Foci Of Atypical Adenomatous Hyperplasia Research Articles

Genomic Evolution in a Patient With Lung Adenocarcinoma With a Germline EGFR T790M Mutation

IntroductionA subset of lung adenocarcinomas (ADs) has been found to have somatic activating mutations in the tyrosine kinase domain of the EGFR gene, associated with response to EGFR tyrosine kinase inhibitor therapy. Rare germline mutations within this domain, including EGFR T790M, have been associated with genetic susceptibility to lung ADs. Using high-throughput sequencing, we elucidate the genomic evolution in tissues from a patient with lung AD carrying a germline EGFR T790M mutation. MethodsWe performed microdissection, targeted panel, and whole-exome sequencing to molecularly characterize multiple foci of atypical adenomatous hyperplasia (AAH), in situ and invasive components of AD, normal lung tissue, and whole blood from the patient. Normal lung tissue was analyzed for potential acquired somatic genome alterations (“field effect”). ResultsAll lesions harbored a secondary somatic EGFR mutation, either L858R or L861Q, in addition to the germline T790M mutation. Clear overlap was observed between the somatic profiles of in situ and invasive AD components, confirming clonal relatedness. AAH lesions shared few to no somatic alterations with the AD, suggesting clonal independence. No robust evidence of field effect was identified in the normal lung tissue. ConclusionsSomatic EGFR mutations are early events in the pathogenesis of lung ADs arising in the context of germline EGFR T790M. Synchronous AAH lesions seem to be independent. Stepwise genomic evolution is observed in association with invasiveness of the neoplastic cell population.

Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate

Atypical adenomatous hyperplasia (AAH) of the prostate is characterized by lobular proliferation of closely packed small acini. It is hypothesized that AAH is a precursor lesion for low-grade prostate cancer arising from the transition zone. Telomere dysfunction is common during malignant transformation of epithelia. In this study, we investigate telomere shortening in AAH (n = 93), high-grade prostatic intraepithelial neoplasia (HGPIN) ( n = 68), and prostatic adenocarcinoma (PCA) ( n = 70) using quantitative fluorescence in situ hybridization. Twenty percent (19 of 93) of AAH specimens, 68% (46 of 68) of HGPIN, and 83% (58 of 70) of PCA showed significant telomere shortening. Thirty-two percent of AAH lesions had α-methylacyl-CoA racemase (AMACR) expression, a sensitive and specific marker for HGPIN and PCA. AMACR expression in AAH was seen more frequently in AAH foci with telomere shortening or coexisting PCA. Our findings indicate that a subset of AAH lesions have telomere shortening and AMACR expression, suggesting that these foci may be precursors for PCA.

Is atypical adenomatous hyperplasia of the prostate a precursor lesion?

Alpha-methylacyl-CoA racemase (AMACR) is highly expressed in prostatic adenocarcinoma. The precursor nature of atypical adenomatous hyperplasia (AAH) is uncertain. One hundred twenty-one AAH foci from 101 patients who underwent transurethral prostatic resection or prostatectomy were immunohistochemically analyzed for AMACR, high molecular weight cytokeratin 34βE12, and p63 expression by a triple antibody (PIN4) cocktail stain. Sixty-eight foci (56%) of AAH showed no AMACR immunostaining. Fourteen cases (12%) showed weak AMACR immunoreactivity in 1-9% of lesional cells. Sixteen cases (13%) showed strong immunopositivity for AMACR in >50% of lesional cells. AMACR expression in AAH was significantly higher in cases in which coexisting PCA was present, compared with its expression in AAH foci without coexisting PCA (P = 0.03). Strong diffuse AMACR positivity in over 50% of lesional cells was seen almost exclusively in AAH foci with coexisting PCA (P = 0.002). AMACR expression in AAH showed no correlation with patient age (P = 0.38), specimen type (P = 0.35), prostate weight (P = 0.80), zonal location (P = 0.50), distance to cancer (P = 0.28), Gleason score (P = 0.06), or pathologic stage (P = 0.23). Increased AMACR expression showed a negative correlation with the size of AAH foci (P = 0.03). All AAH lesions showed fragmented basal cell layers, highlighted by p63 and high molecular weight cytokeratin staining. A significant percentage of AAH cases show stronger and more extensive AMACR expression when associated with prostatic adenocarcinoma, as compared to AAH foci found without coexisting prostate cancer. Our data provide additional evidence linking AAH to prostatic adenocarcinoma.

