Critical analysis of histologic criteria for grading atypical (dysplastic) melanocytic nevi

Low concordance in grading atypical (dysplastic) melanocytic nevi (AMN) has been reported, and no systematic evaluation is available. We studied 123 AMN with architectural and cytologic atypia (40 associated with atypical-mole syndrome), classified according to standard criteria by 3 independent observers. Histologic variables included junctional and dermal symmetry, lateral extension, cohesion and migration of epidermal melanocytes, maturation, regression, nuclear features, nuclear grade, melanin, inflammatory infiltrate location, and fibroplasia. AMN (43 junctional and 80 compound) were graded mild (31), moderate (61), and severe (31). AMN-severe correlated with 3 or more nuclear abnormalities (especially pleomorphism, heterogeneous chromatin, and prominent nucleolus) and absence of regression, mixed junctional pattern, and suprabasilar melanocytes on top of lentiginous hyperplasia. AMN-severe diagnostic accuracy was 99.5% using these criteria, but only the absence of nuclear pleomorphism differentiated AMN-mild from AMN-moderate. No architectural features distinguishing AMN-mild from AMN-moderate were selected as significant by the discriminant analysis. AMN from atypical-mole syndrome revealed subtle architectural differences, but none were statistically significant in the discriminant analysis. Histologic criteria can reliably distinguish AMN-severe but fail to differentiate AMN-mild from AMN-moderate. AMN from atypical-mole syndrome cannot be diagnosed using pathologic criteria alone.     

Grading of atypia in nevi: correlation with melanoma risk.

Nevi with architectural disorder and cytologic atypia of melanocytes (NAD), aka "dysplastic nevi," have varying degrees of histologic abnormalities, which can be considered on a spectrum of grades of atypia. Somewhat controversial and subjective criteria have been developed for grading of NAD into three categories "mild," "moderate," and "severe." Grading involves architectural and cytological features, which often correlate with each other. Architectural criteria were intraepidermal junctional extension beyond any dermal component, complex distortion of rete ridges, and dermal fibrosis. Cytological criteria were based on nuclear size, dispersion of chromatin, prominence of nucleoli, hyperchromasia and variation in nuclear staining. Few tests have been made of the relationship between specific grades of atypia and patient risk for melanoma. Retrospective review of pathology reports was performed on 20,275 nevi examined between 1989 and 1996. From the total, 6,275 were diagnosed as NAD, which were in 4,481 patients. These patients were divided into those whose worst NAD was mild (2,504), moderate (1,657), or severe (320). Review of accession data revealed that a personal history of melanoma was present in 5.7% of patients with mild, 8.1% with moderate, and 19.7% with severe atypia. The male/female ratios were similar in each group. In the three groups, the mean ages of men were similar and of women were similar, but the mean age of men tended to be 6-11 yrs. older than women in each group. Family histories of melanoma were not considered. The odds ratio as a measure of association between NAD and personal history of melanoma, shows an odds ratio of 4.08 (2.91-5.7) for NAD-severe versus NAD mild, odds ratio 2.81 (2-3.95) for NAD-severe versus NAD-moderate and odds ratio 1.45 (1.13-1.87) for NAD moderate versus NAD-mild. These data show that the probability of having personal history of melanoma, for any given NAD patient, correlates with the NAD grade. Likewise, the risk of melanoma is greater for persons who tend to make nevi with high grade histological atypia.     

IgA nephropathy. Correlation of clinical and histologic features

The clinical and histologic features of 81 patients with IgA nephropathy were analyzed. Azotemia was present in 32 per cent of the patients, proteinuria was present in 88 per cent, and gross or microscopic hematuria was present in all of the patients tested. The median age of histologic diagnosis was 27 years. The median age at onset of clinical signs was 20 years. There was no increased incidence in any HLA-A or -B antigen within the patient population over our control population. All patients had glomerular mesangial IgA deposition (by definition) greater than or equal to IgG or IgM. Histologic changes were quantitated and ranged from normal to necrotizing and/or crescentic glomerulonephritis. Many patients (48 per cent) had mild or moderate generalized glomerlular hypercellularity. Nonparametric statistical analysis showed strong correlations among patient age at histologic diagnosis, creatinine, proteinuria, global glomerular sclerosis, and interstital fibrosis. Our analysis suggests that IgA nephropathy is an indolent disease generally beginning in childhood. It is a cause of renal insufficiency in a significant number of patients. Interpretation of this series and other reported studies suggests that most cases of IgA nephropathy in the United States are best considered idiopathic but that hereditary and secondary forms may exist.     

