Treatment‐related changes in the prostate: past, present and future therapies

Abstract

A broad spectrum of therapies is available for the management of prostate cancer, ranging from well‐established interventions like radical prostatectomy, androgen deprivation therapy (ADT) and radiation therapy (RT), to emerging modalities such as focal ablative treatments and targeted molecular therapies. These therapies can induce profound histologic alterations in both benign and malignant prostate tissue. Hormonal and radiation therapies are particularly known for their distinctive and often extensive morphologic effects, which have been well documented across needle biopsies, transurethral resection of the prostate (TURP) or enucleation specimens and prostatectomy samples. Novel ablative techniques—including cryotherapy, high‐intensity focused ultrasound (HIFU), photodynamic therapy (PDT) and interstitial laser thermotherapy—are gaining traction, yet the histologic consequences of these newer modalities are still being characterized. These treatment‐induced changes can obscure residual carcinoma, complicate tumour grading and staging and sometimes render traditional parameters such as Gleason scoring unreliable. As therapies evolve, pathologists must remain informed about the spectrum of post‐treatment changes to accurately interpret prostate specimens. Diagnostic accuracy hinges not only on recognizing these morphologic effects but also on integrating clinical history, particularly when treatment details are not readily available. This review provides an overview of current and investigational prostate cancer therapies, their histologic impact and practical guidance for post‐treatment evaluation.

Radiation therapy alters tumour morphology and immunoprofile in prostate cancer. Residual carcinoma shows distorted glandular architecture on H&E and loss of basal markers with preserved AMACR expression by immunohistochemistry, aiding in the recognition of treatment effect in prostate biopsies.

Abbreviations

ADT

androgen deprivation therapy

AR

androgen receptor

CAP

College of American Pathologists

CRPC

castration‐resistant prostate cancer

DDR

DNA damage repair

DHT

dihydrotestosterone

EBRT

external beam radiation therapy

GUPS

Genitourinary Pathology Society

HIFU

high‐intensity focused ultrasound

IHC

immunohistochemistry

IMRT

intensity‐modulated radiation therapy

ISUP

International Society of Urological Pathology

LCNEC

large cell neuroendocrine carcinoma

LHRH

luteinizing hormone‐releasing hormone

PARP

poly (ADP‐ribose) polymerase

PDT

photodynamic therapy

PET

positron emission tomography

PSMA

prostate‐specific membrane antigen

RP

radical prostatectomy

RT

radiation therapy

SBRT

stereotactic body radiation therapy

SCNEC

small cell neuroendocrine carcinoma

TURP

transurethral resection of the prostate

Introduction

Prostate cancer remains one of the most common malignancies affecting men worldwide, with a broad array of therapeutic options tailored to disease stage and patient‐specific factors. Conventional treatments—such as radical prostatectomy (RP), radiation therapy (RT) and androgen deprivation therapy (ADT)—are well established and often used in combination. In more advanced or castration‐resistant cases, chemotherapy and emerging immunotherapies offer additional options. More recently, minimally invasive focal therapies—including cryotherapy, high‐intensity focused ultrasound (HIFU), photodynamic therapy (PDT) and laser ablation—have gained attention due to their potential for reduced morbidity and preservation of prostate function, though long‐term outcome data remain limited.

Each of these treatments induces a distinct spectrum of histopathologic alterations in both benign and malignant prostate tissue, often complicating the recognition of residual carcinoma and assessment of tumour grade or stage. Familiarity with therapy‐induced morphologic changes is essential for pathologists, as misinterpretation can lead to diagnostic errors that affect subsequent clinical management. While clinical context should ideally accompany pathology specimens, pathologists must sometimes rely solely on characteristic histologic features to infer prior treatment. This review aims to provide an overview of current and investigational therapies for prostate cancer, outline their associated histologic changes and offer practical guidance for accurate evaluation and Gleason grading of post‐treatment specimens.

