Introduction

As males age, the prostate becomes one of the most common organs to be affected, accounting for significant mortality and morbidity. It can present with a wide spectrum of lesions, such as hyperplasia, atrophy, inflammation, metaplasia, premalignant lesions, and malignancy. While a pathologist must be well versed in the features of malignancy, it is also essential to identify and get familiarised with the various benign lesions of the prostate, which are a handful. Most of them coexist with each other.

The numerous benign alterations can mimic carcinomas and premalignant lesions. Thus, making the histopathological diagnosis of prostate adenocarcinoma challenging. Furthermore, both benign mimickers and adenocarcinoma can occur in the same age group. Therefore, it is important to prevent incorrect interpretation since it could lead to serious implications.

The lesions that are most often misdiagnosed as cancer are atrophy and its variants, including simple atrophy, partial atrophy, and postatrophic hyperplasia due to their high nuclear to cytoplasmic ratio, infiltrative nature, and inconspicuous basal cell layer.[1] Benign hyperplastic lesions are a group with proliferating glands and no atypia.[1] Among these, the architecture of adenosis is most alarming since it is composed of small, crowded glands with a fragmented basal cell layer.[1] A variant of basal cell hyperplasia with prominent nucleoli can also create confusion since it presents small dark glands, variable nuclear atypia, and prominent nucleoli.[1] Benign clear cell cribriform hyperplasia can mimic Gleason grade 4 prostatic adenocarcinoma, which also forms glands in the cribriform arrangement.

Among the metaplasia, florid mucinous metaplasia can mimic the rare foamy variant prostatic adenocarcinoma, where both show the presence of characteristic abundant foamy cytoplasm and minimal cytologic atypia. Nephrogenic metaplasia can mimic signet ring cell carcinoma of Gleason grade 5 when the tubules of metaplastic glands are lined by hobnail cells with prominent nucleoli.[2] Sometimes, the small lumens may also contain blue mucin, mimicking Gleason grade 3 prostatic adenocarcinomas.[2]

Clinically, in the aging male population, benign enlargement of the prostate gland compresses the urethra and causes urinary obstruction with symptoms such as increased urinary frequency, hesitation, dribbling, and incomplete emptying of the bladder[3], while carcinoma comes with its challenges! The development of histologic features of BPH is dependent on the bioavailability of testosterone and its metabolite, dihydrotestosterone.[4]

Globally, prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of cancer death in men.[5] In a populated country like India, it constitutes about 5% of all malignancies in males.[6] The prevalence of BPH increases from 20% at 40 years of age to about 90% by the eighth decade of life![7] Prostate-specific antigen (PSA), digital rectal examination, and transrectal ultrasound are important tools for evaluation.[8] However, biopsy remains the gold standard for final diagnosis.[8]

Although we have a limitation due to the lack of immunohistochemistry, we took a keen interest in conducting a study on the benign mimickers of prostate adenocarcinoma relying solely on morphology, the fundamental skill of a pathologist. It has been challenging but fruitful in improving our knowledge and observation skills. We also did not come across many studies on the web, that are focused entirely on the numerous benign histopathological lesions. Hence, this study is conducted considering the features of various benign lesions, highlighting the mimickers of carcinoma, and comparing their prevalences.

Materials and Methods

This retrospective study was done in the Department of Pathology of Veer Chandra Singh Garhwali Government Institute of Medical Sciences for a period of two years, i.e., from January 2022 to December 2023, after approval from the Institutional Ethical Committee. A total of 173 radical prostatectomy specimens were received during this period.

The histopathological data maintained in the department of pathology were reviewed. Haematoxylin and eosin (H&E) stained sections were re-examined. New H&E-stained paraffin sections were made whenever required, such as in the case of faded slides, and re-staining and re-mounting were done whenever required. All relevant clinical details were reviewed from the respective requisition forms submitted to the Department of Pathology. The various prostate lesions were listed, and the data was expressed numerically and in percentages. Photomicrographs of the benign lesions were taken.