A Subset of Lung Adenocarcinomas and Atypical Adenomatous Hyperplasia–Associated Foci Are Genotypically Related

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.

Genetic relationship among atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and adenocarcinoma of the lung

Atypical adenomatous hyperplasia (AAH) has been recently defined by WHO as a small lesion, not exceeding 5mm in major axis, composed of slightly enlarged alveolar septa lined by pneumocytes with plump, atypical nuclei. AAH is frequently found in tissue surrounding lung adenocarcinoma and is considered a precursor of this subtype of lung cancer by many Authors. However, the genetic relationship between adenocarcinoma and the associated foci of AAH is not well defined. In particular, it is not clear whether multiple foci of AAH and of adenocarcinoma in the same patients are clonally related to each other or represent independent neoplastic foci. To clarify if AAH and the associated cancer are clonally related, we evaluated the genetic distance between these two lesions in 16 patients, using direct sequencing of mitochondrial DNA (D-loop region). Furthermore, LOH analysis for 7 microsatellites (D3S1478 at 3p21, D3S1300 at 3p14.2, D9S942 at 9p21, D5S346 at 5q21, D17S261 at 17p13.1, D18S46 at 18q21, D19S246 at 19q13.2) was also performed. Our results indicate that, in at least 9 out of 13 informative cases (69.2%), AAH and the associated cancer were not clonally related as they showed a different mutation pattern in the mitochondrial D-loop region. These findings were also in agreement with the LOH data which showed losses in different loci in at least three cases. On the contrary an identical LOH pattern between BAC and AAH was found in one case. Similar but not identical LOH pattern between AAH and related tumors was found in other three cases. Therefore, our results suggest that AAH and the associated cancer are genetically independent in agreement with the concept of cancerization field. Less frequently AAH foci could represent an early spread of cells from the main tumor, rather than a precursor lesion.

Distinguishing atrophy and high-grade prostatic intraepithelial neoplasia from prostatic adenocarcinoma with and without previous adjuvant hormone therapy with the aid of cytokeratin 5/6.

We evaluated the sensitivity and specificity of cytokeratin (CK) 5/6 for distinguishing foci of atrophy from prostatic adenocarcinoma with and without previous hormonal adjuvant therapy and observed the intensity and pattern of staining in mimickers of prostatic adenocarcinoma (basal cell hyperplasia, atypical adenomatous hyperplasia, and tangentially cut high-grade prostatic intraepithelial neoplasia [PIN]). We reviewed 146 acinar proliferations in 81 specimens (radical prostatectomy, previously untreated, 41; radical prostatectomy, following androgen-deprivation therapy, 11; transurethral resection, previously untreated, 29). All benign acinar proliferations stained positively for CK5/6, with immunoreactivity restricted to basal cells. Untreated and androgen-deprived prostatic adenocarcinomas were invariably negative. The pattern of staining was continuous in 79% of the atrophy cases (15/19), and all foci stained with CK5/6. Characteristic double-layer staining in basal cell hyperplasia was observed in 93% of cases (13/14), and foci of high-grade PIN had a characteristic "checkerboard" staining with areas of discontinuity. Foci of atypical adenomatous hyperplasia showed continuous staining, including cauterized acini in 53% of cases (8/15), with a fragmented basal cell layer pattern in 47% of cases (7/15). CK5/6 staining of the basal cells in foci of atrophy is sensitive and specific for excluding prostatic adenocarcinoma with and without androgen-deprivation effect.