Therapeutic Modalities and their Pathologic Impact

Radiation Therapy

Types of radiation therapy

Radiation therapy (RT) is used to treat prostate cancer in various clinical settings, including as primary therapy, neoadjuvant treatment before prostatectomy or adjuvant therapy after surgery. RT types include external beam radiation therapy (EBRT), intensity‐modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), brachytherapy and proton beam therapy. The two main delivery methods are interstitial brachytherapy and EBRT. Brachytherapy, which involves implanting radioactive seeds directly into the prostate, has shown excellent outcomes for localized disease. ¹ In contrast, EBRT—especially conformal and IMRT—is more commonly used for locally advanced cases, ² , ³ often in combination with antiandrogen therapy. ⁴

Histopathologic features of radiation‐induced changes

The histologic alterations seen in prostate tissue following RT—whether administered alone or alongside ADT—are well documented and can be striking. For accurate assessment of post‐RT biopsy samples, it is critical that pathologists are informed of the patient's treatment background. Current data do not support any variation in tissue response between different RT delivery methods in either benign or malignant glands. RT induces a variety of histologic changes in benign prostate tissue, such as a reduction in glandular elements, expansion of the stromal compartment, epithelial cell shrinkage and a conspicuous basal cell layer often exhibiting significant cytologic atypia. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹  These alterations are typically visible even under low‐power magnification. However, their intensity can differ significantly not only between patients but also within different areas of the same biopsy. ¹⁰ On closer examination, basal cells may show cytoplasmic vacuolization and nuclei that are pleomorphic, darkly staining and smudged. Some nuclei contain large nucleoli resembling those of invasive adenocarcinoma, especially concerning when seen in glands with a deceptively infiltrative growth pattern. In addition, metaplastic changes—such as Paneth‐cell, mucinous and squamous types—can occur following RT alone or in combination with hormonal therapy. ¹⁰ Stromal alterations may include varying degrees of fibrosis, along with vascular changes like hyalinization, narrowed lumina and obliterative fibrosis. These modifications, in our experience, can remain evident for over 5 years after RT completion. The histologic presentation of adenocarcinoma following RT varies widely. In some cases, tumour morphology remains largely unchanged, while in others, radiation‐induced damage so severely distorts the malignant glands and cells that they can become difficult to recognize. ⁶ , ⁸ , ⁹ , ¹⁰ A single needle biopsy may contain the entire spectrum of treatment‐related changes. This pattern is particularly prominent in brachytherapy‐treated cases and is thought to reflect the localized variation in radiation dose delivered around individual radioactive seeds. This morphologic variability is observed in needle core biopsies, TURP specimens and salvage prostatectomies. In such samples, carcinoma often appears as irregularly arranged glands or isolated tumour cells characterized by vacuolated cytoplasm and enlarged nuclei with macronucleoli. (Figure 1A) ⁶ , ⁸ , ⁹ , ¹⁰ The disorganized, infiltrative growth pattern seen at low‐to‐medium magnification helps separate treated cancer from benign glands showing radiation‐induced atypia. The presence of perineural invasion, if identified, also supports a diagnosis of residual carcinoma.

Figure 1.

Treatment‐induced changes observed after radiation therapy. (A) Residual adenocarcinoma with radiation effect is seen, with tumour glands that are small, poorly formed and exhibit compressed lumens, scattered singly in a haphazard infiltrative pattern within fibromuscular stroma. (B) Immunohistochemical staining with p63, high‐molecular weight cytokeratin and AMACR shows negative staining with basal cell markers and positive immunoreactivity for AMACR.