Results

During the two-year study period from January 2022 to December 2023, the Department of Pathology received 173 radical prostatectomy specimens. Of these, 156 were diagnosed as benign lesions and 17 as malignant. A variety of benign histopathological features were observed and identified. They are listed in Table 1.

The most common alteration found was Basal cell hyperplasia, which was present in 66% of the cases, and the least common was Nephrogenic metaplasia, which was found in 3% of the cases.

These histopathological features have been broadly classified into five categories for comparison. The categories are hyperplasia, metaplasia, atrophy, inflammation, and premalignant lesion, high grade prostatic intraepithelial neoplasia, referred to as HGPIN.

Among the hyperplastic lesions, the most common was Basal cell hyperplasia constituting 66% of the cases.

Graph 1: Hyperplastic lesions

The hyperplastic lesions are plotted in Graph 1.

We have found the three types of inflammation mentioned in various literatures. They are acute, chronic, and granulomatous. Among these, chronic inflammation was the most common with a percentage of 55%.

A variety of metaplastic lesions were observed in our study. Out of these, transitional metaplasia was the most common with a percentage of 39%. These are shown in Graph 2.

Graph 2: Metaplastic lesions

The various types of atrophy found are plotted in Graph 3. Simple atrophy was the most common which comprised 44% of cases.

Graph 3: Atrophic lesions

The only premalignant lesion found was High-Grade Prostatic Intraepithelial Neoplasia (HGPIN), which accounted for 12% of all benign cases. Although some of the slides did show features favouring Low-grade Prostatic Intraepithelial Neoplasia (LGPIN), it was not reported since LGPIN is highly subjective, does not hold any pathologic significance, and lacks clinical relevance.[9]

The age range in our study was 49 – 85, with the maximum number of cases in the 7th decade of life. The age-wise distribution of cases is shown in Graph 4.

Graph 4: Age-wise Distribution of Cases

Discussion

Diseases of the prostate are one of the most common causes of decreased quality of life in the elderly male population. They can cause urinary symptoms and, in turn, discomfort to aging males. Being able to distinguish benign mimics from prostatic adenocarcinoma is of prime importance since an incorrect diagnosis will cause trouble for the patient and the doctor.

In our study, 156 prostate specimens were analysed that were diagnosed as benign lesions. The age of the patients ranged from 49 – 85 years, with the maximum number of cases in the 7^th decade of life. Albasri et al. also found a peak incidence of benign lesions in the age range of 70-79.[10]

This supports the fact that the frequency of prostatic lesions increases as males grow older, with a high risk for someone who has a family history of prostate disease thereby revealing an underlying genetic cause. In older males, testosterone starts to decline, dihydrosterone increases, and oestrogen remains the same. These hormonal changes bring about an increase in growth factors, leading to epithelial and stromal proliferation. Prostate lesions are also associated with a lack of physical activity, obesity, type 2 diabetes, erectile dysfunction, and cardiovascular disease. Most of these factors are common among the older males.

Among inflammation,chronic inflammation was found to be the most common in our study. This concurs with the study done by Pushpa et al., where it comprised 40% of the cases.[11]

On microscopy, lymphoplasmacytic infiltrates are present around the glands and in the stroma. Lymphocytes may show perinuclear clearing, appearing as signet ring cells. This can mimic Gleason pattern 5 prostatic adenocarcinoma which can exhibit signet ring cell change.[12] Careful observation of the glandular nuclear features is key. Chronic inflammation is believed to be multifactorial. These include previous infection of the genitourinary system, instrumentation, immune system dysfunction, psychological stress, and irregular hormone activity, which are common in the aging male population.