Expression of the proteoglycans versican and mel-CSPG in dysplastic nevi

Nevi with architectural disorder and cytologic atypia of melanocytes (NAD) (also called dysplastic nevi) have been controversial with regard to their relationship with melanoma risk and to their gradation in 3 degrees of atypia. Versican and the melanoma-associated proteoglycan (mel-CSPG) are 2 major proteoglycans expressed by malignant melanoma, and they have a role in the regulation of cell adhesion, migration, and differentiation. We evaluated the differences in versican and mel-CSPG expression in nevi, NAD with several degrees of atypia, and primary malignant melanoma. Immunoreactivity for versican was negative in benign melanocytic nevi, positive in NAD (ranging from weakly to intensely positive), and intensely positive in malignant melanoma. Immunostaining for mel-CSPG was negative in benign melanocytic nevi and mild to moderately positive in NAD and melanoma. Our results suggest that versican expression may be of value for distinguishing NAD from benign melanocytic nevi and for distinguishing severe NAD from mild and moderate NAD.     

1,2-Dibromo-3-chloropropane (DBCP)-induced nuclear atypia in rat kidney

The reversibility of the nematocide 1,2-dibromo-3-chloropropane (DBCP)-induced renal injury was studied in adult male F344 rats. After a single dose of 200 mg DBCP/kg body weight, rats were sacrificed at 1, 3, 6, 9, 14, 28, and 196 days. Twenty-four hours after DBCP treatment, the animals showed signs of acute renal insufficiency, which, based on serum chemistry and urinalysis results, was reversed by the 14th day. Morphologic findings consisted of severe acute tubular necrosis, which was localized to the juxtamedullary cortex. The lesion was recognizable at 24 hrs and fully developed at 3 days post-exposure. The proximal convoluted tubuli were primarily affected, but there were also spotty necroses in distal convoluted tubuli and loops of Henle. Beginning regeneration was evident at 3 days post-exposure. Multiple mitoses, some of them abnormal, were seen. Four weeks after treatment some mitotic activity was still present, but the regeneration of the tubular epithelium was largely completed. There were several dilated, distorted tubuli lined with abnormal epithelial cells with large, hyperchromatic nuclei. Interstitial fibrosis was mild and there was no interstitial inflammation. Twenty-eight weeks post-exposure the nuclear atypia persisted in the tubular epithelium. Glomerular findings were minimal and consisted of focal hyperplasia of the epithelial cells of the parietal layer of Bowman's capsule and shrinking of the glomerular tufts at 4 weeks post-exposure. At 28 weeks post exposure only rare foci of glomerulosclerosis were seen. Epithelial cells of the renal pelvis showed minimal nuclear and cytoplasmic swelling 24 hrs after DBCP exposure. Urothelial atypia was not present. The results indicate that a single dose of DBCP is capable of producing nuclear atypia that persists in the renal tubuli beyond the regenerative phase. Follow-up of patients that have been chronically exposed to DBCP with periodic examination of urinary cytology is suggested.     

Epithelioid angiomyolipoma of kidney with atypical nuclear features and intranuclear inclusions on cytology

Described herein are the cytological findings of epithelioid angiomyolipoma (EAML) of the kidney with atypical nuclear features mistaken for renal cell carcinoma (RCC) in a 61‐year‐old male patient. Aspirates from this large renal mass were cellular and showed epithelioid cell clusters with focally crowded nuclei showing moderate anisonucleosis, small nucleoli, and prominent eosinophilic intranuclear inclusions. Failure to recognize the scanty adipose tissue component and preponderance of epithelioid cells with nuclear pleomorphism lead to a diagnosis of RCC on cytology. On histology, the tumor was essentially composed of epithelioid and spindle cells that showed the typical immunoprofile of an angiomyolipoma and only occasional foci of typical AML were seen. The hilar lymph node was involved in contiguity. However, in view of lack of obvious features of malignancy, the tumor was labeled as EAML with atypical features. Immunocytochemistry on the destained cytology aspirates revealed strong smooth muscle actin staining of all cells. To conclude, EAML can mimic a RCC. In such instances, lack of arborizing vasculature, absence of cytoplasmic fatty vacoulation, crowded nuclei with intranuclear inclusions, and lack of prominent nucleoli along with typical immunophenotype of EAML may assist in the cytology diagnosis. Diagn. Cytopathol. 2011;39:278–282. © 2010 Wiley‐Liss, Inc.     

Correlation of types of cortical grain structure with architectural features of the human skull

Seven grain-form relationships, as indicated by the split-line patterns, are recognized in the cortical bone of the adult human skull: (1) random pattern of braincase, (2) planes and (3) ridges with elongated grain, (4) troughs with transverse grain, (5) concavities with circular grain, (6) edges, and (7) spines. Concavities may show superimposed trough or ridge structure, and troughs may be marked by localized ridges and planes. That is, trough patterns are dominant over concavity patterns, and ridge patterns are dominant over both trough and concavity patterns. Finally, there are a few small cranial areas that are random distributions in some skulls and planes in others; the skull vault proper, however, except for the forehead region and internal sagittal markings, has a random pattern throughout. The mechanical significance of the various patterns and the areas on which they are found are discussed and explained on the basis of principles of mechanics and architecture. The form-texture relationships are discussed as architectural features of the skull, and their adequacy and limitations are analyzed in terms of their reaction to force systems and their proneness to fracture.     