Diagnostic Challenges

One of the central diagnostic challenges is differentiating radiation‐induced changes from residual or recurrent tumour, particularly when cytologic atypia is prominent but the architectural context is ambiguous—a task made more difficult in the absence of clinical history indicating prior RT. Radiation effects can closely mimic high‐grade carcinoma, especially when nuclear pleomorphism is striking; however, in contrast to viable tumour, these atypical cells typically lack mitotic activity, which serves as a helpful distinguishing feature. In diagnostically difficult cases, immunohistochemistry (IHC) with markers such as high molecular weight cytokeratin, p63 and AMACR can aid in confirming malignancy (Figure 1B), as RT does not interfere with their staining profiles. Additional markers such as PSA and Ki‐67 can further help in distinguishing treatment effect from viable tumour, with Ki‐67 especially useful for assessing proliferative activity. For patients treated with both RT and hormonal therapy, no additional histologic changes beyond those caused by RT alone are typically seen, provided hormone therapy was not administered around the time of biopsy. ¹⁰ Recurrent or residual prostate cancer following RT remains a significant clinical concern, with rates reported between 30% and 50% within the first decade after initial treatment. ¹² , ¹³ Management of local recurrence is often challenging due to the limited efficacy of salvage options. In a study by Crook et al., patients whose post‐treatment biopsies revealed residual tumour without evidence of treatment effect experienced local failure rates exceeding 55% within 5 years, whereas those with residual tumour exhibiting marked treatment response had substantially lower failure rates, under 20% during the same period. ¹⁴ More recent findings by Shah et al. highlighted that radiorecurrent prostate cancers frequently demonstrate cribriform architecture and harbour distinct genomic alterations. ¹⁵ Several investigators have questioned the utility of salvage prostatectomy for achieving local control, noting an increased risk of disease progression or metastasis in these settings. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²²

Recognizing and accurately documenting radiation‐induced treatment effects is essential for guiding clinical management. In cases where these effects are prominent, assigning a Gleason score is generally avoided, as it may not accurately reflect tumour biology or prognosis. However, when residual tumour exhibits minimal or no evidence of prior therapy, Gleason grading can be applied and remains clinically meaningful. In our practice, we stratify tumour response to RT into three categories—minimal, intermediate or severe—based on the extent of histologic alteration. This approach aligns with established pathology recommendations. ⁶ , ⁸ , ¹⁰ For specimens showing a combination of treated and untreated tumour areas, we include descriptive assessments estimating the proportion of each response pattern.

Androgen Deprivation Therapy

Mechanism of androgen deprivation therapy

Androgen deprivation therapy (ADT) is a foundational component of the therapeutic approach for patients with prostate cancer that is locally advanced or metastatic. In addition to its role in advanced disease, ADT may also be administered in the neoadjuvant setting, particularly before definitive local therapies such as RP. The therapeutic objective of ADT is to reduce circulating levels of testosterone and other androgens, thereby inhibiting the androgen‐driven growth of prostate cancer cells.

This hormonal manipulation can be achieved through two primary strategies: surgical castration or chemical castration. Surgical castration involves bilateral orchiectomy, which results in an immediate and permanent reduction in serum testosterone. Chemical castration, by contrast, utilizes pharmacologic agents to suppress androgen production or block androgen receptor signalling over the course of treatment.

Several classes of drugs are employed in chemical ADT. Antiandrogens work by directly blocking the androgen receptor, thereby preventing testosterone and dihydrotestosterone (DHT) from activating downstream signalling pathways that drive tumour proliferation. Androgen synthesis inhibitors, which include luteinizing hormone‐releasing hormone (LHRH) agonists and LHRH antagonists, function by suppressing the release of gonadotropins from the pituitary gland, leading to decreased androgen production by the testes. Oestrogens may also be used to inhibit androgen synthesis, although they are less commonly employed in current practice. Another class of agents, 5‐alpha reductase inhibitors, act by inhibiting the conversion of testosterone to DHT, the more potent androgen in prostatic tissue. These therapies can be used as monotherapy or in various combinations, depending on the patient's disease burden, prior treatment history and overall clinical status. The selection and sequencing of ADT agents are often individualized to optimize clinical benefit while managing potential adverse effects.

Histopathologic features of androgen deprivation therapy

Prostate tissue subjected to ADT undergoes a range of recognizable histologic alterations that affect both benign and malignant glandular elements. These morphologic changes are the result of diminished androgen stimulation and typically become evident within approximately 3 months following initiation of therapy. ¹¹ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹

In benign prostate tissue, the most common features include glandular atrophy, characterized by reduced gland size and cellularity; basal cell hyperplasia, which may be subtle but occasionally pronounced; cytoplasmic vacuolization, especially in secretory cells, leading to a foamy or empty appearance; increased stromal prominence, likely reflecting involution of glandular elements and reactive expansion of the fibromuscular stroma; and squamous metaplasia, a less common but recognized finding, possibly due to chronic injury or altered differentiation pathways.

