Cytodifferentiation of atypical adenomatous hyperplasia and bronchioloalveolar lung carcinoma: immunohistochemical and ultrastructural studies

We used immunohistochemistry and electron microscopy to evaluate the differentiation of cells comprising atypical adenomatous hyperplasia (AAH; n = 26), early bronchioloalveolar lung carcinoma (BAC; n = 11), and overt BAC (n = 16), which are assumed to constitute a continuous spectrum of developmental steps of BAC. Surfactant apoprotein (SAP), a marker for type 2 alveolar cells, was expressed in cells from all the lesions of AAH, early BAC, and overt BAC. However, the proportion of SAP-positive cells decreased and their distribution became more heterogeneous with advancing lesion grade. Urine protein 1, which is identical to the Clara cell-specific 10 kDa protein, was expressed in 70% of overt BAC, whereas only 20% of early BAC showed weak reactivity and none of AAH lesions showed any reactivity at all. Ultrastructurally, type 2 alveolar cell differentiation was predominant among cells from AAH and early BAC. Our results suggest that precursor cells of BAC differentiate predominantly towards type 2 alveolar cells. Cells comprising overt BAC retain this differentiation phenotype, but to a reduced extent. In contrast, concomitantly with progression, cells with Clara cell differentiation emerge and their proportion increases. Such phenotypic changes may reflect metaplasia occurring in tumour cells during the development of BAC.     

Unique Cellular Features in Atypical Adenomatous Hyperplasia of the Lung: Ultrastructural Evidence of Its Cytodifferentiation

Atypical adenomatous hyperplasia (AAH) of the lung could be a good material to understand the histogenesis of peripherally occurring, well-differentiated adenocarcinoma. However, its true biological significance remains to be clarified. The authors present the histomorphological studies of this lesion and compare the ultrastructure with that of nonmucinous bronchioloalveolar carcinoma (BAC) to define characteristic features of AAH. Light microscopy showed the well-preserved pulmonary architecture, proliferated neoplastic cells without marked cellular atypia, and no transitional area to obvious adenocarcinoma. Intranuclear inclusion was present in a large number of neoplastic cells. Electron microscopy revealed that cuboidal or low columnar neoplastic cells proliferated actively but were not crowded on slightly thickened fibrous alveolar septa with both Clara-like granules and small lamellar bodies in the cytoplasm resembling that of Clara cell and type 2 pneumocyte. Some of the nuclei had characteristic invaginations of its nuclear membrane. Although the findings appear to be nonspecific for AAH, the authors emphasize that AAH is an alveolar intraepithelial neoplasia that represents a very early stage in the continuous developmental spectrum of adenomatous neoplasia in the bronchioloalveolar region corresponding to dysplasia or intraepithelial neoplasia in other organs, and will give the significance to speculate its histogenesis.     

Unique Cellular Features in Atypical Adenomatous Hyperplasia of the Lung: Ultrastructural Evidence of Its Cytodifferentiation

Atypical adenomatous hyperplasia (AAH) of the lung could be a good material to understand the histogenesis of peripherally occurring, well-differentiated adenocarcinoma. However, its true biological significance remains to be clarified. The authors present the histomorphological studies of this lesion and compare the ultrastructure with that of nonmucinous bronchioloalveolar carcinoma (BAC) to define characteristic features of AAH. Light microscopy showed the well-preserved pulmonary architecture, proliferated neoplastic cells without marked cellular atypia, and no transitional area to obvious adenocarcinoma. Intranuclear inclusion was present in a large number of neoplastic cells. Electron microscopy revealed that cuboidal or low columnar neoplastic cells proliferated actively but were not crowded on slightly thickened fibrous alveolar septa with both Clara-like granules and small lamellar bodies in the cytoplasm resembling that of Clara cell and type 2 pneumocyte. Some of the nuclei had characteristic invaginations of its nuclear membrane. Although the findings appear to be nonspecific for AAH, the authors emphasize that AAH is an alveolar intraepithelial neoplasia that represents a very early stage in the continuous developmental spectrum of adenomatous neoplasia in the bronchioloalveolar region corresponding to dysplasia or intraepithelial neoplasia in other organs, and will give the significance to speculate its histogenesis.     

