The spectrum of morphology in non-neoplastic prostate including cancer mimics

The spectrum of morphology in non-neoplastic prostate includes lesions of prostatic epithelial origin, the most common being atrophy, including partial atrophy, adenosis (atypical adenomatous hyperplasia), basal cell hyperplasia and crowded benign glands, as well as those of non-prostatic origin, such as seminal vesicle epithelium. These lesions often mimic lower-grade prostatic adenocarcinoma whereas others, such as granulomatous prostatitis, for example, are in the differential diagnosis of adenocarcinoma, Gleason grades 4 or 5. Diagnostic awareness of the salient histomorphological and relevant immunohistochemical features of these prostatic pseudoneoplasms is critical to avoid rendering false positive diagnoses of malignancy.     

Differential diagnosis of glandular proliferations in the prostate

 A variety of small acinar lesions of the prostate can mimic prostate cancer in punch biopsies and in transurethral resection material. The first part of this review deals with differential diagnostic problems of the central and transition zone, including atypical adenomatous hyperplasia of the prostate, atrophic processes, sclerosing adenosis, basal cell hyperplasia, and low-grade adenocarcinoma. The second part deals with differential diagnostic problems in the peripheral zone: prostatic intraepithelial neoplasia, postatrophic hyperplasia, Cowper’s glands, seminal vesicles, and ductal and intraductal carcinoma. Finally, atypical and small acinar proliferations are described. Diagnostic perspectives are discussed. Received: 23 June 1998 / Accepted: 13 August 1998     

Usefulness of basal cell cocktail (34betaE12 + p63) in the diagnosis of atypical prostate glandular proliferations

We evaluated the diagnostic usefulness of the 34betaE12-p63 cocktail, compared with 34betaE12 and p63 used alone, in 34 prostate needle biopsy (NBXs) and 3 transurethral resection specimens containing atypical glandular proliferations and in 18 NBXs containing unequivocal prostate carcinoma (PCa). Staining intensity; percentage of basal cells staining in benign, atypical, and malignant glands; number of benign glands lacking basal cell staining; and staining variance were analyzed. All NBXs with unequivocal PCa were negative with all 3 markers. Diagnoses were as follows for the atypical cases after staining for the 3 markers: PCa, 9; postatrophic hyperplasia, 12; high-grade prostatic intraepithelial neoplasia (HGPIN), 5; atypical adenomatous hyperplasia, 6; benign atypical proliferations, 4; and HGPIN with adjacent small atypical acinar proliferation suggestive of PCa, 1. The cocktail demonstrated consistently strong staining intensity and improved basal cell staining in morphologically benign and benign atypical glands compared with p63 and 34betaE12 alone; it had the smallest staining variance compared with 34betaE12 (F < 0.0001) and p63 (F = 0.31), although its advantage for resolving individual atypical cases was limited compared with 34betaE12 and p63 alone. Of 37 atypical cases, 1 (3%) additionally was resolved as benign using the cocktail and p63. Because the diagnosis of PCa is supported by lack of basal cell staining, the immunohistochemical analysis with highest possible sensitivity and lowest possible variability is critical to ensure that a negative reaction is true. The cocktail provides a simple, cost-effective improvement in basal cell immunohistochemical analysis of difficult prostate lesions.     

Premalignant lesions of the prostate

Two putative premalignant lesions of the prostate have been identified. Prostatic intraepithelial neoplasia (PIN) is characterized by proliferation and anaplasia of cells lining ducts and acini. Atypical adenomatous hyperplasia (AAH) consists of a localized proliferation of small round glands without cytologic atypia. PIN and AAH may be confused with well-differentiated carcinoma as well as florid hyperplasia, basal cell hyperplasia, transitional metaplasia, seminal vesicular epithelium, and atypia due to inflammation, infarction, and radiation. These premalignant lesions appear to have a high predictive value for carcinoma, and their presence on prostatic biopsy warrants further search for concurrent invasive adenocarcinoma. The use of strict morphologic criteria and uniform nomenclature will ensure standardization in the diagnosis of premalignant lesions of the prostate.     

Diagnostic utility of a p63/alpha-methyl-CoA-racemase (p504s) cocktail in atypical foci in the prostate.

