Large Cell Neuroendocrine Prostate Cancer: Large Is Not Small

Neuroendocrine prostate cancer is complex, comprising a wide spectrum of phenotypes, which has led to very different entities being inappropriately lumped together or assumed to behave like more common entities. Elucidating subtle differences is critical for treatment decision making, as this commentary describes.


Neuroendocrine Differentiation Does Not Imply Small Cell or Large Cell Carcinoma
Critical to managing NEPC is determining whether an actual NE disease variant requiring different treatment is present.NE differentiation occurs in benign prostate glands-scattered NE cells producing peptide growth hormones are often present. 8,11In conventional prostatic adenocarcinoma, foci of NE differentiation in an otherwise morphological adenocarcinoma does not necessarily imply adverse prognosis. 12,13E features are assumed by many to automatically indicate aggressive features which is not always the case.However, since NE staining is typically not requested without concern for aggressive disease, oncologists may inappropriately conclude all incidences of NE features are an ominous finding.
In contrast, the NE variant of PC (NEPC) is much rarer, associated with a poorer prognosis 1,2,[14][15][16] and the incidence increases after ADT.Treatment-related NEPC can occur as early as 24 months after starting ADT. 1,6,17NEPC is often associated with aggressive molecular features like TP53 and RB1 loss, high Ki67, epigenetic alterations, and growth despite androgen receptor (AR) inhibition. 18he presence of NE features should not automatically lead to NEPC type of therapy, ie, small-cell cancer therapy.Establishing whether there is a pathologic NE variant, and interpreting this finding in the appropriate clinical context, are necessary when deciding whether a different therapeutic approach should be taken.
Three major poorly differentiated NE subtypes have been described in PC, though this current pathologic classification is subject to great variability, even amongst expert pathologists.Small-cell NE carcinoma (SCPC), LCPC, and adenocarcinoma with NE features with either mixed-morphology or overlapping features (ie, amphicrine) are terms that are often used clinically.In addition to tumor morphology, IHC staining for classical PC and NE markers is also typically performed.
SCPC can be challenging to accurately diagnose as its clinical/histological features have only gained traction in recent years. 19While de novo SCPC can occur, SCPC typically arises after periods of ADT.Given similarities with small-cell lung cancer (SCLC), SCPC is treated with platinum and etoposide with a response rate as high as 50%-60%. 4In recent years, adding immunotherapy further improved outcomes. 20Unlike SCPC, adenocarcinoma with NE features often continues to respond to standard prostate cancer therapies.
LCPC is a distinct, extremely rare NEPC with only ~20 cases described in the literature. 7,9,10,21LCPC is very aggressive, with a median survival of ~15 months. 7,22Pathologists and oncologists often do not recognize LCPC as a distinct entity, as the prognostic and therapeutic implications of the diagnosis are unclear.Importantly, the presence of NE features must not trigger physicians to simply treat LCPC like SCPC.
0]21,23 First, due to LCPC's rarity, pathologists will often simply report LCPC tumors as generically "poorly differentiated high-grade PC" without noting specific largecell characteristics.Secondly, LCPC is often found incidentally, in high disease burdens requiring palliative procedures where tissue may otherwise not normally be assessed. 7,21inally, diagnostic criteria for LCPC are more strict 8 making LCPC's precise diagnosis difficult to make.LCPC's incidence is challenging to approximate but likely more prevalent than currently reported.

Treatment Recommendations for LCPC
We recommend that treatment decisions for LCPC should be based on which of three LCPC disease forms are present 7 : (1) de novo LCPC without admixed adenocarcinoma, (2) de novo LCPC with admixed adenocarcinoma, and (3) LCPC arising after ADT/AR-directed therapy.
Physicians should not prematurely abandon traditional PC treatments simply because large-cell differentiation is present. 3It is not advisable to prematurely forgo valuable AR-directed therapies in favor of small-cell chemotherapy in all patients.The expression of AR and AR signaling markers may help guide this decision.
De novo LCPCs, without any ADT history, are exceptionally rarer than post-ADT forms. 7,24Pure de novo LCPC, not associated with adenocarcinoma, often has a larger disease burden and worse prognosis.In general, NEPC typically loses AR (or related gene) expression, secrete little-to-no PSA and may require chemotherapy. 24y contrast, admixed LCPC typically retains AR dependence and secretes PSA.As a result, localized disease may be caught before systemic spread, potentially allowing for curative therapy.With regards to metastatic disease, 3 reported cases of de novo LCPC treated with ADT had responses in the range of 1-2 years. 24CPC retains some degree of androgen dependence as it can present with a high PSA that decreases with ADT.Two patients at our institution with de novo LCPC had an OS ~5 years post-treatment with ADT + conventional therapies (enzalutamide, abiraterone, docetaxel, and cabazitaxel). 22hus a positive response may potentially be from both AR-directed therapy and chemotherapy.
Though data are very limited, many LCPC-reported cases occur after longstanding ADT, sometimes 4-5 years after the original PC diagnosis. 7,8,10Post-ADT LCPC, like post-ADT SCPC or other high-grade NEPCs, may respond better to chemotherapy since they may demonstrate low or absent AR, NKX3.1, and PSA expression and are less likely to respond to AR-targeted therapy. 7,8CPCs may respond to platinum agents or taxanes 25 potentially due to tumor suppressor gene loss or DNA repair deficiencies. 4Cabazitaxel combined with platinum shows a response in many NEPCs, including LCPC 26 likely due to cabazitaxel activity in both CRPC and mixed-tumor histologies. 4Retrospective data suggest checkpoint inhibitors should be explored further. 27