Clonal growth of atypical adenomatous hyperplasia of the lung: cytofluorometric analysis of nuclear DNA content

The nuclear DNA content of 13 cases of atypical adenomatous hyperplasia (AAH) associated with adenocarcinoma, eight cases of small-sized well differentiated adenocarcinoma in which the tumors were less than 2.5 cm in size with no tumor recurrence within 5 yr after surgery, and eight cases of reactive type 2 pneumocyte hyperplasia of the lung was determined by cytofluorometry. Of the AAHs, four were solitary and composed entirely of cells of AAH (Group 1), and the remaining nine were in continuity with the focus of adenocarcinoma (Group 2). The average mean nuclear DNA content of the AAHs was significantly greater than that of reactive type 2 pneumocyte hyperplasia (p less than 0.005) and significantly smaller than that of adenocarcinoma associated with AAH (p less than 0.05). However, no significant difference was found in nuclear DNA content between AAH and small-sized well differentiated adenocarcinoma. Aneuploid stem lines were found in seven of the 13 (53.8%) AAHs, ten of the 13 (76.9%) adenocarcinomas associated with AAH, and five of the eight (62.5%) small-sized well differentiated adenocarcinomas but in none of the reactive type 2 pneumocyte hyperplasias. DNA histogram patterns I and II, in which aneuploid cells were less frequently present than in patterns III and IV, were more common in AAH than in adenocarcinoma associated with AAH and small-sized well differentiated adenocarcinoma. All of the reactive type 2 pneumocyte hyperplasia showed pattern I. As to the average mean nuclear DNA content, incidence of aneuploid stem lines, and DNA histogram pattern, there was no significant difference between groups 1 and 2 of the AAHs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.     

Atypical adenomatous hyperplasia of the lung

Clinicomorphological analysis was performed in 12 cases of atypical adenomatous hyperplasia of the lung (AAH). This is the proliferative lesion consisting of atypical epithelial cells along the alveolar septa which are found incidentally during pathologic examination of the lung resected because of cancer. We studied morphological and biological characteristics of AAH cells including cytodifferentiation, proliferative activity, tumor-suppressor genes. Our review of the studies of AAH revealed that AAH is alveolar intraepithelial dysplasia and a precursor of lung adenocarcinoma. AAH is an important lesion corresponding to a step in carcinogenesis for peripheral lung adenocarcinomas.     

Atypical alveolar hyperplasia: Relationship with pulmonary adenocarcinoma,p53, and c-erbB-2 expression

Atypical alveolar hyperplasia (AAH) has recently been described in human lungs in association with primary lung cancer, particularly adenocarcinoma. Unlike proximal bronchogenic carcinoma, peripheral (parenchymal) adenocarcinoma of the lung does not have a well-recognized progenitor lesion. Epidemiological, morphometric, and cytofluorometric data in the literature suggest that AAH is a candidate premalignant entity. In this study, 97 AAH lesions were found in lungs resected from 29 patients (1–13 lesions per case, mean 3·5) being treated for presumed carcinoma (25/29 had adenocarcinoma). From a study case-load of 285 adenocarcinoma-bearing lungs, the AAH incidence was 8·8 per cent. Sections of 67 AAH lesions from 19 patients were stained using monoclonal antibodies against Ki67 (MIB1), p53 (DO7), and c-erbB-2 (NCL-CB11). Ki67 was expressed in up to 10 per cent of AAH nuclei. Thirty-nine lesions (58 per cent) showed stainable p53 protein, while five (7 per cent) expressed membrane c-erbB-2 oncoprotein. These latter five lesions were all strongly positive for p53, and both p53 and c-erbB-2 staining was associated with increased cellular crowding and pleomorphism in AAH. These data demonstrate that AAH exhibits some genetic changes associated with malignancy and thereby support the hypothesis that AAH is premalignant.     

