Atrophic and Microcystic Limited Prostatic Adenocarcinomas

Introduction

Previously, we have studied foamy carcinoma and pseudohyperplastic carcinoma when they are found in isolated histological fields (limited, minimal, or microcarcinoma).^1-3 In both neoplasms, the histological criteria of conventional acinar carcinoma^4-8 were only partially useful since they correspond to microcarcinomas that show architectural and cytological criteria that are specific to them.^8-13 Atrophic carcinoma may be similar to sclerosing atrophy, post-atrophic hyperplasia, partial atrophy, or cystic atrophy, and can therefore be difficult to recognize, as noted in the literature.^14-20 The purpose of this study was to determine the frequency of limited atrophic and microcystic carcinomas in needle biopsies and prostatectomies and to discuss some useful criteria for their diagnoses.

Materials and Methods

We studied a total of 400 cases. One hundred fifty of them came from prostatectomies, while the remaining 250 came from prostatic biopsies. The 250 cases we selected from the biopsies either measured <1 mm or involved <5% of the biopsied tissue and in accordance of conventional standards of limited adenocarcinoma.

The cases from the 150 prostatectomies were chosen by taking into account, and the following data were recorded: irregular glandular shape with or without infiltrative aspect, cystic glandular dilatation, straight luminal borders, nuclear nucleomegaly, hyperchromatic nuclei, visible nucleoli, amount of cytoplasm in neoplastic cells, eosinophilic or basophilic intraluminal secretions, association with benign atrophic glands or conventional acinar adenocarcinoma, mitosis, crystalloids, perineural invasion, collagenous micronodules, glomerations, and adjacent PIN (prostatic intraepithelial neoplasia). Immunohistochemically, the study was performed with alpha-methylacyl-CoA racemase (AMACoAR) and with p63 and CKBE12 to demonstrate the absence of basal cells.

Results

We found 2 cases of limited atrophic carcinoma in 250 needle biopsies (0.8%) and 2 cases in 150 prostatectomies (1.3%). Microcystic carcinomas were found in 3 prostatectomy products (1.2%) and in 1 needle biopsy (0.67%; Figures 1 and 2). Atrophic carcinoma showed conventional acinar adenocarcinoma alternating with atrophic glands (Figures 1B and 3A) and cystic dilatation (Figure 2A). The architectural atypia with irregular glandular distribution or infiltrative pattern were very useful criteria (Figures 1A and B, and 2A-C). The neoplastic cells had scarce cytoplasm and visible nucleoli, sometimes alternating with small hyperchromatic nuclei (Figure 1B and C). Two needle biopsies showed benign atrophic glands adjacent to the malignant atrophic glands. Immunohistochemical study was necessary to distinguish them (Figure 1D). One patient with atrophic carcinoma (Figure 2) had been treated with hormonal blockers.

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Figure 1.

(A) Limited atrophic carcinoma. The neoplastic glands show an irregular growth pattern que that may resemble a proliferation of benign atrophic glands. (B) At higher magnification, the glands are arranged between larger benign glands. This is an infiltration criterion that allows suspecting the diagnosis. Irregular cords of neoplastic cells infiltrate the stroma. Scarce intraluminal secretions are seen. (C) The nucleomegaly and the visible nucleoli are 2 very constant histological findings in atrophic carcinoma and allow to establish the diagnosis in conventional sections. (D) The immunohistochemical study demonstrates the absence of basal cells and distinguishes malignant neoplastic glands from benign atrophic glands.

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Figure 2.

(A) Atrophic carcinoma. Most of the glands are small and show nucleomegaly and visible nucleoli. Only some of them show cystic dilation. (B) The diffuse infiltrative pattern facilitates the diagnosis of carcinoma. This patient received treatment with hormonal blockers. (C) At higher magnification, some glands show rigid lumens and scarce intraluminal secretion. The nuclei are small and hyperchromatic due to the treatment.

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Figure 3.

