Material and Method: We found 11 atypical adenomatous hyperplasia (22 foci) and 15 prostatic adenocarcinoma grade 1 and 2 (22 foci) lesions in 105 radical prostatectomy specimens. Basal cell-specific keratin (34βE12) was applied and based on the fact that prostatic adenocarcinoma grade 1 and 2 lesions do not have basal cells we grouped the lesions as atypical adenomatous hyperplasia and prostatic adenocarcinoma grade 1 and 2.
Results: Statistically significant differences were found between atypical adenomatous hyperplasia and prostatic adenocarcinoma grade 1 and 2 lesions for some parameters including the largest nuclear diameter, nuclear location, 1-2 μm nucleolus, > 2 μm nucleolus, and nuclei containing multiple nucleoli. We found similar properties between the two lesions for the following parameters: irregularity of nuclear membrane, median diameter of the nucleolus, chromatin pattern, pynotic nucleus, nuclear pleomorphism, < 1 μm nucleolus nucleolar margination, and the ratio of nucleus to cytoplasm and the appearance of cytoplasm in the secretory cells.
Conclusion: Evaluation of the overall histomorphological criteria is important in the differentiation of atypical adenomatous hyperplasia and prostatic adenocarcinoma grade 1 and 2 lesions.
Prostatic adenocarcinoma grade 1 (PACG 1) are round lesions composed of medium-size monotonous glands displaying minimal stromal invasion with cytoplasmic features similar to benign glands that expand by pushing surrounding tissues [25],[26]. Prostatic adenocarcinoma grade 2 (PACG 2) lesions display early infiltrative findings and mild size differences in glands in addition to PACG 1 features [25],[26]. There are many studies on the diagnostic criteria of AAH and differentiating AAH from PACG 1 and 2 [17],[27]-[30]. These studies have reported that nucleolus size, basal cell-specific keratin immunohistochemistry characteristics (34βE12, eIF 3/p66), aspect of the glands' luminal side, and existence of acidic mucin are the principal criteria. However, additional data are required when these are equivocal. Our previous main studies evaluated the distinguishing features of the AAH and PACG grade 1 and 2. Structural and secretory features were published as two separate articles [31],[32]. In this article we evaluated 14 cytological criteria (cytoplasmic, nuclear, nucleolar) in addition to the histological criteria of AAH and low-grade prostatic adenocarcinoma. The aim of this study was to determine the parameters that would enable differentiating these two lesions.
34βE12 immunohistochemistry was performed to show the basal layer on the 4 μm sections obtained from the paraffin blocks of the PACG 1 and 2 where the diagnosis was suspected and in all AAH lesions.
Evaluated Parameters: We studied AAH, PACG 1 and 2 lesions by dividing them using 14 parameters regarding nuclear, nucleolar and cytoplasmic features into 3 groups.
These groups and the parameters are presented at Table I.
Evaluation of the Parameters: Table II presents the evaluation of the nuclear, nucleolar and cytoplasmic parameters.
Largest Mean Nuclear Diameter: All the lesions were scanned under x400 magnification and the diameter of 10 large nuclei was measured with the ocular micrometer. The largest nucleus found was measured again at x1000 magnification with the ocular micrometer and the result was specified as the largest nuclear diameter for that lesion.
Mean Nuclear Diameter: 10 fields at random were analyzed under x1000 magnification; 10 cells were measured in each field with the ocular micrometer and the mean value was determined.
The chromatin pattern was evaluated comparatively under x1000 magnification and all nuclei in the lesion were examined. A value of 1 to 4 was assigned depending on the homogeneity and presence of a chromocenter.
Nuclear membrane irregularity was determined comparatively under x1000 magnification and all cells in a randomly chosen area were examined. A value of 1 to 3 was assigned according to the number of nuclei with these features.
<1 μm nucleolus, 1-2 μm nucleolus, an >2 μm nucleolus parameters were evaluated in an independent and quantitative manner. The number of glandular nuclei in three randomly chosen areas under x1000 magnification were counted and a value of 0 to 3 was assigned after the ratio of nuclei containing <1 μm nucleolus, 1-2 μm nucleolus or >2 μm nucleolus was determined. Oval-round, eosinophilic or amphophilic intranuclear structures were defined as nucleolus and measured with an ocular micrometer. (The grid interval is equal to 25, 10, 5, 2.5 and 1 μm on x40, x100 x200, x400 and x1000 magnification respectively on ocular micrometer measurements).