A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis

Atypical adenomatous hyperplasia (AAH) is considered the preinvasive lesion of pulmonary adenocarcinoma, and mutations of EGFR, HER2, and K-ras are involved in the early stage of lung adenocarcinoma carcinogenesis, also predicting clinical response to anti-EGFR small molecule inhibitors. We analyzed 18 cases of primary lung adenocarcinoma with concomitant AAH foci from 13 patients for mutations of EGFR (exons 18-21), HER2 (exons 19-20), and K-ras (exon 2) by direct sequencing polymerase chain reaction. Among mutated cases, concordant mutations of EGFR or K-ras in adenocarcinoma and related AAH were observed in 5 (63%) of 8 cases. In particular, 3 of 4 adenocarcinomas with EGFR mutations (all L858R point mutations in women, never or former smokers) had a concomitant and identical mutation in AAH, and 2 of 4 adenocarcinomas with K-ras mutations (both at codon 12 in women, a never and a current smoker) showed the same mutation in concomitant AAH. All cases were wild-type for HER2. Mutations of EGFR and K-ras genes represent an early event in lung adenocarcinomagenesis, and AAH convincingly seems to be a precursor lesion in a subset of cases of adenocarcinoma.     

Molecular alterations in atypical adenomatous hyperplasia occurring in benign and cancer-bearing lungs.

Atypical adenomatous hyperplasia (AAH) is considered to be a precursor lesion of the lung adenocarcinoma. Several genetic abnormalities have been reported in AAH associated with adenocarcinoma, but little is known about AAH associated with benign lung lesions. To address this we compared the molecular characteristics of AAH present in benign conditions to those coexisting with carcinoma. Seven cases of AAH from resected non-neoplastic lungs (AAH-B) and 12 cases from lungs resected for primary lung carcinoma (AAH-M) were analyzed for loss of heterozygosity (LOH) using 21 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes on chromosomes 3p, 5q, 7p, 9p, 10q, and 17p. Direct DNA sequencing for K-ras mutation was also performed. There was a broad range of LOH in both groups. No LOH was identified in 3 cases (25%) of AAH-M, but all cases of AAH-B showed LOH (P=0.26). Six cases (50%) of AAH-M and 3 cases (43%) of AAH-B showed loss at 1 marker (P=0.99). LOH at 2 or more markers was identified in 3 (25%) cases of AAH-M and 4 (57%) cases of AAH-B (P=0.32). LOH was most frequently detected on chromosomes 3p and 10q in both groups. The difference in overall fractional allelic loss between the 2 groups did not reach statistical significance. K-ras mutations were not identified in either group. Our results showed a significant overlap in LOH patterns between AAH with or without coexistent lung malignancy. Therefore, AAH may represent a smoking induced low-grade neoplastic lesion that may be a precursor lesion of only a subset of invasive lung adenocarcinoma.     

Lung adenocarcinoma associated with atypical adenomatous hyperplasia. A clinicopathological study with special reference to smoking and cancer multiplicity

Atypical adenomatous hyperplasia (AAH) of the lung has been proposed as a possible precursor lesion of adenocarcinoma of the lung. In the present study, we sought to clarify the clinicopathological characteristics of lung adenocarcinoma cases associated with AAH, with special reference to tobacco smoking and the presence of multiple primary carcinomas of pulmonary and extrapulmonary organs. We examined 123 surgically resected lung adenocarcinomas and conducted histopathological diagnoses for AAH and multiple primary pulmonary carcinomas. Clinicopathological characteristics such as age, sex, smoking index, survival, and the presence of extrapulmonary primary carcinomas were obtained from clinical records, and the associations among these factors were examined statistically. Sixteen lung adenocarcinoma patients had accompanying AAH (the AAH group) and 107 cases did not (the NAAH group). The incidence of primary carcinomas in extrapulmonary organs was higher in the AAH group (37.5%; 6/16) than in the NAAH group (12.5%; 13/107) (P = 0.01). Multiple primary lung cancers tended to be more frequent in the AAH group, but the difference was not statistically significant (P = 0.07). Although there was no difference in tobacco smoking between the two groups, all eight cases with multiple primary lung carcinomas were smokers. Furthermore, multiple primary lung carcinomas were found more frequently in smokers of the AAH group (37.5%; 3/8) than in the smokers of the NAAH group (7.2%; 5/69) (P = 0.04). The results suggested that constitutional or genetic factors might predispose patients to the development of AAH together with extrapulmonary primary carcinomas, and that smoking might contribute to the development of multiple primary lung adenocarcinomas, especially in patients with pre-existing AAH.     