(A) Unlike atrophic carcinoma, the glands of microcystic carcinoma show great size. The so-pronounced dilation of the glandular lumens favors a malignant lesion. (B) Microcystic adenocarcinoma in needle biopsy. The infiltrative aspect supports a malignant lesion. The architectural appearance is necessary in order to suspect the diagnosis, since cytological changes are not diagnostic. (C) The coating cells in the larger glands show flattened nuclei without atypia. (D) Microcystic carcinoma in prostatectomy. Some glands show “rigid” appearance and show intraluminal secretion; in others, there are collagenous micronodules.

Microcystic carcinomas were found in 3 prostatectomy products (1.2%) and in 1 needle biopsy (0.67%; Figure 3A-D). The glandular dilation was much more evident than that of the benign atrophic glands, and most of them showed eosinophilic and basophilic intraluminal secretions. Some glands showed “rigid” glandular lumens in all 4 cases (Figure 3A-C). In 1 of 3 prostatectomies, the nuclear atypia was easily identified in addition to collagenous micronodules and intraluminal secretions (Figure 3D). In a prostatectomy product tumor and in a needle biopsy, both the nucleomegaly and the apparent nucleoli were virtually absent since the malignant glands were lined by flattened and hyperchromatic nuclei (Figure 3A-C). However, the presence of small glands with infiltrative pattern facilitated the diagnosis (Figure 3A). Focal areas of conventional acinar carcinoma were seen alternating in 6 out of 8 biopsies. All cases showed absence of basal cells with basal cell markers (CKBE12 and p63). Three cases of atrophic carcinoma and 4 cases of microcystic carcinoma were positive for AMACoAR, and all cases showed Gleason sum 6.

The morphological features of microcystic and atrophic adenocarcinomas are summarized in Table 1.

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Table 1.

Architectural and Cytologic Changes in Limited and Microcystic Carcinoma ^a .

	Atrophic Carcinoma	Microcystic Carcinoma
Irregular glandular disposition	2/4	3/4
Infiltrative pattern	2/4	1/4
Nucleomegaly	3/4	3/4
Nuclear hyperchromatic	3/4	3/4
Scanty cytoplasm	4/4	4/4
Cystic glandular dilatation	1/4	4/4
Straight luminal borders	4/4	4/4
Eosinophilic secretions	3/4	3/4
Basophilic amorphous secretions	1/4	1/4
Association with benign atrophic glands	2/4	2/4
Association with conventional acinar adenocarcinoma	3/4	3/4
Crystalloids	0/4	2/4
Collagenous micronodules	0/4	1/4
Apocrine blebs	0/4	1/4

a

Other criteria: perineural invasion, mitosis, glomerations, and prostatic intraepithelial neoplasia were not seen in any case.

Discussion

Atrophic carcinoma and microcystic carcinoma are variants of conventional acinar adenocarcinoma.^12,13 The incidence of atrophic carcinoma is of 2% in needle biopsies and of 16% in radical prostatectomies. ¹⁰ There are also 2 documented cases of transurethral resection products. ⁹ The atrophic carcinoma has been found in 10% to 90% of needle biopsies and in 1% to 70% in samples of radical prostatectomies. ¹³ In this study, we found an incidence of 0.8% in needle biopsies and 1.3% in prostatectomies. ¹³ The selected cases represented <5% of the neoplastic tissue in biopsies and prostatectomies.

The limited atrophic carcinoma may present irregular borders or an infiltrative pattern (Figures 1 and 2). The irregular growth of the glands suggests atrophic carcinoma diagnosis (Figure 1). Another very useful criterion is to observe small atrophic glands among larger glands (Figure 1). If the patient has been given hormonal blockers or radiotherapy, and there is an evident infiltration pattern, then one can establish the diagnosis even in the absence of nuclear atypia (Figure 2B and C). Atrophic adenocarcinoma may show stromal sclerosis (Figures 1B and 2B). As has been mentioned, nucleomegaly and visible or even prominent nucleoli have constantly been found^9-13 (Figures 2A and 3D). However, both atrophic and microcystic carcinomas may present either atypical nuclei with nucleomegaly and visible nucleoli, or small hyperchromatic nuclei; these changes are frequently associated to conventional acinar carcinoma, but also may be found in benign atrophic glands. In some biopsies, the only way to distinguish neoplastic malignant glands from benign ones is with immunohistochemical study (Figure 1D).