Prostatic needle biopsy is the preferred method for diagnosing early prostate cancer, providing specific information. In cases of histological cancer mimics, a diagnosis of atypical small acinar proliferation suspected of but not diagnosed as malignancy can be made. In such cases, and in small focus carcinomas, pathologists use 34betaE12, cytokeratin (CK) 5/6 or p63 immunostaining to label basal cells, and alpha-methylacyl-CoA racemase (AMACR/p504s) immunostaining as a positive prostate cancer marker on two distinct slides. However, in cases of small foci, ambiguous lesions might disappear. The purpose of our study was to improve the sensitivity of a cocktail of two antibodies (p63/p504s) with a sample incubation on 260 prostatic specimens, in order to help make a decision in conjunction with standard histology and CK 5/6 immunostaining. We tested 101 small focus prostatic cancers, 104 atypical small acinar proliferation, 19 high-grade prostatic intraepithelial neoplasia, two atypical adenomatous hyperplasia and 34 benign mimics of cancer. After p63/p504s immunostaining, the final diagnoses retained were as follows: 154 prostatic cancers, 14 atypical small acinar proliferation, 30 high-grade prostatic intraepithelial neoplasia, three atypical adenomatous hyperplasia and 62 benign mimics of cancer. To differentiate malignant from benign lesions, we used the criteria of greater sensitivity to p504s/p63 (95%) than to CK 5/6 (57%) or p63 (86%), and higher specificity for p504s/p63 (95%) than for CK 5/6 (88%) or p63 (81%). With the p504s/p63 cocktail, 89% of the ambiguous lesions were classified vs 53% for CK 5/6. Combined use of the two antibodies, one (p504s) as a positive marker and the other (p63) as a negative marker, with a simple immunostaining procedure, may improve diagnostic performance, sensitivity and specificity, leading to a reduction in the risk of false negatives; this technique in cases of atypical small acinar proliferation should reduce the percentage of residual ambiguous lesions and the need for additional biopsies.     

Benign mimickers of prostatic adenocarcinoma.

The diagnosis of prostatic adenocarcinoma, especially when present in small amounts, is often challenging. Before making a diagnosis of carcinoma, it is prudent for the pathologist to consider the various benign patterns and processes that can simulate prostatic adenocarcinoma. A useful method of classifying benign mimickers is in relationship to the major growth patterns depicted in the classical Gleason diagram. The four major patterns are small gland, large gland, fused gland and solid. Most mimickers fit within the small gland category and the most common ones giving rise to false-positive cancer diagnosis are atrophy, post-atrophic hyperplasia, atypical adenomatous hyperplasia and seminal vesicle-type tissue. A number of other histoanatomic structures such as Cowper's gland, verumontanum mucosal glands, mesonephric glands and paraganglionic tissue may be confused with adenocarcinoma. Additionally, metaplastic and hyperplastic processes within the prostate may be confused with adenocarcinoma. Furthermore, inflammatory processes including granulomatous prostatitis, xanthogranulomatous prostatitis and malakoplakia may simulate high-grade adenocarcinoma. Atypical adenomatous hyperplasia (adenosis), a putative precursor of transition zone adenocarcinoma, has overlapping features with low-grade adenocarcinoma and may cause problems in differential diagnosis, especially in the needle biopsy setting. The pathologist's awareness of the vast array of benign mimickers is important in the systematic approach to the diagnosis of prostatic adenocarcinoma. Knowledge of these patterns on routine microscopy coupled with the prudent use of immunohistochemistry will lead to a correct diagnosis and avert a false-positive cancer interpretation.     