Papillary adenoma of type II pneumocytes might have malignant potential

Papillary adenoma of type II pneumocytes is a rare tumour. It is considered to be a benign neoplasm and is derived from immature cells in the bronchioloalveolar epithelium, however, its biological nature has not been elucidated. We report a case of an adenomatous tumour; a papillary adenoma of type II pneumocytes, which we regard as possessing malignant potential. Light microscopically, as well circumscribed, papillary tumour of predominantly cuboidal cells resembling type II pneumocytes was found, but Clara type and ciliated cells were also present. Immunohistochemically, the tumour cells reacted positively with antibodies to surfactant apoproteins (A, B), carcinoembryonic antigen, cytochrome P-450 1A1-2 and 2B1-2. Ultrastructurally, many osmiophilic lamellar bodies and electron-dense granules were demonstrated. Semi-serial sections revealed signs of transbronchial dissemination and vascular invasion. Morphometry using 12-dimensional cluster analysis disclosed features of the tumour cells which resembled those of pneumocyte type II adenocarcinoma. These findings suggest that the present case has some malignant characteristics and originates from immature bronchiolar or alveolar cells, with a potential to develop into both type II pneumocyte and Clara cell type adenocarcinomas.     

Pulmonary preinvasive neoplasia

Advances in molecular biology have increased our knowledge of the biology of preneoplastic lesions in the human lung. The recently published WHO lung tumour classification defines three separate lesions that are regarded as preinvasive neoplasia. These are (1) squamous dysplasia and carcinoma in situ (SD/CIS), (2) atypical adenomatous hyperplasia (AAH), and (3) diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIP-NECH). SD/CIS is graded in four stages (mild, moderate, severe, and CIS), based upon the distribution of atypical cells and mitotic figures. Most airways showing SD/CIS demonstrate a range of grades; many epithelia are hard to assess and the reproducibility of this complex system remains to be established. Detailed criteria are, however, welcome and provide an objective framework on which to compare various molecular changes. Alterations in gene expression and chromosome structure known to be associated with malignant transformation can be demonstrated in CIS, less so in dysplasias, but also in morphologically normal epithelium. The changes might be sequential, and their frequency and number increase with atypia. Less is known of the "risk of progression" of SD/CIS to invasive "central" bronchial carcinoma. It may take between one and 10 years for invasion to occur, yet the lesion(s) may be reversible if carcinogen exposure ceases. AAH may be an important precursor lesion for peripheral "parenchymal" adenocarcinoma of the lung: the "adenoma" in an adenoma-carcinoma sequence. There is good morphological evidence that AAH may progress from low to high grade to bronchioloalveolar carcinoma (BAC; a non-invasive lesion by definition). Invasion then develops within BAC and peripheral lung adenocarcinoma evolves. The molecular events associated with this progression are not well understood and studies are hampered by a lack of clear criteria to distinguish high grade AAH from BAC. Nonetheless, as with SD/CIS, the patterns of expression of tumour associated genes are consistent with neoplastic progression. We have little idea of the incidence of AAH in the normal or "smoking" populations. It is found more frequently in cancer bearing lungs, especially in those with adenocarcinoma, and is more common in women. No data are available on the risk of progression of AAH. DIPNECH is an exceptionally rare lesion associated with the development of multiple carcinoid tumours. Almost nothing is known of its biology. Knowledge of these lesions will be crucial in the design and understanding of lung cancer screening programmes, where it is likely that the morphological and, more importantly perhaps, the molecular characteristics of these lesions will provide useful targets for detection and possibly even treatment.     

Genetic Analysis of Prostatic Atypical Adenomatous Hyperplasia (Adenosis)

Atypical adenomatous hyperplasia (AAH) of the prostate, a small glandular proliferation, is a putative precursor lesion to prostate cancer, in particular to the subset of well-differentiated carcinomas that arise in the transition zone, the same region where AAH lesions most often occur. Several morphological characteristics of AAH suggest a relationship to cancer; however, no definitive evidence has been reported. In this study, we analyzed DNA from 25 microdissected AAH lesions for allelic imbalance as compared to matched normal DNA, using one marker each from chromosome arms 1q, 6q, 7q, 10q, 13q, 16q, 17p, 17q, and 18q, and 19 markers from chromosome 8p. We observed 12% allelic imbalance, with loss only within chromosome 8p11-12. These results suggest that genetic alterations in transition zone AAH lesions may be infrequent. This genotypic profile of AAH will allow for comparisons with well-differentiated carcinomas in the transition zone of the prostate.     