Nucleolar margination (the number of nucleoli touching the nuclear membrane) and nuclei with multiple nucleoli parameters were evaluated quantitatively and all cells in a randomly chosen area were counted. The nuclei with these characteristics were assigned a numerical value from 0 to 3.
Immunohistochemical staining method: (34βE12); keratin, HMW Ab-3 (1/50; clone 34 beta E12; MS-1447-S1; Neomarkers, CA, USA). The streptavidin biotin/horseradish peroxidase (Str.AB/HRP) method was used to show keratin expression. A drop of Ultra V Block (Ultra Vision Kit; TP- 125-HL; Lab Vision, CA, USA) was used on the slides to prevent nonspecific staining. The tissues were incubated for 10 minutes in biotinylated secondary antibody (Ultra Vision Kit; TP-125-HL; Lab Vision, CA, USA). Streptavidine peroxidase (Ultra Vision Kit; TP-125-HL; Lab Vision, CA USA) was applied. DAB (TA-125-HD, Lab Vision) was used as the chromogen. Cytoplasmic brown staining of the basal cells was accepted as positive.
Table I: Grouping of evaluated parameters
Table II: Evaluation of the parameters of the cytological features
Statistical evaluation: The results of the study were analyzed by SPSS (Statistical Package for Social Sciences for Windows, version 11.0) package software.
Mann-Whitney U test was used to compare the numeric variables between types (largest mean nuclear diameter mean nuclear diameter, largest mean glandular diameter mean glandular diameter, lesion width, and lesion height parameters).
Chi-square test was used to compare the non-numerical data between the types. Accordingly, the nuclear pleomorphism, nuclear membrane irregularity, chromatin pattern, stratification, <1 μm nucleolus, 1-2 μm nucleolus >2 μm nucleolus, nucleolar margination, multinucleolated and multinucleated nucleus, secretory cell cytoplasmic appearance, and secretory cell nucleus/cytoplasm ratio parameters were statistically evaluated.
Fisher exact probability test, a subgroup of the Chi-square relation test, was used when evaluating four-cell tables where the expected values were less than 5 (pynotic nucleus nucleus localization).
The results were evaluated at the p<0.05 significance level.
The nuclei tended to localize at the basal cytoplasm in PACG 1 and 2 and mixed in both the basal and middle sections of the cytoplasm in AAH (Figure 2A, B). There was a significant difference between AAH and PACG 1 and 2 lesions for nuclear localization (p<0.05). The largest mean nucleus diameter was smaller in AAH than PACG 1 and 2.
The difference was statistically significant (p<0.05). There was no statistically significant difference between the groups for nuclear pleomorphism (Figure 3, B) nuclear membrane irregularity (Figure 4), pynotic nucleus chromatin pattern and mean nucleus diameter parameters (p>0.05).
We found <1 μm nucleolus in all AAH and PACG 1 and 2 lesions in our study and there was no significant difference between the groups for <1 μm nucleolus (p>0.05).
The percentage of 1-2 μm nucleolus was 63.6% for AAH (Figure 3A), and 95.5 for PACG 1 and 2 lesions. PACG 1 and 2 lesions had >2 μm nucleolus at a rate of 50% (Figure 4) while no AAH lesions had such nucleolus. There was a significant difference between AAH and PACG 1 and 2 lesions for 1-2 μm nucleolus and >2 μm nucleolus (p<0.05).
The statistical significance of the 1-2 μm nucleolus parameter in PACG 1 and 2 was due to the higher percentage of nuclei with 1-2 μm nucleolus than in the AAH group and the statistical significance of the >2 μm nucleolus parameter in PACG 1 and 2 was due to none of the AAH lesions containing >2 μm nucleolus.
Multinucleolated nuclei were present in more cells in PACG 1 and 2 lesions than AAH lesions and this result was statistically significant (p<0.05). The statistical significance of the multinucleolated nuclei was due to a higher chance of multiple nucleoli in 5-50% of nuclei in PACG 1 and 2 and no AAH lesion containing multiple nucleoli in >50% nuclei.