Atypical sclerosing adenosis of the prostate: a rare mimic of adenocarcinoma

Cheng L & Bostwick D G
(2010) Histopathology 56 , 627–631 Atypical sclerosing adenosis of the prostate: a rare mimic of adenocarcinoma Aims: Sclerosing adenosis of the prostate is a benign, small, acinar proliferation in dense spindle cell stroma, with a distinct immunohistochemical profiles. It is incidentally found in about 2% of transurethral resection specimens. The aim was to describe cases with significant cytological atypia mimicking cancer, which have not been previously reported. Methods and results: We describe five cases of sclerosing adenosis with significant cytological atypia, referred to as atypical sclerosing adenosis (ASA), which were initially considered suspicious or diagnostic of adenocarcinoma. Seven other cases of typical sclerosing adenosis were used as controls. All cases of typical and atypical sclerosing adenosis displayed an intact basal cell layer, which was immunoreactive for high‐molecular‐weight keratin, S100 protein, smooth muscle actin, and prostate‐specific antigen, with no differences between ASA and the control group. Alpha‐methylacyl‐coenzyme A racemase was negative. Three of four cases of ASA had aneuploid DNA content by digital image analysis. All cases of typical sclerosing adenosis were diploid. During a mean follow‐up of 33 months (range 5–73 months), none developed recurrence or prostatic cancer. Conclusions: ASA is an unusual small, acinar proliferation of the prostate that may be mistaken for adenocarcinoma, and should be distinguished from other mimics, including atypical adenomatous hyperplasia, mesonephric remnant hyperplasia, and post‐atrophic hyperplasia. ASA is a benign lesion and aggressive treatment is unwarranted.     

Diagnostic usefulness of monoclonal antibody P504S in the workup of atypical prostatic glandular proliferations

We stained 37 prostate needle biopsies and 3 transurethral resections (TURP) containing atypical foci and 20 morphologically unequivocal prostate cancer biopsies, including 4 with foamy features, with P504S. Of 20 biopsies with unequivocal cancer, 18 showed variable P504S staining (sensitivity, 90%); 1 minute cancer and 1 foamy cancer lacked P504S staining. Of 40 cases with atypical foci (biopsies, 37; TURP, 3), 9 were diagnosed as high-grade prostatic intraepithelial neoplasia (HGPIN), 2 were excluded, and 29 had foci of atypical small glandular proliferation. Of these 29 cases, 7 were highly suggestive of cancer, 2 of which lacked P504S staining. In 22 cases with benign atypical foci, 11 were diagnosed as postatrophic hyperplasia (none expressed P504S) and 7 as atypical adenomatous hyperplasia (AAH; 1 showed focal weak P504S staining). Of 9 HGPIN specimens, 8 showed predominantly diffuse, moderate P504S staining. P504S has slightly lower sensitivity for detection of prostate cancer than found previously. Heterogeneous expression patterns may explain negativity in some biopsy specimens with minute cancer. In atypical small glandular proliferations, diffuse positive P504S staining in atypical glands strongly supports a cancer diagnosis, but negative staining does not exclude it. P504S seems to have low sensitivity for detecting foamy prostate cancer. Most HGPINs show diffuse moderate P504S staining. AAH may show focal P504S staining. We recommend using P504S along with morphologic examination and conventional basal cell markers.     

Benign mimickers and potential precursors of prostatic adenocarcinoma

The diagnosis of prostatic adenocarcinoma (PCa) in needle biopsy, especially when present in small amounts, is often challenging. Before making a malignant diagnosis, it is imperative to consider and rule out various benign processes that can simulate cancer. A useful method of classifying benign mimickers is in relationship to the major architectural patterns depicted in the Gleason diagram. The four major patterns are small gland, large gland, fused gland and solid nests and single cells. Most mimickers have small gland architecture and include atrophy, post-atrophic hyperplasia and atypical adenomatous hyperplasia. Normal anatomical and vestigial structures such as seminal vesicle/ejaculatory duct tissue, Cowper’s gland, verumontanum mucosal glands, mesonephric glands and paraganglionic tissue may be confused with PCa. Additionally, metaplastic and hyperplastic processes may be mistaken for PCa. Furthermore, inflammatory processes including non-specific granulomatous prostatitis, xanthoma and malakoplakia may simulate high-grade PCa. In addition to mimickers there are a number of putative precursors of PCa. High-grade prostatic intraepithelial neoplasia has been expensively studied and is thought to be a precursor of at least a subset of PCa. The pathologist’s awareness of the vast array of benign mimickers coupled with prudent use of immunohistochemistry is a critical step in the systematic approach to the diagnosis of PCa. Recognition of PCa precursors in pathological specimens may significantly impact patient management.     

Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy.

The diagnosis of limited adenocarcinoma of the prostate is one of the more difficult challenges in surgical pathology. This paper highlights the methodological approach to diagnosing limited cancer, based on a constellation of features more commonly present in adenocarcinoma than benign glands. In assessing small foci of atypical glands on needle biopsy, one looks for differences between the benign glands and the atypical glands in terms of nuclear features, cytoplasmic features, and intraluminal contents. Only a few features, such as glomerulations, mucinous fibroplasia (collagenous micronodules), and perineural invasion are diagnostic in and of themselves for prostate cancer. Immunohistochemistry may be a useful adjunct in the diagnosis of limited adenocarcinoma of the prostate, although as with any immunohistochemical studies, there are problems with both sensitivity and specificity. Basal cell markers, such as high molecular weight cytokeratin and more recently, p63, highlight basal cells found in benign glands, yet are absent in adenocarcinoma of the prostate. However, not all benign glands label uniformly with basal cell markers. Certain mimickers of adenocarcinoma of the prostate are even less frequently labeled uniformly with these stains. Consequently, negative staining in a small focus of atypical glands for basal cell markers is not diagnostic of adenocarcinoma of the prostate. More recently, a marker has been identified that relatively selectively labels adenocarcinoma of the prostate. AMACR will label the cytoplasm of approximately 80% of limited adenocarcinoma of the prostate cases on needle biopsy. In positive cases, not all of the glands will be positive and those that are positive are often not intensely positive. Certain variants of adenocarcinoma of the prostate that are a little more difficult to recognize, such as foamy glands adenocarcinoma, pseudohyperplastic adenocarcinoma, and atrophic adenocarcinoma, are labeled with AMACR in only approximately 60-70% of cases. In addition to problems with sensitivity, AMACR is not entirely specific for adenocarcinoma, and will label almost all cases of high-grade prostatic intraepithelial neoplasia, some foci of adenosis, and even some entirely benign glands. Finally, this paper will briefly cover the significance of atypical or suspicious prostate needle biopsies, and how to report the key diagnostic and prognostic information on needle biopsy.     

Respiratory cytology in the era of molecular diagnostics: a review

Carcinoma of the lungs remains one of the primary causes of cancer mortality in the United States and represents a significant diagnostic challenge. Current diagnostic protocols depend substantially on cytology as an initial diagnostic modality. Pulmonary cytology can be diagnostically challenging with false positive and false negative diagnoses being relatively frequent. False positive diagnoses remain a significant problem for the cytologist with benign conditions including reactive atypia of type II pneumocytes, reactive bronchial respiratory epithelium, basal cell hyperplasia, and reactive metaplastic squamous cells being potentially misinterpreted as carcinoma. False negative diagnoses also occur usually attributable to sampling. Traditionally, cytopathologists were expected to recognize carcinoma when present and subdivide it into small cell or nonsmall cell varieties. With the advent of targeted therapy, expectations now include separation of adenocarcinoma from squamous cell carcinoma. Additionally, molecular testing for EGFR mutations and ALK rearrangements is now required as an accompaniment to morphologic diagnosis. This review summarizes the morphologic appearances of the common and diagnostically important carcinomas of the lung and discusses diagnostic pitfalls responsible for false positive and false negative diagnoses. Molecular testing for selection of targeted therapy is also reviewed.     

Atypical breast lesions: a challenging pathological diagnosis and an uncertain malignant potential

Atypical epithelial breast lesions are a heterogeneous group of entities, the diagnosis of which can be challenging. In this review, we discuss the wide spectrum of atypical epithelial breast proliferations including atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), flat epithelial atypia (FEA), atypia in a papilloma, atypical microglandular adenosis, apocrine atypia and post neo-adjuvant chemotherapy associated atypia. We aim to review the histologic diagnostic criteria for these entities, with an emphasis on the salient morphologic features and differential diagnoses to consider, in order to provide a comprehensive and practical guide to their diagnosis.     