Acute inflammation is associated with various nonneoplastic epithelial alterations, such as atrophy, hyperplasia, squamous metaplasia, and transitional metaplasia.[1,3] It is almost always associated with benign lesions and rarely seen with malignancy.[13]

Histologically, we see sheets of neutrophils in and around the glands, and in the stroma. Most cases of acute inflammation are caused by bacteria responsible for other urinary tract infections, including Escherichia coli (80% of infections), other Enterobacteriaceae, Pseudomonas, Serratia, Klebsiella, and Enterococci.[14]

Granulomatous inflammation occurs due to several reasons. They can occur following procedures, due to infectious agents, and systemic disease but mostly it is nonspecific.[15] The nonspecific type is a reaction to destroyed prostatic ducts/acini from which bacterial toxins, cellular debris, and glandular secretions spill into the stroma.[16] Post-procedural granulomatous reaction is the second most common cause of granulomatous inflammation and may be seen following transurethral resections or needle core biopsies.[15] Infectious agents involved are Bacillus Calmette-Guerin (BCG)-related therapy, bacterial, fungal, parasitic, and viral pathogens.[15] Systemic causes include Sarcoidosis, Wegener granulomatosis, Churg-Strauss syndrome, and allergic prostatitis.[17]

In the nonspecific variant, there are dilated ducts and acini filled with histiocytes, foamy macrophages, and rarely multinucleated giant cells.[18] Stroma comprises epithelioid histiocytes and occasional multinucleated giant cells.[18] In the infectious, postsurgical, and systemic variants, multiple granulomas with or without necrosis are seen, along with histiocytes and giant cells.[18] It is quite common to find a mixed inflammatory infiltrate comprising neutrophils and lymphocytes in all the variants. Eosinophils are found in allergic prostatitis.[18]

In prostatic adenocarcinoma post-therapy, tumor cells are single with foamy cytoplasm and less nucleolar prominence.[19] This mimics lipid-laden epithelioid macrophages. Identifying the residual glands in such cases is important, too.[19] Diffuse granulomatous inflammation may mimic high-grade prostatic adenocarcinoma.[19] Taking note of nucleolar prominence in carcinoma is important.

Basal cell hyperplasia (BCH)was the most common hyperplastic lesion found in our study, which is similar to the study done by Mahapatra et al.[20] The presence of nodular proliferation of glands with multiple layers of basal cells having scant cytoplasm gives the glands a basophilic appearance. Intraluminal eosinophilic amorphous secretions and cribriform architecture may be seen. Nuclei are crowded with pinpoint nucleoli. At higher magnification, basal cells are seen oriented both parallel and perpendicular to the basement membrane.[21]

Florid BCH, BCH with prominent nucleoli, and BCH with cribriform pattern must be distinguished from adenocarcinoma. BCH is basophilic due to the multilayering of basal cells and scant cytoplasm. It can present as solid nests and lack nuclear pleomorphism. Adenocarcinoma has an irregular arrangement of cells, with relatively more abundant cytoplasm, giving an eosinophilic or amphophilic appearance. It exhibits pleomorphism and prominent nucleoli. BCH, with prominent nucleoli, mimics HGPIN as well. Its cells are perpendicular and parallel to the basement membrane, with frequent solid nests and uniform nuclei. On the contrary, HGPIN shows crowding of large pleomorphic nuclei. BCH occurs either due to a primary response to the luminal epithelial apoptosis or a secondary response to inflammation.[22] It also occurs following androgen deprivation therapy and radiation therapy.[23]

Adenosis, formerly called atypical adenomatous hyperplasia, comprises a nodular, well-circumscribed proliferation of small, crowded glands with pale, abundant cytoplasm without prominent nucleoli. The flattened basal cell layer is partially intact and fragmented, which may be difficult to visualize.

Adenosis mimics low-grade prostatic adenocarcinoma, which also comprises small, crowded glands. Carcinoma has enlarged pleomorphic nuclei with prominent nucleoli. It also has straight luminal borders and a more infiltrative growth pattern. It lacks larger, classic-appearing nonneoplastic glands that are often intermixed with benign adenosis.[24]

In clear cell cribriform hyperplasia, hyperplastic prostatic glands show cribriform architecture and contain pale cytoplasm. Lumens are of varying sizes. The basal cell layer is intact and prominent. Nuclei are small and uniform with pinpoint nucleoli. Prostatic adenocarcinoma Gleason pattern 4 variant also appears to have a cribriform pattern but with enlarged pleomorphic nuclei, prominent nucleoli, and absence of basal cells.[25 ]

Leiomyomatous hyperplasia is when there is increased proliferation of stromal cells with minimal glandular proliferation. The glands are compressed by the increasing stroma. Bland fibromuscular spindle cells, small blood vessels, and a myxoid or hyalinised stroma form stromal nodules.

