Ductal adenocarcinoma of the prostate with oncocytic morphology

Prostatic adenocarcinoma with oncocytic morphology is exceedingly rare, with only six cases published in the English literature (Table 1).1Ordonez N.G. Ro J.Y. Ayala A.G. Metastatic prostatic carcinoma presenting as an oncocytic tumor.Am J Surg Pathol. 1992; 16: 1007-1008Crossref PubMed Scopus (19) Google Scholar, 2Pinto J.A. González J.E. Granadillo M.A. Primary carcinoma of the prostate with diffuse oncocytic changes.Histopathology. 1994; 25: 286-288Crossref PubMed Scopus (18) Google Scholar, 3Fiandrino G. Lucioni M. Filippin F. et al.Prostatic adenocarcinoma with oncocytic features.J Clin Pathol. 2011; 64: 177-178Crossref Scopus (6) Google Scholar, 4Khadim M.T. Hassan U. Ejaz A. Mamoon N. Oncocytic variant of prostatic adenocarcinoma-a case report.Pak Armed Forces Med J. 2012; 1: 142Google Scholar, 5Klairmont M.M. Zafar N. Prostatic adenocarcinoma oncocytic variant: case report and literature review.World J Clin Oncol. 2017; 8: 289Crossref Scopus (0) Google Scholar, 6García-Cuerva M.S. Algaba F. Arce Y. Oncocytic prostate carcinoma “case report”.SN Compr Clin Med. 2022; 4: 107Crossref Google Scholar Herein we present a case of prostatic ductal adenocarcinoma with extensive oncocytic change. To the best of our knowledge, this is the first reported case of oncocytic morphology in prostatic ductal adenocarcinoma, in contrast to the cases of acinar adenocarcinoma reported in the literature.1Ordonez N.G. Ro J.Y. Ayala A.G. Metastatic prostatic carcinoma presenting as an oncocytic tumor.Am J Surg Pathol. 1992; 16: 1007-1008Crossref PubMed Scopus (19) Google Scholar, 2Pinto J.A. González J.E. Granadillo M.A. Primary carcinoma of the prostate with diffuse oncocytic changes.Histopathology. 1994; 25: 286-288Crossref PubMed Scopus (18) Google Scholar, 3Fiandrino G. Lucioni M. Filippin F. et al.Prostatic adenocarcinoma with oncocytic features.J Clin Pathol. 2011; 64: 177-178Crossref Scopus (6) Google Scholar, 4Khadim M.T. Hassan U. Ejaz A. Mamoon N. Oncocytic variant of prostatic adenocarcinoma-a case report.Pak Armed Forces Med J. 2012; 1: 142Google Scholar, 5Klairmont M.M. Zafar N. Prostatic adenocarcinoma oncocytic variant: case report and literature review.World J Clin Oncol. 2017; 8: 289Crossref Scopus (0) Google Scholar, 6García-Cuerva M.S. Algaba F. Arce Y. Oncocytic prostate carcinoma “case report”.SN Compr Clin Med. 2022; 4: 107Crossref Google ScholarTable 1Summary of reported cases of prostatic epithelial lesions with oncocytic morphologyAuthor, yearAge of patientMorphology and Gleason score (GS)ImmunoprofileUltrastructural examinationExtent of disease and treatmentFollow-upBeer, 19908Beer M. Occhionero F. Welsch U. Oncocytoma of the prostate: a case report with ultrastructural and immunohistochemical evaluation.Histopathology. 1990; 17: 370-372Crossref Scopus (7) Google Scholar87Tubulo-acinar nodules composed of polygonal cells with abundant eosinophilic granular cytoplasm adjacent to hyperplastic prostatic glands with basal cell hyperplasia.Interpreted as oncocytic transformation of hyperplastic prostate glands(+) cytochrome oxidase, cytokeratin (w), EMA (w)(–) PSAAbundant large mitochondria and scant other cytoplasmic organellesUnderwent TURP. No evidence of metastasisNSOrdonez et al., 19921Ordonez N.G. Ro J.Y. Ayala A.G. Metastatic prostatic carcinoma presenting as an oncocytic tumor.Am J Surg Pathol. 1992; 16: 1007-1008Crossref PubMed Scopus (19) Google Scholar63Adenocarcinoma forming small to medium-sized glands.Cuboidal cells with eosinophilic granular cytoplasm and round nuclei.GS 8(+) PAP, PSAFilled with mitochondria.No evidence of neuroendocrine differentiationPresented with metastasis to right inguinal lymph node. Underwent lymphadenectomy and TURP. Received hormonal therapyDeveloped recurrence in groin and retroperitoneal metastasis 1 year. DOD 2 years with lung at abdominal metastasisPinto et al., 19942Pinto J.A. González J.E. Granadillo M.A. Primary carcinoma of the prostate with diffuse oncocytic changes.Histopathology. 