Diagnostik benigner duktaler Epithelproliferationen der Mamma in der Stanzbiopsie

The pathological evaluation of radiological or sonographical abnormalities by needle core biopsy of the breast frequently involves the differential diagnosis of benign epithelial cell proliferations. The lesions to be considered include usual type and atypical ductal epithelial cell hyperplasia, columnar cell changes including flat epithelial cell atypia, the spectrum of hyperplastic and atypical apocrine epithelial cell proliferations and papillary lesions. This review provides an overview of the diagnostic criteria, the current terminology and the differential diagnosis of these lesions. The clinical management and the prognosis of the lesions are discussed.     

Atypical acinar proliferations of the prostate

Small acinar lesions of the prostate may mimic prostate cancer. In the central and transition zone of the prostate, atypical adenomatous hyperplasia (AAH) must be differentiated from low grade carcinoma (Gleason score 2-5). In the dorso-peripheral zone, high grade prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferations (ASAP) are the most important lesions mimicking carcinoma. Further differentiation is necessary between high grade PIN and intraductal carcinoma. ASAP, on the other hand, may mimic low grade carcinoma. The significance of basal cell type cytokeratin immunohistochemistry (IHC) in the differentiation between ASAP and low grade carcinoma of the prostate was substantiated by additional MIB-1 IHC. The status of the basal cell layer in ASAP was found to be variable (complete, fragmented and absent). Independent of the status of the basal cell layer, the mean MIB-1 proliferation index of ASAP was significantly higher than that of clearly benign lesions and did not differ from that of low grade carcinoma. As carcinoma is frequently detected in rebiopsies, close clinical follow up of patients with ASAP is advisable.     

Phyllodes tumor of the prostate with exuberant glandular hyperplasia

Reported herein is an unusual case of prostatic phyllodes tumor with exuberant glandular hyperplasia that led to misdiagnosis of adenocarcinoma. The tumor was detected in a 52-year-old man who had a 1 year history of dysuria. Adenocarcinoma of the prostate was diagnosed from a needle biopsy specimen. The patient received hormonal therapy for 6 months and underwent radical prostatectomy. Histologically, the tumor had an atypical stromal cell proliferation and elongated slit-like glands characteristic of a phyllodes tumor. The tumor was also accompanied by a florid proliferation of small acini, most of which lacked basal cells, a common manifestation of adenocarcinoma in the overall tumor area. The following features of the resected tumor were helpful for concluding that these acini were benign: lack of cytological anaplasia in spite of structural atypia, presence of scattered basal cells confirmed by immunohistochemistry (high-molecular-weight cytokeratin), and histological transition from these acini to apparently benign slit-like glands. The final diagnosis was then made as 'phyllodes tumor of the prostate with exuberant glandular hyperplasia'. Atypical stromal cells might provide a clue for the recognition of this rare tumor at initial diagnosis by needle biopsy.     

Florid basal cell hyperplasia of the prostate

Florid basal cell hyperplasia of the prostate is an uncommon proliferative condition, most often associated with adenomatous hyperplasia. It is considered a benign lesion although confusion with prostatic cancer is possible when one is not familiar with the histopathological appearance. We report another two cases of the glandular type of basal cell hyperplasia with immunohistochemical findings. Both lesions were composed of crowded and rather small glands with piling up of basaloid cells. They showed immunohistochemical positivity for high molecular weight cytokeratin 34βE12, confirming their relationship with basal cells. We detected focal positivity of these basal cells for α-smooth muscle actin, suggesting myoepithelial differentiation. Paucity of actin-positive smooth muscle cells in the stroma was noticed. One of the lesions showed some mild cytological atypia with prominent nucleoli and increased mitotic activity.     

Endometrial hyperplasia

Endometrial hyperplasia is a heterogeneous set of pathologic lesions that range from mild, reversible glandular proliferations to direct cancer precursors. These lesions comprise a continuum of morphologic appearances, with the earliest proliferation represented by crowded glands with simple tubular architecture lined by cells resembling proliferative endometrium, whereas advanced proliferations in this continuum are characterized by crowded glands with complex architecture, often containing cells with nuclear atypia resembling low-grade endometrioid adenocarcinoma. The former "early" proliferations may be isolated to an endometrial polyp, but advanced proliferations are generally more diffusely present throughout the endometrium. There are at least three major classification systems for endometrial carcinoma precursor lesions, each of which trend toward overlap at the complex end of the spectrum. Although some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), each classification scheme ultimately uses a series of histologic features, usually a combination of architecture and cytology, to establish a diagnosis of hyperplasia. Because different pathologists may apply different histologic criteria for endometrial hyperplasia depending on the classification system used, this article will provide an overview of the classifications used in current daily practice, present the histologic criteria and relative merits of each classification system, and discuss common and not so common causes of misclassification.     