The morphological differences between clear cell cribriform hyperplasia, adenosis, and prostatic adenocarcinoma have been enumerated in Table 2.

According to an article by Bostwick et al., the incidence of isolated HGPIN averages 9% (range 4%-16%) of prostate biopsies in the United States every year.[26] In our study, HGPIN comprised 12% of the cases during the 2-year time frame.

High-grade prostatic intraepithelial neoplasia,orHGPIN, is a premalignant lesion with cytological and architectural atypia. Epithelial cells proliferate, comprising nuclear and nucleolar abnormalities.

On microscopy, four architectural patterns can be seen. They are tufting, micropapillary, cribriform, and flat. Under low power, the glands appear darker and more basophilic than normal. Layers of crowded, pseudostratified secretory cells show enlarged and irregular nuclei, hyperchromasia, and prominent nucleoli at 20× magnification.[27] Chromatin is coarse and clumpy.[27]

HGPIN is more common in the peripheral zone of the prostate and is often located adjacent to the foci of cancer.[27] The presence of a basal cell layer differentiates it from adenocarcinoma. Transitional cell metaplasia has nuclear grooves which helps to distinguish it from HGPIN.

HGPIN is more common in men with prostate cancer.[27] Men with HGPIN on initial core biopsy have a higher risk of prostate carcinoma in the subsequent biopsy as compared to those without HGPIN.[27] Carcinoma is most likely to develop within 10 years of HGPIN.[26] HGPIN and adenocarcinoma share the same causative factors, including excess dietary fat, androgens, chronic inflammation, and genetic mutations.[28] Loss of p27 in HGPIN ultimately causes localized prostatic adenocarcinoma.[28] Figure 1 shows the morphological features of basal cell hyperplasia, clear cell cribriform hyperplasia, adenosis, and HGPIN.

Figure 1: (a) Photomicrograph showing basal cell hyperplasia of prostate glands (40x, H&E). Inset shows a prostate gland with multilayered basal cells (400x, H&E). (b) Photomicrograph of prostate glands showing cribriform architecture (100x, H&E). Inset shows a gland with clear cells arranged in cribriform pattern (400x, H&E). (c) Photomicrograph of adenosis showing small crowded glands (100x, H&E). (d) Photomicrograph of HGPIN with flat architecture (100x, H&E). Inset shows tufted HGPIN with pleomorphic nuclei and prominent nucleoli (400x, H&E).

Although not many studies have encountered a wide range of metaplasia, Abdollahi et al. conducted a study where transitional cell metaplasia showed the highest incidence, similar to ours.[29]

In transitional cell metaplasia, transitional (urothelial) cells line prostatic ducts or glands.[30] Glands may show a spectrum of changes like that in the bladder, including von Brunn’s nests and cystitis cystica with punched-out lumens.[30] Lumens often contain corpora amylacea. The glands have a multilayered epithelial lining that imparts a basophilic appearance. The cytoplasm is minimal and pale.[30] Perinuclear clearing and longitudinal nuclear grooves are present.[30]

Transitional cell metaplasia can mimic high-grade prostatic intraepithelial neoplasia. In contrast to transitional cell metaplasia, HGPIN comprises cytological atypia with prominent nucleoli and lacks nuclear grooves. HGPIN also shows an array of architectural patterns that are not present in metaplasia.

It is induced by tissue damage and associated with inflammation, infarction, and post-therapy.[30] It is often associated with a previous local irritation or trauma due to surgical resections, instrumentation, or stones.[2] In some cases, it may occur after renal transplantation.[2] Such situations are most prevalent in aging males.