In prostatic adenocarcinoma, ADT induces distinct yet variable morphologic changes in tumour cells and architecture. Tumour glands become sparse, with residual neoplastic glands typically small and having compressed or absent lumina. Individual tumour cells may appear isolated or form cords, showing pyknotic nuclei, inconspicuous or absent nucleoli and finely vacuolated or foamy cytoplasm, which may resemble histiocytes (Figure 2A–D). An inflammatory infiltrate, composed primarily of lymphocytes and macrophages, may be present in both benign and malignant areas ²⁴ , ³⁰ These treatment‐induced histologic changes are generally reversible upon cessation of ADT, ²⁶ although the time course of recovery may vary. Recognizing these features is crucial, as they provide important context for interpreting prostate biopsies or surgical specimens from patients with known or suspected prior hormonal therapy.

Figure 2.

Treatment‐induced changes observed after androgen deprivation therapy. (A–D) Composite image showing the spectrum of antiandrogen effects, including shrunken nuclei, indistinct nucleoli and abundant foamy, vacuolated cytoplasm resembling foamy histiocytes.

Histologic features of combination therapy (RT + ADT)

In patients receiving both ADT and RT, the histologic changes often reflect a combination of treatment effects. These include marked glandular atrophy, cytoplasmic vacuolization, nuclear pyknosis and loss of glandular architecture, often accompanied by stromal fibrosis and decreased tumour cellularity. Basal cell prominence and cribriform or therapy‐resistant patterns may be seen, particularly in higher‐grade disease. Immunohistochemically, PSA, NKX3.1 and AMACR expression is typically diminished, while androgen receptor (AR) staining may be reduced or patchy. In some cases, prolonged ADT may promote neuroendocrine differentiation, highlighting the importance of clinical context and immunostaining in evaluating treated specimens.

Diagnostic and Grading Considerations

The histologic changes induced by ADT can present significant diagnostic challenges, particularly in biopsy specimens with limited tissue or in cases with overlapping morphologic features. Many of the treatment‐associated alterations can mimic histologic variants of prostatic adenocarcinoma, such as atrophic or foamy gland patterns, potentially leading to misclassification or diagnostic uncertainty.

The interpretation of treated prostate tissue may be further complicated by the subtlety of these changes, which can be overlooked even by experienced pathologists. The distinction between treatment effect and poorly differentiated carcinoma can be particularly problematic when the architecture is disrupted or when classic cytologic features are no longer evident. In such cases, ancillary studies—most notably immunohistochemistry—may aid in identifying residual carcinoma and evaluating its differentiation status. A notable therapeutic consideration is the emergence of treatment‐related neuroendocrine differentiation, particularly following prolonged ADT, typically after 18–36 months of exposure. ³¹ These tumours may closely mimic primary prostatic small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) in histology, making it difficult to distinguish primary from treatment‐related neuroendocrine carcinoma based on morphology or immunohistochemistry alone. (Figure 3A–D) ²⁶ , ³² , ³³ , ³⁴ Clinically, these tumours often exhibit aggressive clinical behaviour, poor responsiveness to conventional therapies. Diagnosis relies on immunohistochemical expression of neuroendocrine markers including CD56, synaptophysin and chromogranin, while traditional prostatic epithelial markers like PSA and PSAP are typically absent in the neuroendocrine components. ³² The identification of neuroendocrine differentiation should prompt consideration of a distinct biologic subtype with different therapeutic implications. Importantly, Gleason grading should not be applied to prostate tumours that show clear histologic evidence of treatment effect. However, in cases where there is a history of ADT but no discernible treatment‐associated changes, a Gleason score may be assigned, provided the diagnosis is otherwise straightforward. In all cases, documentation of the patient's treatment history and any suspected or confirmed histologic effects of therapy should be clearly stated in the pathology report to guide appropriate clinical management.

Figure 3.