Distinguishing Atrophy and High-Grade Prostatic Intraepithelial Neoplasia From Prostatic Adenocarcinoma With and Without Previous Adjuvant Hormone Therapy With the Aid of Cytokeratin 5/6

We evaluated the sensitivity and specificity of cytokeratin (CK) 5/6 for distinguishing foci of atrophy from prostatic adenocarcinoma with and without previous hormonal adjuvant therapy and observed the intensity and pattern of staining in mimickers of prostatic adenocarcinoma (basal cell hyperplasia, atypical adenomatous hyperplasia, and tangentially cut high-grade prostatic intraepithelial neoplasia [PIN]). We reviewed 146 acinar proliferations in 81 specimens (radical prostatectomy, previously untreated, 41; radical prostatectomy, following androgen-deprivation therapy, 11; transurethral resection, previously untreated, 29). All benign acinar proliferations stained positively for CK5/6, with immunoreactivity restricted to basal cells. Untreated and androgen-deprived prostatic adenocarcinomas were invariably negative. The pattern of staining was continuous in 79% of the atrophy cases (15/19), and all foci stained with CK5/6. Characteristic double-layer staining in basal cell hyperplasia was observed in 93% of cases (13/14), and foci of high-grade PIN had a characteristic “checkerboard” staining with areas of discontinuity. Foci of atypical adenomatous hyperplasia showed continuous staining, including cauterized acini in 53% of cases (8/15), with a fragmented basal cell layer pattern in 47% of cases (7/15). CK5/6 staining of the basal cells in foci of atrophy is sensitive and specific for excluding prostatic adenocarcinoma with and without androgen-deprivation effect.

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.

The association between atypical adenomatous hyperplasia and primary lung cancer.

Atypical adenomatous hyperplasia (AAH) has been suggested as the adenoma in an adenoma–carcinoma sequence in the lung periphery. From 1989–1998, we undertook a systematic, prospective search for AAH in lungs resected for cancer. AAH was found in 67 of 554 patients (12.1%) with primary lung carcinoma (9.2% in male patients and 19.0% in females). AAH was found in lungs bearing adenocarcinoma (23.2%) more frequently than with large cell undifferentiated carcinoma (12.5%) or squamous carcinoma (3.3%). A greater percentage of females with adenocarcinoma had AAH (30.2%) than did males with adenocarcinoma (18.8%). Numbers of AAH ranged from 1–42 per patient and more patients had small numbers of AAH, although 12 patients had 6 or more AAH foci. Larger numbers of AAH tended to be found in adenocarcinoma-bearing lungs. Ten of the 67 patients with AAH and primary lung carcinoma (15%) had multiple primary cancers (range 2–6), all of which were adenocarcinoma. Synchronous cancers were rare in lung tumour-bearing resections without AAH. Patients with AAH show no difference in post-operative survival to those without, for all stages of carcinoma and for Stage I disease alone. This study provides evidence for a strong association between atypical adenomatous hyperplasia and primary lung adenocarcinoma and lends weight to the AAH/adenoma-carcinoma hypothesis. © 2000 Cancer Research Campaign

Epidemiology of prostate cancer.

Malignant transformation of the prostate and progression of carcinoma appear to be the consequence of a complex series of initiation and promotional events under genetic and environmental influences. Increased incidence of the condition may be the result of improved detection, greater awareness of the condition, and possibly an increased life expectancy accompanied by a decrease in competing causes of death rather than a true increase in the prevalence of the disease. The marked racial and geographic differences are probably multifactorial, with genetic, environmental, and possibly social influences affecting progression of the disease. Among several risk factors, evidence for the familial inheritance of some prostate cancers is compelling. Dietary influences, hormonal milieu, and the role of environmental carcinogens are currently under intense investigation. As further risk factors are identified, it will become increasingly important to identify individuals at increased risk for the disease. These men should undergo regular evaluation with state-of-the-art methods.