1994; 25: 286-288Crossref PubMed Scopus (18) Google Scholar66Solid nests and cords of polygonal cells with abundant bright red granular cytoplasm and hyperchromatic eccentric nuclei, some with prominent nucleoli.GS 9(+) PSANumerous round to ovoid mitochondria with clear matrix and partial loss of cristaePresented with metastasis (right retro-ocular tumour and bone). Underwent bilateral orchidectomy and removal of the retroocular metastatic depositAlive at 1 yearFiandrino et al., 20113Fiandrino G. Lucioni M. Filippin F. et al.Prostatic adenocarcinoma with oncocytic features.J Clin Pathol. 2011; 64: 177-178Crossref Scopus (6) Google Scholar72Fused glands of polygonal tumour cells with abundant eosinophilic cytoplasm, bland nuclei, and small nucleoli.PNI present.GS 4+4(+) PSA, PAP, AE1/AE3, Cam 5.2, CK7 (f), CK20 (f), anti-mitochondrial antibodyMarkedly increased numbers of oval mitochondriaUnderwent RP. No evidence of metastasisAlive at 30 monthsKhadim et al., 20124Khadim M.T. Hassan U. Ejaz A. Mamoon N. Oncocytic variant of prostatic adenocarcinoma-a case report.Pak Armed Forces Med J. 2012; 1: 142Google Scholar57Primarily solid sheets of large cells with eosinophilic granular cytoplasm, round to ovoid hyperchromatic nuclei.GS 5+4(+) PSAPNSUnderwent TURPNSKlairmont et al., 20175Klairmont M.M. Zafar N. Prostatic adenocarcinoma oncocytic variant: case report and literature review.World J Clin Oncol. 2017; 8: 289Crossref Scopus (0) Google Scholar64Well-formed glands with rare distorted and fused glands. Tumour cells with eosinophilic granular cytoplasm, small to intermediate sized vesicular nuclei, rare prominent nucleoli.PNI present.GS 3+4(+) AMACRNSUnderwent targeted cryoablation of the prostateNSGarcía-Cuerva et al., 20226García-Cuerva M.S. Algaba F. Arce Y. Oncocytic prostate carcinoma “case report”.SN Compr Clin Med. 2022; 4: 107Crossref Google Scholar59Poorly differentiated monomorphic carcinoma without glandular structures. Tumour cells with abundant eosinophilic granular cytoplasm and round nuclei.GS 5+5(+) AE1/AE3, NKX3.1, PSMA(–) PSA, ERG, P504S, p63, GATA3, 34βE12, HMB45, S100, MelanA, calretinin, chromogranin, synaptophysin, CD56, SMA, desminNSLocally advanced prostate tumour with extension to bladder and pelvic lymph node metastasis. Underwent pelvic exenterationDeveloped massive pelvic recurrence at 3 months and subsequently metastatic dissemination to bones and gluteal muscles. Received chemotherapy and hormonal therapy. DOD at 18 monthsThis case68Solid, cribriform, and papillary architecture. Columnar tumour cells with eosinophilic granular cytoplasm, vesicular nuclei, and conspicuous nucleoli.PNI and LVI present.GS 4+4(+) NKX 3.1, AMACR, PSMA (f), CK20 (p), CK7 (f)(–) PSA, synaptophysin, PAX2, PAX8, GATA3Not performedUnderwent RP. No evidence of metastasisNED at 6 months(–), negative; (+), positive; DOD, died of disease; (f), focal; LVI, lymphovascular invasion; NED, no evidence of disease; NS, not specified; P, patchy; PNI, perineural invasion; RP, radical prostatectomy; TURP, transurethral resection of prostate; (w), weak. Open table in a new tab (–), negative; (+), positive; DOD, died of disease; (f), focal; LVI, lymphovascular invasion; NED, no evidence of disease; NS, not specified; P, patchy; PNI, perineural invasion; RP, radical prostatectomy; TURP, transurethral resection of prostate; (w), weak. The patient is a 68-year-old male who presented with fever and dysuria. He was treated for urinary tract infection and referred for specialist urological work-up. On digital rectal examination, there was a 1–2 cm hard nodule in the right lobe of the prostate, protruding into the rectum and visualised on transrectal ultrasound. Serum prostate specific