prostate cancer. PDL1 staining was identified in two cases, including patient 7 (A). ARv7 expression was present in 4 FNAs from three patients, including patient 5 (B). FNA indicates fine‐needle aspiration