The Extent and Zonal Location of Prostatic Intraepithelial Neoplasia and Atypical Adenomatous Hyperplasia: Relationship with Carcinoma in Radical Prostatectomy Specimens

High grade prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH) are considered putative precursors of prostatic adenocarcinoma. We determined the extent and zonal distribution of PIN and AAH in totally-embedded radical prostatectomies with prostate cancer, including 195 cases with PIN and 217 with AAH. PIN was identified in 86% of the cases. The mean volume of PIN was 1.32 cc (range, 0-8.12 cc), and was greater for PIN within 2 mm of cancer (mean, 1.0 cc) than for PIN more than 2 mm from cancer (mean, 0.3 cc). PIN was usually multicentric (64.5% of cases) and located in the non-transition zone (63%) or all zones (36%). The volume of PIN was positively correlated with the volume of cancer, patient age, pathologic stage and Gleason score. AAH was identified in 23.0% of the cases, and was more frequent in the transition zone (19.8% of cases) than in the non-transition (peripheral and central) zone (6.0%). The number of foci of AAH in the transition zone was always greater than that in the non-transition zone. AAH was frequently multicentric (46% of cases), especially in the transition zone (47% of transition zone cases) compared with the non-transition zone (23% of non-transition zone cases). The mean volume of AAH was 0.029 cc (range, 0-1.29 cc), and was much higher in the transition zone than in the non-transition zone. AAH was more common in older patients and those with greater prostatic weight, higher prostatic volume, greater percent of nodular hyperplasia, greater volume of cancer, greater percent of Gleason patterns 4 and 5 cancer, higher volume of prostatic intraepithelial neoplasia and higher serum prostate specific antigen concentration. Our results indicate that the extent and zonal distribution of high grade PIN and carcinoma are strongly associated, and that PIN is frequently multicentric; this supports the hypothesis that PIN is a premalignant lesion. AAH and carcinoma show a weak but significant association; if AAH is a premalignant lesion, it probably is associated with a subset of cancers arising in the transition zone.

Atypical adenomatous hyperplasia of the prostate. Relationship with carcinoma in 217 whole-mount radical prostatectomies.

Atypical adenomatous hyperplasia (AAH) of the prostate is a microscopic proliferation of small glands that may be mistaken for adenocarcinoma. The extent and multicentricity of this histopathologic lesion have not been fully defined, and the spatial relationship with carcinoma has not been described in whole-mount surgical specimens. We sought to determine whether the extent and zonal location of AAH is related to prostate cancer by evaluating 217 totally embedded radical prostatectomy specimens with cancer. All but 17 patients had clinically localized cancer, and none had received preoperative therapy. The number of foci and volume of AAH were measured using a grid-counting method; proximity to cancer was recorded as either less than or equal to 2 mm from cancer or greater than 2 mm from cancer. AAH was identified in 23.0% of cases and was more frequent in the transition zone (19.8% of cases) than in the nontransition (peripheral and central) zone (6.0%). It was found within 2 mm of cancer in 34% of cases of AAH, including 30% of cases in the transition zone and 31% cases in the nontrasition zone. The number of foci of AAH in the transition zone was always greater than that in the nontransition zone, regardless of whether it was within 2 mm of cancer or more than 2 mm from cancer. AAH was frequently multicentric (46% of cases), especially in the transition zone (47% of transition zone cases) compared with the nontransition zone (23% of nontransition zone cases). The mean volume of AAH was 0.029 cc (range, 0-1.29 cc) and was much higher in the transition zone than the nontransition zone, regardless of whether it was within 2 mm of cancer or more than 2 mm from cancer. In cases of AAH within 2 mm of cancer, the volume was lower than in cases more than 2 mm from cancer; this was true regardless of zonal location. AAH was more common in older patients and in those with greater prostatic weight, higher prostatic volume, greater percentage of nodular hyperplasia, greater volume of cancer, greater percent of Gleason patterns 4 and 5 cancer, higher volume of prostatic intraepithelial neoplasia, and higher serum prostate-specific antigen level. There was no correlation of number of foci of AAH or volume of AAH with pathologic stage, seminal vesicle invasion, Gleason primary pattern or score, nuclear grade, perineural invasion by tumor, or DNA ploidy. Our results indicate that AAH is usually found iin the transition zone in association with nodular hyperplasia and is often multicentric. The extent and zonal distribution of AAH and carcinoma show a weak but significant association.