Squamous metaplasia is when squamous cells line prostate glands or ducts.[30] It is also induced by tissue damage and related to inflammation, infarction, radiation therapy, and androgen deprivation therapy.[30 ]It shows the presence of intercellular bridges, dense eosinophilic cytoplasm, and inflammatory cell infiltrate.

It should be kept in mind that squamous cell carcinoma of the prostate is a rare entity.[31] In carcinoma, the nucleus shows marked atypia, hyperchromasia, and abnormal mitotic figures. These nuclear features are not found in metaplasia. Carcinoma is also not associated with areas of infarction or inflammation.[31]

In Mucinous metaplasia, the prostate glands have mucin-filled apical cells. The acinar cells are columnar, containing abundant clear to blue cytoplasm. Nuclei are pyknotic, small, and round, but mostly it is flattened. As the acinar cell nuclei are pushed by mucin towards the basal surface, basal cells may be difficult to visualize without immunohistochemistry.[32]

The extravasation of mucin into the lumens may raise concern, as this is a feature of adenocarcinoma. One must look for the presence of basal cells, whether or not there is an infiltrative growth pattern, and the presence of more classic benign appearing prostate glands to differentiate it from foamy-variant prostatic adenocarcinoma. Although this variant of prostatic adenocarcinoma is rare, it shows minimal to no cytological atypia and pink luminal secretions. It also comprises small hyperchromatic nuclei which may make it difficult to visualise the nucleoli. In such cases, special stains may be required. The foamy variant of adenocarcinoma is positive for colloidal iron, alcian blue, and P504S[33] whereas mucinous metaplasia is positive for mucicarmine and PAS.

In Nephrogenic metaplasia, small glands show renal tubular expression close to the urothelium. It is associated with prior urothelial trauma due to instrumentation, urethral catheterization, infection, or calculi. It also occurs after renal transplantation.

It is associated with acute and chronic inflammation. Lesions are composed of small tubules showing a variety of histologic appearances. They may be small or dilated and lined by a single layer of epithelial cells that are cuboidal or flattened. Cells may also show a hobnail or signet ring appearance. When it involves the surface, it gives a papillary appearance. The cells contain eosinophilic to clear cytoplasm. The tubules may contain dense eosinophilic material, resembling the thyroid. Nephrogenic metaplasia can mimic prostate acinar adenocarcinoma. A thickened eosinophilic hyaline rim may form around the tubules, which helps differentiate it from carcinoma. Carcinoma also has prominent cellular atypia with a diffused and disordered growth pattern. The cells are amphophilic and pleomorphic, with large and prominent nucleoli. Inflammation is rare.

Paneth cell-like change can be seen in both benign and malignant lesions. The presence of collections of prostatic cells with eosinophilic granules in the cytoplasm resembles intestinal Paneth cells.[34] Represents either (a) PAS-positive, diastase-resistant eosinophilic cytoplasmic granular change in the benign prostatic epithelium or (b) endocrine differentiation with neuroendocrine granules in the dysplastic and malignant prostatic epithelium.[35] There is no cytological atypia. It is also called eosinophilic metaplasia.

It is a reactive change of the prostatic epithelium to radiation therapy, granulomatous prostatitis, and hormone therapy. It is almost always associated with inflammation. It can mimic prostatic adenocarcinoma with Paneth cell differentiation. Glands in adenocarcinoma are infiltrative and angulated, often with collapsed lumina. However, they tend to be of low grade and low stage.[36] Paneth cell metaplasia has round, uniform, and circumscribed groups of glands without atypia. Figure 2 shows the morphology of squamous metaplasia, mucinous metaplasia, transitional cell metaplasia, and paneth cell-like change.

Figure 2: (a) Photomicrograph of squamous metaplasia of prostate glands. (100x, H&E). (b) Photomicrograph showing mucinous metaplasia of prostate glands. (400x, H&E). (c) Photomicrograph of transitional cell metaplasia of prostate glands showing multilayered epithelial lining comprising cells with nuclear grooves. (400x, H&E). (d) Photomicrograph of Paneth cell-like change showing eosinophilic granules in the cytoplasm of glandular epithelial cells. (400x, H&E).