antigen (PSA) levels were low, 0.55 μg/L at initial presentation and 0.441 μg/L several months later. Magnetic resonance imaging (MRI) showed a 1.2×1.8×1.7 cm PIRADS 4 lesion in the right peripheral zone, with extra-prostatic extension, and abutting the rectum. There were no enlarged pelvic lymph nodes. The patient underwent transrectal ultrasound-guided prostate biopsy. Targeted cores showed patchy tumour involvement, featuring mostly solid groups of epithelial cells (Fig. 1A ) with enlarged vesicular nuclei, distinct nucleoli, and eosinophilic granular cytoplasm, culminating in an oncocytic appearance (Fig. 1B). There was a hint of possible luminal differentiation, although no well-formed glands were present. The tumour cells were positive for NKX 3.1 and AMACR, with blush-like cytoplasmic staining for PSMA and no convincing staining for PSA. Basal marker 34βE12 was negative, and p63 disclosed focal nuclear staining regarded as likely aberrant. Synaptophysin and GATA3 were negative, providing no support for neuroendocrine differentiation or urothelial carcinoma, respectively. The overall findings were consistent with prostatic adenocarcinoma (at least Gleason 4+4, Grade Group 4), and the oncocytic features were regarded as unusual, prompting clinicopathological correlation. Positron emission tomography (PET)-computed tomography (CT) showed increased fluorodeoxyglucose (FDG) uptake in the right peripheral zone of the prostate. The FDG-avidity was accounted for by the oncocytic morphology which represents increased numbers of mitochondria in response to mitochondrial defects and ineffective glycolytic metabolism.7Pattison D.A. Bozin M. Gorelik A. Hofman M.S. Hicks R.J. Skandarajah A. 18F-FDG–avid thyroid incidentalomas: the importance of contextual interpretation.J Nucl Med. 2018; 59: 749-755Crossref PubMed Scopus (33) Google Scholar There was no evidence of metastasis nor tumours of other organs. The patient had no prior therapy. The patient subsequently underwent robotic-assisted laparoscopic radical prostatectomy with bilateral pelvic lymph node dissection. The specimen weighed 57 g. On macroscopic examination, there was a pale-yellow tumour at the right posterolateral region of the prostate, with foci of haemorrhage and a partial peripheral fibrous rim (Fig. 2A ). Correspondingly, low power light microscopic examination showed an eosinophilic tumour with foci of haemorrhage and adjacent fibrosclerosis (Fig. 2B). There was a protruding tumour nubbin posterolaterally, with tumour islands beyond the prostate circumference and adipose tissue present in the same field, consistent with extraprostatic extension (Fig. 2B, black arrow). The tumour comprised papillary structures (Fig. 2C,D) as well as confluent glands forming cribriform structures (Fig. 2E) and solid islands, composed of columnar epithelial cells with eosinophilic granular cytoplasm, vesicular nuclei, and conspicuous nucleoli (Fig. 2F). The resection margins were negative. Perineural invasion and lymphovascular invasion were present. The pelvic lymph nodes were benign. The tumour cells showed patchy CK20 reactivity and scattered CK7 reactivity. The majority of tumour cells disclosed nuclear reactivity for NKX3.1, with variable staining intensity (Fig. 2G). PSMA highlighted few tumour cells covering papillary structures (Fig. 2I) and PSA showed blush-like unconvincing cytoplasmic reactivity (Fig. 2H). AMACR was diffusely positive (Fig. 2K). Basal cell markers 34βE12 and p63 were negative (Fig. 2L). PAX2 and PAX8 were negative (Fig. 2J), providing no support for a renal origin. The overall impression was of a prostatic adenocarcinoma, with solid, cribriform, and papillary architecture, composed of columnar cells consistent with a ductal type (Gleason 4+4, Grade Group 4), albeit with an unusual oncocytic morphology. Unlike other sites such as the salivary glands, kidneys and endocrine organs, oncocytic change in epithelial lesions of the prostate is an uncommon phenomenon. Of the seven reported cases in the literature, one was benign (hyperplasia with oncocytic change)8Beer M. Occhionero F. Welsch U. Oncocytoma of the prostate: a case report with ultrastructural and immunohistochemical evaluation.Histopathology. 