Rectal ulcer and pseudomalignant epithelial changes after prostate seed brachytherapy: A rare complication with a diagnostic pitfall

BackgroundImplant brachytherapy (IBT) is a well-recognized treatment modality for early stage prostate cancer. Rectal ulcer and rectourethral fistula complicating IBT may cause an alteration of the normal anatomic landmarks. In this context, pseudomalignant radiation-induced changes within prostatic epithelium may be misinterpreted as a primary rectal malignancy. Such challenging and misleading findings have not been described, and may not be recognized as such.Materials and methodsWe present the clinical and pathologic aspects of two patients who underwent IBT for low stage prostate cancer that was complicated by deep rectal ulcer. Both patients underwent extensive palliative surgical resection for disease control.ResultsThe histologic changes in both cases were noteworthy for extensive necrosis and inflammation of the prostate, associated with loss of recto-prostatic anatomical landmarks. Prostatic glands showed striking radiation-induced atypia and pseudomalignant epithelial changes extending to the rectal ulcer bed, with no residual viable tumor. The first patient had undergone a biopsy of the rectal ulcer bed that was misinterpreted as a rectal adenocarcinoma prior to surgery. The similarity between atypical glands of the biopsy and the benign prostatic tissue with radiation-induced atypia in resection specimen confirmed their benign nature.ConclusionsDeep rectal ulcer complicating IBT may lead to distortion of the normal recto-prostatic anatomical landmarks, resulting in detection of pseudo-malignant prostatic glands at the ulcer base. Such findings may be mistaken for a primary rectal malignancy in limited biopsy material if not familiar to the pathologist.     

Utility of immunohistochemistry for alpha-methylacyl-CoA racemase in distinguishing atrophic prostate cancer from benign atrophy

Small atrophic prostate cancers on needle biopsy are rare and difficult to distinguish from benign atrophy on needle biopsy. We report on a study of 23 needle biopsy specimens with small foci of atrophic prostate cancer from the consult service of one of the authors. In 19 cancer cases the atrophic component was pure; in 4 cases it was dominant with a minor (<5%) nonatrophic cancer component. These atrophic cancers and 16 cases of florid benign atrophy on needle biopsy were examined by immunohistochemistry for alpha-methylacyl-CoA-racemase (AMACR). All cases of cancer and atrophy were verified immunohistochemically with antibodies to basal cells (34betaE12 and p63). AMACR staining were scored as 1+ (5% to 25% of glands expressing AMACR), 2+ (26% to 50% of glands expressing AMACR), or 3+ (>50% of glands expressing AMACR). Positive staining was defined as staining above that of surrounding benign glands. AMACR was expressed in 69.6% of atrophic prostate cancers (3+, 11 cases; 2+, 3 cases; 1+, 2 cases); 30.4% (7 cases) of atrophic prostate cancer exhibited no AMACR expression. In the 4 cases with a few glands of ordinary (nonatrophic) prostate cancer, the nonatrophic cancer demonstrated more intense and a greater extent of AMACR staining. Fourteen cases (87.5%) of benign atrophy showed no AMACR expression. In 2 cases (12.5%) of benign atrophy, background immunostaining made it difficult to assess AMACR expression. We conclude that AMACR immunostaining alone is not sufficiently discriminatory in the differential diagnosis of atrophic prostate cancer versus benign atrophy. Atrophic prostate cancers are not as frequently or as strongly positive as ordinary prostate cancer. Using a panel of immunostains including AMACR, 34betaE12 and p63 (positive AMACR immunostaining along with negative basal cell markers) is recommended in the differentiation of atrophic prostate cancer and benign atrophy.