Treatment‐related neuroendocrine prostatic carcinoma. (A–D) Composite image showing conventional acinar‐type adenocarcinoma adjacent to neuroendocrine carcinoma characterized by solid sheets of poorly differentiated cells with enlarged nuclei, prominent nucleoli and brisk mitotic activity. The interface between the two components highlights their distinct architectural and cytological features.

Minimally Invasive Therapies

Focal and ablative therapies for localized prostate cancer

Focal therapy represents a growing treatment paradigm for patients with localized prostate cancer, offering a middle ground between conservative management and definitive interventions such as RP or RT. These minimally invasive approaches aim to selectively destroy areas of known cancer within the prostate while sparing uninvolved tissue, thus preserving glandular function and reducing morbidity. Therapeutic modalities include cryotherapy, HIFU, PDT, microwave thermotherapy and interstitial laser ablation—each utilizing different forms of energy delivery (cold, heat, light or electromagnetic) to achieve tumour ablation. ³⁵ , ³⁶ , ³⁷ These techniques may be employed as primary interventions for partial or whole‐gland ablation or as salvage therapies following failure of conventional RT. ³⁷ In most cases, histologic injury is confined to the treated zones, and untreated tissue retains normal morphology. As such, standard Gleason grading remains applicable, and residual viable cancer often maintains typical histologic features. ¹¹ , ²⁴ , ²⁵

Cryotherapy

Cryotherapy, also referred to as cryoablation, uses cycles of rapid freezing and thawing to achieve targeted tissue necrosis. It can be employed for primary or recurrent prostate cancer but is less suitable for patients with substantially enlarged glands. Cryoablation can be safely repeated and is sometimes used in conjunction with other therapies. ³⁵ , ³⁶ Histologic findings after cryotherapy vary by time since treatment. Acute changes include oedema and haemorrhage, while chronic alterations include interstitial fibrosis, chronic inflammatory infiltrates, glandular atrophy, hemosiderin deposition, squamous and urothelial metaplasia and focal calcification. Multinucleated giant cells may be present, consistent with a foreign body response. ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² Residual viable carcinoma may persist despite treatment and can either show recognizable treatment‐related changes—such as nuclear smudging or cytoplasmic swelling—or retain typical morphology. Importantly, tumour architecture is generally preserved, allowing reliable Gleason scoring post‐treatment. RP following cryoablation is uncommon but has consistently shown the presence of residual viable cancer.

High‐intensity focused ultrasound

High‐intensity focused ultrasound (HIFU) delivers concentrated ultrasound energy to raise tissue temperature to cytotoxic levels (>60°C), causing precise areas of coagulative necrosis. It is used for both whole‐gland and focal ablation, either as a primary modality or following RT failure. Advances in multiparametric magnetic resonance imaging (MRI) have enhanced lesion detection and characterization, improving patient selection and treatment targeting. ⁴³ , ⁴⁴ , ⁴⁵ Nonetheless, limitations remain, including reduced sensitivity for low‐grade tumours, ⁴⁶ underestimation of tumour burden ⁴⁷ and challenges associated with multifocal disease. ⁴⁸ HIFU‐treated tissue exhibits well‐demarcated necrosis, dense stromal fibrosis, reactive fibroblastic proliferation, glandular atrophy and inflammatory infiltrates, often containing hemosiderin‐laden macrophages. These features are typically limited to the ablated regions, with adjacent non‐treated areas showing preserved benign glands or residual viable carcinoma without obvious treatment‐induced changes. ¹¹ , ⁴⁹ (Figure 4) Patterns of focal ablation include unifocal ablation, index lesion targeting and subtotal ablation (e.g. ‘hockey stick’ configuration) designed to manage extensive or multifocal disease while deferring more aggressive therapy. ⁵⁰ Data from biopsy follow‐up suggest that residual viable carcinoma is common; in one institutional series, 63% of men undergoing post‐HIFU biopsy had persistent tumour, even in the absence of PSA elevation. ²⁴ Standard morphologic evaluation remains useful, as neoplastic cytology typically appears unaffected and immunoreactivity for commonly used markers such as high molecular weight cytokeratin, p63 and AMACR remain interpretable following treatment. ¹¹ , ²⁴ , ²⁵

Figure 4.