Guide for Histologic Diagnosis
Tables 1 and 2 summarize some of the major histologic differences between SCPC and LCPC as well as de novo vs. post-ADT LCPC.
SCPC typically has relatively small cells (<3 lymphocyte diameters), a high nuclear-to-cytoplasm ratio, and salt-andpepper chromatin with small (or absent) nucleoli. 28Nuclear molding is frequently present, with tumors in large sheets, trabeculae, or acinar growth patterns.Tumors tend to be mitotically active, with a high proliferation index.
8]10 LCPC cells exhibit NE architecture and markers with cells arranged in large nests, sheets, or cords with peripheral palisading.While LCPC cells demonstrate brisk mitotic activity (often with geographic necrosis), 9 mitotic activity may be lower than in SCPC. 23he 2013 Prostate Cancer Foundation Working Group on Neuroendocrine Differentiation developed diagnostic criteria for LCPC: cells were required to express at least one NE marker by IHC and show specific morphologic characteristics (eg, large nests with peripheral palisading). 8This makes LCPC's diagnosis rare by design, to sharply differentiate it from more generic poorly-differentiated adenocarcinoma with NE features.
A 2010 publication by Aparicio et al 29 hypothesized that LCPC may represent a cytologically intermediate phase in the morphologic evolution from adenocarcinoma to SCPC.Whether LCPC truly represents a distinct entity, versus a mere transition, is unclear.

Recommendation for Immunohistochemical Diagnosis
Some key IHC differences separate de novo and post-ADT NEPCs (Tables 1 and 2).Post-ADT LCPC can have a lower expression of synaptophysin/chromogranin and a higher CD56 expression than de novo cases. 7Lower/absent expression of PSA, PSAP, and AR is common, compared with de novo LCPC.
A large series of a variety of genitourinary malignancies reported INSM-1 expression of 21% in LC tumors, lower than typically seen in SCPC. 33This trend was also found in lung and other malignancies.Therefore INSM-1 staining might differentiate SCPC from LCPC, but there is still limited data.

LCPC Molecular Features
Given LCPC's rarity, its molecular characterization is still investigational.We recently completed a retrospective study of 6 patients with de novo LCPC at our institution. 22Patients were all microsatellite-stable, had TP53 mutations, PTEN loss, and Rb1 loss.Fifty percent of our cases coexisted with a grade 5 adenocarcinoma and were not entirely NE in composition.These alterations are similar to those found in SCPC.Future work is necessary to understand if there are molecular markers that differentiate LCPC from other NEPCs to potentially provide new therapeutic targets.

Conclusions and Recommendations for Future Investigation
1. Increase awareness of LCPC: Improved awareness could guide oncologists to better understand the spectrum of NEPC and not reflexively treat all patients like SCPC. 21mportantly, oncologists should not forgo life-prolonging AR-directed therapy simply because LCPC is identified, especially if AR and AR signaling is present.2. Need better pathologic criteria: NE-tumor diagnosis rests on morphological, functional, and IHC criteria, subject to interobserver variation. 21Determining LCPC-specific genetic/ epigenetic evolution may help predict a patient's future trajectory. 3New biomarkers might identify large-cell NE differentiation before advanced-disease develops.While most NEPC features are typically not detected early, there may be early transcriptomic changes associated with AR independence. 37,38Most targetable alterations are acquired after therapy.0][41] Repeat biopsies on progression should be considered.5. Cell of origin: Whether disease originates after long-term hormonal pressure versus de novo disease may have implications on clinical decisions.While most NEPCs typically develop after long periods of treatment, this does not explain de novo disease or why certain forms retain AR susceptibility.There have not been substantial investigations into cells of origin or the molecular genesis for less common pure NE malignancies.Improved understanding of cellular origins may inform treatment.

Table 1 .
Histologic guide for differentiating LCPC and SCPC.
Plus signs (+) indicate relative levels of expression by the indicated assay.