1990; 17: 370-372Crossref Scopus (7) Google Scholar and six were malignant (acinar adenocarcinoma, various Gleason grades)1Ordonez N.G. Ro J.Y. Ayala A.G. Metastatic prostatic carcinoma presenting as an oncocytic tumor.Am J Surg Pathol. 1992; 16: 1007-1008Crossref PubMed Scopus (19) Google Scholar, 2Pinto J.A. González J.E. Granadillo M.A. Primary carcinoma of the prostate with diffuse oncocytic changes.Histopathology. 1994; 25: 286-288Crossref PubMed Scopus (18) Google Scholar, 3Fiandrino G. Lucioni M. Filippin F. et al.Prostatic adenocarcinoma with oncocytic features.J Clin Pathol. 2011; 64: 177-178Crossref Scopus (6) Google Scholar, 4Khadim M.T. Hassan U. Ejaz A. Mamoon N. Oncocytic variant of prostatic adenocarcinoma-a case report.Pak Armed Forces Med J. 2012; 1: 142Google Scholar, 5Klairmont M.M. Zafar N. Prostatic adenocarcinoma oncocytic variant: case report and literature review.World J Clin Oncol. 2017; 8: 289Crossref Scopus (0) Google Scholar, 6García-Cuerva M.S. Algaba F. Arce Y. Oncocytic prostate carcinoma “case report”.SN Compr Clin Med. 2022; 4: 107Crossref Google Scholar (Table 1). Of note, oncocytic morphology was recognised as a subtype of prostate acinar adenocarcinoma in the third edition of the World Health Organization Classification of Urinary System and Male Genital Organs,9Humphrey P.A. Histological variants of prostatic carcinoma and their significance.Histopathology. 2012; 60: 59-74Crossref PubMed Scopus (185) Google Scholar however it was not mentioned in the fourth edition onwards. Given that these tumours are rare, it would be prudent, especially when presented with biopsy material, to exclude other diagnostic possibilities such as metastatic carcinoma and therapy-related changes. In this case, a metastasis to the prostate from other sites was excluded by clinicoradiological correlation and an immunohistochemical (IHC) panel which included markers for renal and urothelial differentiation (PAX2, PAX8 and GATA3). While the tumour showed nuclear expression of NKX3.1, expression of PSMA was focal and PSA largely negative. Including this case, three of six reported cases of prostatic epithelial lesions with oncocytic morphology on which PSA IHC was performed, were negative for PSA (Table 1). This emphasises the utility of a broad panel to establish prostatic origin, and the value of lineage restricted transcription factor NKX3.1, in addition to conventional prostate differentiation markers PSA and PSMA. In retrospect, the low serum PSA level was a paradox in the diagnostic evaluation, as the resection specimen revealed the tumour had columnar morphology indicating ductal adenocarcinoma, which is associated with low serum PSA levels, in contrast to acinar adenocarcinoma.10Ranasinghe W. Shapiro D.D. Zhang M. et al.Optimizing the diagnosis and management of ductal prostate cancer.Nat Rev Urol. 2021; 18: 337-358Crossref PubMed Scopus (16) Google Scholar It is also known that a subset of prostatic carcinoma shows cytoplasmic granularity due to neuroendocrine differentiation, which may be treatment related. In this case, the absence of prior treatment and negativity for synaptophysin argued against this. None of the six reported cases of prostatic adenocarcinoma with oncocytic morphology in the literature were related to prior therapy.1Ordonez N.G. Ro J.Y. Ayala A.G. Metastatic prostatic carcinoma presenting as an oncocytic tumor.Am J Surg Pathol. 1992; 16: 1007-1008Crossref PubMed Scopus (19) Google Scholar, 2Pinto J.A. González J.E. Granadillo M.A. Primary carcinoma of the prostate with diffuse oncocytic changes.Histopathology. 