Treatment‐induced changes observed after high‐intensity focused ultrasound (HIFU) therapy. Residual adenocarcinoma located outside the boundary of the treated area. The malignant glands display preserved architecture with no obvious treatment‐induced changes.

Photodynamic therapy

Photodynamic therapy (PDT) involves the administration of a photosensitizing agent followed by light activation to generate reactive oxygen species, resulting in vascular thrombosis and tumour necrosis. ⁵¹ , ⁵² , ⁵³ , ⁵⁴ It has shown particular promise in treating low‐risk localized prostate cancer with minimal morbidity and few complications. ⁵⁵ Histologic descriptions of PDT effects are relatively sparse. In available studies, biopsies taken 6 months post‐treatment show reduced gland volume and sharply demarcated regions of hyalinized fibrosis, necrosis and occasional atrophic glands accompanied by mild chronic inflammation. ⁵⁶ , ⁵⁷ As with other focal therapies, residual viable carcinoma, when present, is typically found outside the treatment zone and displays no histologic features suggestive of prior therapy. Therefore, Gleason grading remains a necessary and feasible component of post‐treatment biopsy interpretation.

Diagnostic and Reporting Implications

Across all focal therapies, post‐treatment histologic alterations tend to be localized and sharply demarcated. Common findings in treated zones include coagulative necrosis, granulation tissue, stromal fibrosis and inflammatory infiltrates. In contrast, untreated regions may harbour residual viable carcinoma with unaltered morphology, necessitating routine Gleason scoring for accurate assessment. ¹¹ , ²⁴ , ²⁵ Although imaging techniques such as prostate‐specific membrane antigen (PSMA) positron emission tomography (PET) and contrast‐enhanced ultrasound are under active investigation, histologic analysis remains crucial for treatment monitoring and outcome prediction. Further studies are warranted to evaluate long‐term oncologic efficacy and refine diagnostic criteria in the postablation setting.

Systemic Therapies

Chemotherapy

Use in Castrate‐Resistant Prostate Cancer

Chemotherapy has traditionally been used to manage metastatic castration‐resistant prostate cancer (CRPC), typically in patients who have progressed despite hormonal therapy. Commonly used agents in a palliative context include mitoxantrone, etoposide, cisplatin, vinblastine, estramustine, paclitaxel and most prominently, docetaxel. The current first‐line standard incorporates docetaxel (Taxotere) alongside prednisone, although mitoxantrone (Novantrone) and estramustine (Emcyt) may still play a role in symptom‐focused care. ⁵⁸ Although several randomized controlled trials have evaluated chemotherapy in this setting, overall survival benefits have been limited. However, new agents targeting signal transduction, apoptosis, angiogenesis and immunologic pathways continue to emerge. ⁵⁹ , ⁶⁰ Despite ongoing drug development, there remains limited understanding of their direct histopathologic effects on prostate tissue due to infrequent post‐treatment biopsies and the confounding influence of prior therapies such as ADT and RT. ⁶¹ , ⁶²

Histopathologic Features of Chemotherapy

Most histologic studies of chemotherapy‐induced changes focus on rare neoadjuvant trials where treatment precedes RP. One notable study by O'Brien et al. examined prostatectomy specimens after neoadjuvant docetaxel and mitoxantrone, without prior ADT or RT. They identified several distinctive changes, including collapsed glands without lumina (46%), scattered single cells or small clusters with pyknotic, basophilic nuclei and no nucleoli (28%), vacuolated cytoplasm (26%) and prominent stromal inflammation. Intraductal carcinoma and cribriform architecture were also present in 20% and 14% of cases, respectively. Other, less frequent findings from additional studies include basophilic tumour‐associated mucin, nested growth patterns and large pleomorphic eosinophilic tumour cells. These features may aid in recognizing chemotherapy effects, especially in the neoadjuvant setting. ⁶³

Diagnostic Challenges

The morphologic changes induced by chemotherapy are often subtle and may be difficult to distinguish from treatment effects caused by ADT or RT. In the metastatic setting, biopsies are rarely performed, limiting the available tissue for pathologic analysis. ⁶¹ Moreover, the variability in treatment regimens and prior therapies complicates interpretation. Currently, there is little published experience concerning the histologic impact of emerging chemotherapy and targeted agents, particularly when used short‐term or in combination with other modalities. ⁶⁴ Ongoing research is needed to better characterize these changes and to define reliable markers that can help differentiate residual carcinoma from therapy‐related alterations.