Preneoplastic lesions of pulmonary carcinoma

The World Health Organization (WHO) 2004 classification includes 3 categories of pulmonary preneoplastic lesions, including squamous dysplasia and carcinoma in situ (CIS) for squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) for the majority of adenocarcinomas and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) for carcinoids. The distinction of the 3 grades of squamous dysplasia and CIS is mainly based on the degree by which the basal cell zone is expanded, the degree of cellular atypia and the level of mitoses. The category AAH consists of a proliferation of atypical epithelial cells with Clara cells or type 2 pneumocyte features. They grow along the alveolar septae in a lepidic fashion, sometimes reaching into the terminal bronchioles. In contrast to the newly described adenocarcinoma in situ (AIS), AAH is smaller (≤ 5 mm), has a lower cell density and a lower degree of cellular atypia. The putative cancer stem cells of peripheral adenocarcinomas reside in the bronchioloalveolar duct junction, while those of central squamous cell carcinomas are located in the basal cell compartment of the bronchi. This review provides an overview of the current knowledge on preneoplastic lesions of the lungs and their clinical impact.     

Expression profile of early lung adenocarcinoma: identification of MRP3 as a molecular marker for early progression

Early lung adenocarcinoma is well-recognized as a small-sized non-invasive adenocarcinoma or localized non-mucinous bronchioloalveolar carcinoma (LNMBAC); however, the molecular events associated with these early lesions are not clear. To determine the genes involved in tumorigenesis at the early stage of lung adenocarcinoma, we compared the mRNA expression profiles of LNMBAC and normal lungs with an oligonucleotide array. Immunohistochemical analyses were performed to confirm the expression of detected genes. We identified 183 differentially expressed genes, of which 15 were up-regulated and 168 down-regulated. Among them, most up-regulated genes, such as AQP3 and Claudin-4, were expressed in both adenocarcinoma cells and type II alveolar pneumocytes, corresponding to the histological similarity between these cell types. However, multidrug resistant protein 3 (MRP3) was only expressed on tumour cell membranes and not in type II alveolar pneumocytes, as confirmed by immunohistochemistry. Moreover, the number of MRP3-positive cells significantly increased from AAH (the precursor lesion of lung adenocarcinoma) to LNMBAC. We conclude that MRP3 could be a novel molecular marker for LNMBAC, whose expression increases during the early progression of tumourigenesis.     

Expression patterns of type II pneumocyte apical surface glycoconjugates in lung adenocarcinoma cells

 Monoclonal antibodies and lectins were used to examine the expression patterns of apical membrane oligosaccharide sequences specific to type II pneumocytes in atypical adenomatous hyperplasia (AAH) and lung cancer. Atypical cells of AAH and papillary adenocarcinoma cells expressed abundant sialyl Thomsen-Friedenreich (TF) antigen: this was not observed in acinar adenocarcinoma, bronchioloalveolar carcinoma with mucin production or squamous cell carcinoma. Sialyl Tn antigens was also detected on a few cells in AAH and papillary adenocarcinomas. Asialo TF and Tn antigen were not observed on the surface of carcinoma cells of any type. Alpha(α)2,3-linked sialic acids predominated in type II pneumocyte, AAH and papillary adenocarcinoma, whereas ciliated columnar cells expressed α2,6-linked sialic acids. Lewis^x and sialyl Lewis^x antigens capped the TF antigen in both O- and N-linked side chains on the surface of AAH and papillary adenocarcinoma cells, but were not expressed by type II pneumocytes. The findings demonstrate that papillary adenocarcinoma cells resemble type II pneumocytes in that they express abundant sialyl TF surface antigen, but they also express TF-related antigens not found in type II pneumocytes. Apical surface glycoconjugates of AAH have structural characteristics shared by both type II pneumocytes and papillary adenocarcinoma cells. Received: 6 July 1998 / Accepted: 25 September 1998     

Clinicopathologic and Immunohistochemical Characteristics of Goblet Cell Type Adenocarcinoma of the Lung