There are four types of atrophy found in our study. They are simple, partial, sclerotic, and postatrophic hyperplasia (hyperplastic). Out of these, the most common atrophy was simple atrophy, which is similar to the study done by Postma et al., where the incidence of simple atrophy was 91%.[37]

Atrophy is when there is a decreased volume of cytoplasm in prostatic acinar luminal cells. The decrease in cytoplasm leads to an increased nuclear-to-cytoplasmic ratio. This alteration is a response to injury caused by chronic ischemia.[38] Ischemia can be due to locoregional arteriosclerosis which is common in the older male population. Atrophy is also caused by radiation treatment or androgen ablation.[38]

Simple atrophy is when the decrease in cytoplasm is severe, making the glandular epithelial cells appear flattened and basophilic. The glands appear dilated. The cell membrane lies just adjacent to the nucleus, yielding a high nuclear-to-cytoplasmic ratio, and is often associated with inflammation. Cystic glandular dilation may also occur. In the article by Trpkov et al., it is mentioned that simple atrophy is the most common morphologic variant, and the term ‘atrophy’ is typically used to designate simple atrophy.[2] It is typically associated with inflammation.[2] Chronic inflammatory infiltrates are often found within and around the foci of atrophy.[2] On the contrary, inflammation is rarely seen in the foci of prostatic adenocarcinoma.[2] Simple atrophy occurs following treatment with antiandrogens and radiation.[2]

Partial atrophy occurs when the decrease in cytoplasm is moderate, with cells having some pale eosinophilic cytoplasm. The glands may have an infiltrative appearance. Various luminal shapes can be seen. They are infoldings, undulations, and straight luminal borders. Since basal cells are difficult to identify and due to prominent acinar architectural distortion, partial atrophy can be misinterpreted as low-grade prostatic adenocarcinoma. This variant of atrophy is the most problematic since it can appear disorganized and infiltrative with irregular growth.[39] It also lacks the basophilic appearance that is typically seen in simple atrophy and postatrophic hyperplasia.[39] Acinar adenocarcinoma has prominent atypia in addition to diffused and disordered growth.[39] Cells have amphophilic cytoplasm and nuclear crowding. Nuclei are large and atypical, comprising large prominent nucleoli.[39] In carcinoma, blue-tinged mucin is commonly seen, while corpora amylacea is rare.[39]

In Sclerotic atrophy, there is marked sclerosis around the acini. This makes the glands appear angular, distorted, and infiltrative. Postatrophic hyperplasia (hyperplastic atrophy) has a central dilated duct with smaller atrophic acini around it in a lobular configuration.[40] Stroma appears sclerotic.

Prostatic adenocarcinoma (atrophic type) can mimic simple and sclerotic atrophy.[40] Atrophic adenocarcinoma is often intermixed with non-atrophic conventional prostate carcinoma and has less basophilic cytoplasm and cytological atypia. Figure 3 shows the morphology of nephrogenic metaplasia, partial atrophy, sclerotic atrophy, and postatrophic hyperplasia.

Figure 3: (a) Photomicrograph of nephrogenic metaplasia where prostate glands display a single cell lining with fine chromatin and hobnailing (arrows) (400x, H&E). (b) Photomicrograph of partial atrophy in which many prostatic acini are infiltrative and display infoldings and angulated luminal contours (100x, H&E). (c) Photomicrograph of sclerotic atrophy showing marked sclerosis surrounding prostatic acini (100x, H&E). (d) Photomicrograph of postatrophic hyperplasia showing a central atrophic dilated duct with surrounding smaller atrophic acini. (400x, H&E).

Conclusion

With a wide array of benign lesions and mimics, it is important to be aware of and get familiarised with the characteristic morphological features of each lesion, to identify them correctly and prevent any false positive interpretation. In addition, proper handling and processing of the tissue specimens must be ensured. Special stains and immunostains must be used whenever required.

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