Immunotherapy

Immunotherapeutic strategies in prostate cancer are evolving, with most research focused on two main modalities: therapeutic cancer vaccines and immune checkpoint blockade. ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ Sipuleucel‐T, an autologous cellular immunotherapy, aims to activate tumour‐specific T cells via antigen‐presenting cell stimulation. Meanwhile, agents targeting immune checkpoint pathways—including inhibitors of CTLA‐4, PD‐1 and PD‐L1—are under clinical evaluation, although their efficacy in prostate cancer has so far been modest compared to other solid tumours. Morphologic changes associated with immunotherapy remain poorly characterized. In one study, Merino et al. noted a prominent lymphocytic and eosinophilic infiltrate within both the glandular epithelium and stroma of prostate tissue following treatment. ⁶⁹ As with other systemic therapies, interpretation of these changes is complicated by prior exposure to ADT or RT, which can independently induce overlapping histologic alterations.

Targeted Therapies

PSMA‐directed therapy

Prostate‐specific membrane antigen (PSMA) has emerged as both a valuable imaging biomarker and a therapeutic target in advanced prostate cancer. ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ The most extensively studied therapeutic agent to date is ¹⁷⁷Lu‐PSMA‐617, although other radionuclide‐conjugated ligands such as ⁶⁸Ga, ⁶⁴Cu, ²²⁵Ac and ⁴⁴Sc are also in clinical use or under investigation. The efficacy of PSMA‐targeted treatments appears closely linked to tumour expression levels and interlesional heterogeneity. High PSMA expression and low heterogeneity within lesions correlate with better treatment response and improved outcomes. ⁷⁷ , ⁷⁸ These findings highlight the importance of imaging and molecular profiling in patient selection and therapeutic planning.

PARP Inhibitors

Poly (ADP‐ribose) polymerase (PARP) inhibitors, such as olaparib (Lynparza), rucaparib (Rubraca) and niraparib (Zejula), represent a growing class of targeted therapies under active investigation for use in metastatic castration‐resistant prostate cancer (mCRPC), particularly among patients harbouring defects in DNA damage repair (DDR) pathways, including BRCA1 and BRCA2 mutations. Clinical trials (e.g. NCT02952534, NCT02975934, NCT03012321) have shown promising clinical activity in this biomarker‐defined population. ⁷⁹ These agents work by exploiting synthetic lethality in tumours with impaired homologous recombination repair, offering a personalized approach to therapy. However, questions remain regarding optimal integration into treatment regimens—particularly around potential toxicities, durability of response and whether combination strategies with chemotherapy or radiotherapy may yield superior outcomes. Further studies are needed to define the most effective use of PARP inhibition in prostate cancer.

Given the limited understanding of histologic correlates associated with PSMA‐targeted therapies and PARP inhibitors, there is a critical need for standardized, biopsy‐based studies to better characterize treatment‐related changes and guide pathologic assessment in this evolving therapeutic landscape.

Challenges and Future Directions

As the landscape of prostate cancer treatment continues to evolve, so too must the tools for evaluating therapeutic response. One major challenge lies in the lack of standardized reporting criteria for therapy‐induced histopathologic changes, which can lead to inconsistent interpretation across institutions. The development of novel molecular and imaging biomarkers is essential to better distinguish viable tumour from treatment‐related effects, particularly in the setting of advanced or post‐treatment disease. In addition, the integration of digital pathology and artificial intelligence holds promise for the automated recognition and quantification of therapy‐associated alterations, potentially enhancing diagnostic accuracy and reproducibility. Collectively, these efforts will be crucial in refining both prognostication and patient selection for emerging therapies.