Nucleolar margination was present in more cells in PACG 1 and 2 lesions (Figure 5) and this was very close to being statistically significant (p=0.057). This result was due to a low rate of nucleolar margination in 5-50% of nuclei in AAH lesions.
Figure 5: Nucleolar margination in prostatic adenocarcinoma grade 1 and 2 (H&E, x400).
AAH and PACG 1 and 2 lesions have a slightly eosinophilic cytoplasm. The rate of lesions consisting of high columnar cells was higher in PACG 1 and 2 (Figure 6) but there was no significant difference between the groups for secretory cell cytoplasmic appearance and secretory cell nucleus/ cytoplasm parameters (p>0.05).
We did not find any studies on nuclear membrane irregularity in AAH and PACG 1 and 2 lesions. We found nuclear membrane irregularity at a rate of 23% in AAH and 41% in PACG 1 and 2 lesions with no statistically significant difference. We believe that nuclear membrane irregularity is not a criterion that can be used to differentiate between these lesions. However, more studies are needed to make a definite comment.
Some studies have reported that nuclear anaplasia is important in PACG 1 and 2 lesions [17],[24],[34]-[36]. The study by Bostwick DG et al. reported a significant difference between AAH and PACG 1 and 2 lesions for nuclear size while there was no difference between the groups for nuclear pleomorphism [17]. We used nuclear pleomorphism, largest nucleus diameter and mean nucleus diameter to evaluate nuclear atypia in our study. AAH and PACG 1 and 2 lesions were similar for nuclear pleomorphism and average nucleus diameter. The largest nucleus diameter was higher in cancer (11.64 μm) than in AAH (9.76 μm) and the difference was statistically significant.
AAH has a uniform granular chromatin structure similar to normal prostatic cells [17],[37]. Bostwick DG et al. have reported the chromatin pattern in all AAH and PACG 1 and 2 lesions as generally uniform and finely dotted [17]. Other studies have also not found the chromatin pattern useful to differentiate AAH from adenocarcinoma [27],[28],[30],[38].
We found the chromatin finely and coarsely dotted in AAH and found a chromocenter in 4.5% of the lesions. PACG 1 and 2 lesions were similar to AAH but a higher percentage of lesions had a chromocenter (27.3%). However, this difference was not statistically significant.
Kramer CE et al. and Haussler O have reported a higher rate of apoptosis in PIN and cancer than AAH [24],[25].
McNeal JE et al found 8 PACG 1 lesions in 77 radical prostatectomy specimens and compared these with PACG 2 and surrounding areas of benign nodular hyperplasia. A pynotic nucleus was seen in almost all large magnification fields in 47% of the PACG 1 cases [22]. We only observed pynotic nuclei from an apoptotic nucleus characteristic in AAH and PACG 1 and 2 lesions. We found pynotic nuclei in a single lesion of AAH and PACG 1 and 2, a lower rate than the results in the references. There are few studies on the subject and the use of different fixatives on the tissues may have led to the different results.
PACG 1 lesions have nuclei placed linearly basally while this arrangement disappears in PACG 2. We did not find an English study comparing AAH with PACG 1 and 2 for nucleus localization. In our study, there were 6 AAH lesions (27.3%), and 19 PACG 1 and 2 lesions (86.4%) with basal arrangement of nuclei. The nuclei of non-malignant epithelia were generally arranged in a mixed manner at the basal center and apical parts of the cytoplasm. We felt that basal localization of nuclei was an important histological feature for PACG 1 and 2 while central and apical localization was an important histological feature for AAH. This difference was very significant statistically.
One of the most important criteria reported for the differential diagnosis of AAH and PACG 1 and 2 lesions is the prominence of nucleoli [36],[37],[39]-[45]. However, there are no common criteria for defining prominent nucleolus.
Various studies have defined prominent nucleolus as measuring 1-3 μm [17],[36],[37],[39]-[41],[43]-[45]. We defined three groups in our study for the presence of nucleoli as <1 μm 1-2 μm, and >2 μm. There was no difference between the AAH and PACG 1 and 2 lesions for the presence of <1 μm nucleoli but 1-2 μm nucleoli and >2 μm nucleoli were more common in PACG 1 and 2 lesions. There was a statistically significant difference between the two lesions.