Most patients show Gleason sum 6 and may be treated with active surveillance since the atrophic phenotype has not been associated with a worse prognosis.^10,13 It must be mentioned that atrophic carcinomas may exhibit Gleason pattern 4 ¹³ and sporadically pattern 5. ⁹ Other changes that have been mentioned in atrophic carcinoma include apocrine blebs, collagenous micronodules, and high-grade prostatic intraepithelial neoplasia. We only found one case with collagenous micronodules (Figure 3D).

The majority of cases can be diagnosed using conventional sections and basal cell markers. The immunohistochemical study is very useful, but it also has limitations. Farinola and Epstein have found that the use of AMACoAR is insufficient given that it does not always permit one to separate benign atrophic glands from malignant glands. ²⁰ It is necessary to use basal cell markers such as keratin 34βE12 or p63. The positivity of the AMACoAR and the negativity of the antibodies against basal cells allow to establish the diagnosis. Nevertheless, it must be mentioned that the expression of AMACoAR is absent in ~30% of the atrophic carcinomas, and ~24% had a cancer pattern for both basal cells and AMACoCR.^18,19 In this study, only one case was negative.

Differential diagnosis includes sclerosing atrophy, post-atrophic hyperplasia, and partial atrophy. When the atrophic glands are associated with stromal sclerosis, they may have an angulated aspect or an infiltrative pattern.^14-16 The post-atrophic hyperplasia resembles moderately differentiated carcinomas, and in ~14% of them, prominent nucleoli and occasional mitosis are observed.^15,16 Partial atrophy is frequently confused for acinar adenocarcinoma. This type of atrophy displays partial loss of cytoplasm and the nuclei are crinkled. Visible nucleoli appear in 25% of the biopsies, and the basal cells can be rather difficult to identify.^18,19

Radiotherapy and administration of hormonal blockers should always be investigated, because they may produce diverse alterations in benign and malignant atrophic glands.^21-24 Most atrophic carcinomas are not related to any treatment. ⁹ In Epstein’s series, which included 44 cases of atrophic carcinoma, only 2 had received hormonal therapy treatment. ⁹ In the present study, just one of the patients received hormonal treatment.

In the microcystic carcinoma, the infiltration pattern is less evident than in the atrophic carcinoma because it is formed by larger glands and the glandular lumens are “rigid” (Figure 3A-D), and, occasionally, flattened nuclei with minimal atypia predominate (Figures 2A and 3A-C). In most cystic glands, there are intraluminal secretions (Figure 3D) or crystalloids in variable quantities, even though at times it might not be obvious (Figure 3A and B). This is due to the fact that the carcinomas in isolated histological fields are not representative of the whole neoplasia and could be found in other needle biopsies or in the study of the prostatectomy. In contrast to atrophic carcinoma, when using 34βE12 and p63 antibodies, 51 out of 53 cases (96%) of microcystic carcinoma expressed AMACoAR as well as loss of basal cells. Most cases are Gleason pattern 3. However, the presence of moderately differentiated microcystic carcinoma does not exclude the possibility of finding Gleason pattern 4 in tissues obtained from other biopsies or radical prostatectomies. ¹³

Yaskiv et al found that microcystic adenocarcinoma may be associated to pseudohyperplastic or atrophic patterns. ¹¹

In conclusion, both atrophic and microcystic adenocarcinomas are neoplasia that can be found in isolated histological fields. It is necessary to recognize them in order to avoid underdiagnosis of malignancy.