Conclusion

Recognizing treatment‐induced changes in prostate cancer is critical for accurate diagnosis, prognostication and therapeutic decision‐making. As systemic therapies continue to evolve, pathologists play a key role in identifying the morphologic and molecular alterations associated with these treatments. The Gleason grading system is recommended for all prostatic adenocarcinomas, except in cases showing treatment effects, most commonly following androgen deprivation or RT. ⁸⁰ , ⁸¹ , ⁸² In such settings, grading is generally not applicable, in accordance with CAP, ISUP and GUPS guidelines. ²¹ , ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ While Gleason grading is generally discouraged in the setting of treatment effect, it may be appropriate when tumour areas show no or only minimal histologic treatment effect. In those instances, the treated component is excluded from grading. The Gleason score can be included in a comment, noting the limitations of grading in the post‐treatment setting. This assessment may also vary across prostate core biopsies within the same sampling. ⁸² Integration of these observations into care requires close collaboration among pathologists, oncologists and radiologists. A summary of the histologic and immunophenotypic features associated with common therapies is provided in Table 1.

Table 1.

Histologic and immunophenotypic features of common prostate cancer therapies

Therapy type	Clinical setting	Histologic changes	Immunophenotypic features	Notes
Androgen deprivation therapy (ADT)	Neoadjuvant, mHSPC or mCRPC	Glandular atrophy, basal cell prominence, cribiform/intermediate patterns, vacuolated cytoplasm	↓ PSA, ↓ NKX3.1, patchy/↓ AR, variable ERG	Treatment effect can resemble radiation changes; NE features may emerge with prolonged use
Radiation therapy (RT)	Post‐external beam or brachytherapy	Nuclear pyknosis, cytoplasmic vacuolization, fibrosis, loss of glandular architecture	↓ PSA, patchy NKX3.1, ↓ AMACR, variable AR	Features may persist for years; overlaps with ADT‐induced changes
AR Pathway Inhibitors (e.g. enzalutamide, abiraterone)	mCRPC	Cribriform/intraductal patterns, potential for NE differentiation, therapy‐emergent small cell change	Variable AR; ↑ NE markers if progression occurs	May promote lineage plasticity; biopsy can show mixed phenotypes
High‐Intensity Focused Ultrasound (HIFU)	Focal therapy for localized PCa	Coagulative necrosis, fibrosis, gland dropout, stromal hyalinization	No specific marker change	Treatment changes can mimic high‐grade cancer or infarct; viable tumour may persist at margins
Chemotherapy (e.g. docetaxel)	mCRPC, post‐AR therapy failure	Tumour necrosis, decreased cellularity, fibrosis, apoptosis	No specific marker change; ↑ p53 or Ki‐67 occasionally	Effect often subtle in biopsies; response assessed radiographically
Immunotherapy (e.g. pembrolizumab)	MSI‐H/dMMR tumours (rare subset of PCa)	↑ Tumour‐infiltrating lymphocytes, regression‐like changes, minimal cytologic atypia	↑ PD‐L1, ↑ CD8+ T cells	Applicable to a minority of patients; check MMR/MSI
PARP Inhibitors (e.g. olaparib)	BRCA1/2, HRR‐mutated mCRPC	Variable; not well described; potential apoptotic or treatment effect changes	No consistent changes; underlying tumour may show genomic instability	May be used in combination with AR inhibitors or chemotherapy

ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castration‐resistant prostate cancer; dMMR, deficient mismatch repair; EBRT, external beam radiation therapy; HSPC, hormone‐sensitive prostate cancer; HRR, Homologous Recombination Repair; mCRPC, metastatic castration‐resistant prostate cancer; MSI‐H, microsatellite instability‐high; PARP, poly (ADP‐Ribose) polymerase; PCa, prostate cancer; RT, radiation therapy.

Author contributions

KC and LC wrote the article. All authors provided substantial contributions to this review, drafted and critically revised the article and approved the final version for publication.

Conflict of interest

The authors declare that they have no conflicts of interest pertaining to the content of this manuscript.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.