The only comparative study between AAH and PACG 1 and 2 lesions for the cytological criterion nucleolar margination has been by Montironi et al. They have reported a significant finding of nucleolar margination in more than 50% of the cells in 60% of cancer lesions [37]. We found a difference very close to statistical significance (p=0.057). This difference was due to the presence of nucleolar margination in 5-50% of the nuclei in 22.7% of AAH lesions and 50% of PACG 1 and 2 lesions.
Nuclei with multiple nucleoli have been studied in a single study comparing AAH and PACG 1 and 2. Montironi R et al. have found the rate of multiple nucleolated nuclei as 30% and 70% in AAH and cancer respectively [37].
This rate was 59% in AAH and 72% in PACG 1 and 2 in our study and the difference was statistically significant (p<0.05). This significant difference was due to the presence of multiple nucleoli in more than 50% of nuclei in 4 PACG 1 and 2 lesions and no AAH lesions and the presence of multiple nucleolated nuclei in 5-50% of nuclei in 13.6% of AAH lesions and 31.8% of PACG 1 and 2 lesions. More studies are needed on the matter for a more comprehensive evaluation.
Cytoplasmic clarity is a characteristic feature of normal prostatic secretory cells. This clarity is lost in dysplastic and malignant prostatic epithelial cells and amphophilic (dark) cytoplasmic staining is encountered [35]. AAH and PACG 1 and 2 consist of cells with pale or clear cytoplasm. Continuing cytoplasmic clarity in PACG 1 and 2 may be a sign of well differentiation. Many vesicles filling the cytoplasm are responsible for this cytoplasmic clarity [46]. These vesicles are not observed if the tissue is fixed with fixatives such as 95% ethyl alcohol, 4% and 10% buffered formaldehyde, 1% buffered glutaraldehyde B5 or Bouin's. However, if the tissue is fixed with 3% and 5% buffered gluteraldehyde, the cytoplasmic granules are stained dark eosinophilic in routine H&E staining as the secretory granules are preserved. Cytoplasmic clarity is therefore thought of as a fixation artifact. These granules immunohistochemically stain positively with prostatespecific antigen and prostatic acid phosphatase. Eosinophilic staining is not found in routine H&E staining in high-grade dysplasia and cancer as the granules decrease in number or disappear. [46]. Montironi R et al. have observed the secretory cell cytoplasmic appearance in AAH in PACG 1 and 2 as clear in 70% and 30% of lesions and granular (eosinophilic) in 30% and 70% of lesions respectively [37].
However, the cytoplasmic staining quality has not been found useful in differentiating AAH from adenocarcinoma in some studies. We found an eosinophilic appearance in 13.6% of PACG 1 and 2 lesions and 4.4% of AAH lesions.
The mild eosinophilic appearance and cytoplasmic clarity was similar in both lesions and there was no statistically significant difference. The results are consistent with other reports [27],[28],[30],[38].
AAH and PACG 1 and 2 lesions consist of cuboidal or columnar cells [17],[27],[28],[30],[38],[47]. The quality of cytoplasm has not been reported to help differentiate between AAH and adenocarcinoma [17],[27],[28],[38]. We also observed that AAH and PACG 1 and 2 lesions were made of low and high columnar cells and did not find a significant difference for the nucleus/cytoplasm ratio of secretory cells between the groups. We believe that cell size is not a criterion that can be used in the differential diagnosis of AAH and PACG 1 and 2 lesions.
In conclusion, we accepted the absence of basal cells in PACG 1 and 2 and their interrupted presence in AAH as the most important diagnostic criterion. The percentage of cells with nuclei containing 1-2 μm nucleolus or multiple nucleoli was higher in the PACG 1 and 2 lesions than AAH lesions while AAH lesions did not have the >2 μm nucleolus observed in PACG 1 and 2 lesions and these were important parameters for the differentiation of these lesions. We also concluded that the nuclear localization, reported for the first time, was important for differentiation between AAH and PACG 1 and 2.
The difference between the groups for nucleolar margination observed more commonly in PACG 1 and 2 almost reached significance. Although prominent nucleolus, crystalloid mucin, lobular pattern and the presence of basal cells are important parameters to differentiate between AAH and PACG 1 and 2, the differential diagnosis is still difficult in some cases where a limited number of histological parameters can be evaluated, especially following needle biopsies. It is important to evaluate the histological parameters in AAH lesions where basal cells are focal and limited in number.
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