Twenty-two resected goblet cell type adenocarcinomas of the lung were examined clinicopathologically and immunohistochemically. The stage and survival curve of goblet cell type adenocarcinomas were compared with those of 44 cases of pure or mixed Clara cell and bronchial surface epithelial cell (Clara and BSE) type adenocarcinomas. Each case of goblet cell type was matched with two cases of Clara and BSE type as to sex, age and date of surgery. In goblet cell type adenocarcinomas, lymph node metastasis was less frequently and intrapulmonary metastasis was more frequently detected than in other types of adenocarcinomas (p < 0.001 and p < 0.05, respectively). Goblet cell type adenocarcinomas showed better prognoses than Clara and BSE type adenocarcinomas. However, the estimated survival curves of those two groups become similar after adjustment of the TNM condition using Cox's proportional-hazard general linear model. This result indicated that the longer survival of goblet cell type adenocarcinoma was due to the characteristic distribution of TNM conditions, that is, unique local growth and low incidence of lymph node metastasis. When goblet cell type adenocarcinoma was macroscopically classified into two types, i.e. solitary peripheral nodule type (nodular type) and multifocal nodular type or consolidation of all or part of a lobe (diffuse type), the nodular type had better prognosis than the diffuse type (p < 0.05). Immunohistochemically, 83%, 11%, and 0% of goblet cell type adenocarcinomas were positive for NCC-CO-450, carcinoembryonic antigen (CEA), and surfactant apoprotein, respectively. Most Clara and BSE type adenocarcinomas were negative for NCC-CO-450, but positive for CEA and surfactant apoprotein. NCC-CO-450 was considered to be a good immunohistochemical marker of goblet cell type adenocarcinoma of the lung. These results indicated that goblet cell type tumors are different from most adenocarcinomas of other types both clinicopathologically and immunohistochemically. Acta Pathol Jpn 41: 737-743, 1991.     

Is high‐grade adenomatous hyperplasia an early bronchioloalveolar adenocarcinoma?

Atypical adenomatous hyperplasia (AAH) is a probable forerunner of bronchioloalveolar carcinoma (BAC) and pulmonary adenocarcinoma (AC) of mixed type. The present study analysed four low-grade AAHs, 13 high-grade AAHs, two BACs, nine mixed ACs, and one squamous cell carcinoma derived from 13 patients using comparative genomic hybridization. The average number of chromosomal aberrations was 1.2 in low-grade AAH, 9.6 in high-grade AAH, and 12.5 in AC. A high degree of overlap of genetic changes was found in high-grade AAH, BAC, and AC within individual patients. The high number of aberrations and the degree of shared aberrations found in high-grade AAH and AC raises questions about the separation of these two entities. In addition, in view of the monoclonal origin of multiple foci within the same patient, AAH may not be a precursor of AC in some cases, but rather may represent intraepithelial spread.     

Atypical adenomatous hyperplasia (adenosis) of the prostate: DNA ploidy analysis and immunophenotype

Atypical adenomatous hyperplasia (AAH) of the prostate is a microscopic proliferation of small acini that may be mistaken for adenocarcinoma. Although some data suggest that AAH is associated with adenocarcinoma arising in the transition zone, the clinical significance of this lesion is uncertain. Therefore we studied the DNA ploidy pattern and immunophenotype of AAH as compared with nodular hyperplasia and well-differentiated adenocarcinoma in 23 formalin-fixed, paraffin-embedded, whole-mounted retropubic prostatectomies. Representative sections were immunostained for keratin 34beta-E12, chromogranin, bcl-2, c-erbB-2, ki67-MIB1, and factor VIII (microvessel density). DNA ploidy was determined by image analysis and Feulgen-stained sections. There were rare scattered immunoreactive cells for chromogranin, bcl-2, and c-erbB-2 in nodular hyperplasia and AAH (mainly in the basal cell compartment) and in carcinoma. The ki67-MIB1 labeling index was different between nodular hyperplasia and AAH (p<0.001) and carcinoma (p=0.003) but not between AAH and carcinoma (p=0.203). Microvessel density was different between AAH and carcinoma (p=0.001) but not between nodular hyperplasia and AAH (p=0.105) or carcinoma (p=0.0820). All foci of nodular hyperplasia, AAH, and carcinoma were diploid. Ploidy status and our selected panel of antibodies did not discriminate among these 3 entities reliably.