1994; 25: 286-288Crossref PubMed Scopus (18) Google Scholar, 3Fiandrino G. Lucioni M. Filippin F. et al.Prostatic adenocarcinoma with oncocytic features.J Clin Pathol. 2011; 64: 177-178Crossref Scopus (6) Google Scholar, 4Khadim M.T. Hassan U. Ejaz A. Mamoon N. Oncocytic variant of prostatic adenocarcinoma-a case report.Pak Armed Forces Med J. 2012; 1: 142Google Scholar, 5Klairmont M.M. Zafar N. Prostatic adenocarcinoma oncocytic variant: case report and literature review.World J Clin Oncol. 2017; 8: 289Crossref Scopus (0) Google Scholar, 6García-Cuerva M.S. Algaba F. Arce Y. Oncocytic prostate carcinoma “case report”.SN Compr Clin Med. 2022; 4: 107Crossref Google Scholar In fact, ultrastructural examination in four early reports of prostatic epithelial lesions with eosinophilic granular cytoplasm showed numerous mitochondria, supporting oncocytic phenotype1Ordonez N.G. Ro J.Y. Ayala A.G. Metastatic prostatic carcinoma presenting as an oncocytic tumor.Am J Surg Pathol. 1992; 16: 1007-1008Crossref PubMed Scopus (19) Google Scholar, 2Pinto J.A. González J.E. Granadillo M.A. Primary carcinoma of the prostate with diffuse oncocytic changes.Histopathology. 1994; 25: 286-288Crossref PubMed Scopus (18) Google Scholar, 3Fiandrino G. Lucioni M. Filippin F. et al.Prostatic adenocarcinoma with oncocytic features.J Clin Pathol. 2011; 64: 177-178Crossref Scopus (6) Google Scholar,8Beer M. Occhionero F. Welsch U. Oncocytoma of the prostate: a case report with ultrastructural and immunohistochemical evaluation.Histopathology. 1990; 17: 370-372Crossref Scopus (7) Google Scholar (Table 1). Not surprisingly, the macroscopic appearance of the tumour in this case—pale-yellow cut appearance with fibrosis and haemorrhage, the latter likely biopsy-related—is similar to oncocytic tumours at other sites (e.g., oncocytic adenoma of the thyroid). The macroscopic appearance of prostatic adenocarcinoma with oncocytic change has been described in only one prior report, in which a locally advanced 10 cm tumour extending to the bladder showed a pale-yellow appearance with areas of haemorrhage.6García-Cuerva M.S. Algaba F. Arce Y. Oncocytic prostate carcinoma “case report”.SN Compr Clin Med. 2022; 4: 107Crossref Google Scholar Of the six reported cases of prostatic adenocarcinoma with oncocytic morphology, one presented with nodal metastasis, another presented with distant metastasis, and a third developed recurrence at 3 months with subsequent metastatic dissemination. It is plausible that this apparently ‘aggressive’ clinical behaviour is related to known prognostic factors, including high Gleason scores or late stage at presentation. In conclusion, this is a rare example of prostatic ductal adenocarcinoma with oncocytic morphology. Currently, the prognostic and therapeutic significance of oncocytic morphology in prostatic adenocarcinomas is uncertain, limited by the small number of reported cases, and therefore requiring future study. This morphological subtype of prostatic adenocarcinoma expands the differential diagnosis when faced with a metastatic carcinoma (of undetermined primary) displaying oncocytic morphology, as was demonstrated in two cases in the literature that presented with nodal and distant metastasis requiring work-up. Targeted clinical examination, radiological correlation, and a broad panel of immunohistochemical stains are key to clinching the diagnosis. Written patient consent was obtained for the publication of this case report. Following institutional guidelines (Singapore General Hospital, Research Office, Document 85040-PP-016, Title: Requirements for Preparing a Case Report for Publication), a case report involving one or two patients does not require review by the Centralised Institutional Review Board. The authors state that there are no conflicts of interest to disclose.