Anterior buccal mandibular depression (ABMD) anatomic and histologic features

Summary The anterior buccal mandibular depression (ABMD) is a bilateral symmetrical depression located anterior to the mental foramen and extends under the alveoli of the first premolar to the central incisor. The prevalence, dimensions and contents of the ABMD in cadavers of fetuses and adult modern humans were evaluated. ABMD was found in all fetuses and in 31.8% of adults. The average dimensions of the ABMD in adults were depth 2.36 mm, width 5.44 mm and length 12.43 mm. The present study contributes to a better evaluation of the differential diagnosis and treatment planning in the anterior region of the mandible. A possible etiology for the development of ABMD is suggested.

---

La dépression orale antérieure de la mandibule (DOAM). Constatations anatomiques et histologiques

Résumé La dépression orale antérieure de la mandibule (DOAM) est une dépression bilatérale et symétrique située en avant du foramen mentonnier, s'étendant sous les alvéoles de la première prémolaire à l'incisive centrale. La prévalence, les dimensions et le contenu de cette dépression ont été appréciés sur les cadavres de foetus et d'adultes. La dépression a été trouvée chez tous les foetus et chez 31,8 % des adultes. Ses dimensions moyennes chez l'adulte sont 2,36 mm de profondeur, 5,44 mm de largeur et 12,43 mm de longueur. La présente étude contribue à une meilleure évaluation du diagnostic différentiel et de la planification opératoire au niveau de la partie antérieure de la mandibule. Une cause possible au développement de cette dépression est suggérée.

     

Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas

We studied the inverse relationship between HER-2 and estrogen (ER) and progesterone (PR) receptors using HER-2 testing and correlated HER-2 status with histologic features in 3,655 unselected invasive breast carcinomas. Immunohistochemical analysis for ER, PR, and HER-2 and fluorescence in situ hybridization for HER-2 were performed. ER and PR expression were decreased significantly in HER-2+ tumors compared with HER-2- tumors (ER, 49.1% vs 78.17%; PR, 24.3% vs 53.13%). Even among HER-2+ tumors, the rate of ER or PR expression in high-grade tumors was significantly decreased compared with intermediate-grade tumors. HER-2 was positive in 10.87% of grade 2 and 27.84% of grade 3 ductal carcinomas and negative in all grade 1 ductal carcinomas. HER-2 overexpression or amplification essentially was limited to grades 2 and 3 ductal carcinomas and correlated inversely with ER or PR expression. Although ER or PR expression is decreased in HER-2+ tumors, a substantial proportion of them still express ER or PR.     

Proliferating cell nuclear antigen (PCNA) in atypical and malignant meningiomas.

Because it is not easy to determine the tumor status of meningiomas by current diagnostic procedures, we investigated these tumors immunohistochemically using the monoclonal antibody PC 10. This antibody recognizes a fixation- and processing-resistant epitope of the proliferating cell nuclear antigen (PCNA), which is a 36-KD nuclear antigen associated with the cell cycle. We studied paraffin-embedded and formalin-fixed tissue specimens of a group of 21 atypical/malignant meningiomas together with 18 benign meningiomas. PCNA staining results were compared with the mean number of silver-stained nucleolar organizer region-associated proteins (AgNORs), tumor grading, and mitotic indices of these tumors. The percentage of PCNA-positive cells was found to range between 0.1% and 40%, irrespective of the tumor grade. When all tumors were collectively considered, no positive correlation was found between PCNA scores and histologic grading and only a weak one between PCNA score and mitotic index. A higher correlation was seen between AgNOR counts and tumor grading. Our results suggest that PCNA labeling and histologic grading seem to be independent parameters. The correlations found between AgNOR counts and tumor grading should be substantiated in further series.     

Correlation between visual clues, objective architectural features, and interobserver agreement in prostate cancer

Three pathologists evaluated a number of designated architectural features to assign grades to 41 cases of well- to moderately differentiated adenocarcinoma, and their opinions were compared. The consensus opinion was obtained and evaluated against objective measurements of glandular architecture that were obtained by morphometric techniques. The observers agreed on gland size, gland uniformity, and the number of glands per field in only 49%, 31%, and 39% of cases, respectively. There were significant differences in the Gleason grades assigned by observers. Paired matching of individual Gleason grades showed agreement among observers in 44% (18 of 41), 56% (23 of 41), and 75% (31 of 41) of cases, respectively. This level of interobserver disagreement occurred even though cases with predominant patterns were selected carefully and those with variable patterns were excluded. A direct relationship appears to exist between increasing Gleason grade and increasing glandular variability, and there is an inverse relationship between Gleason grade, gland lumen area, and the number of glandular nuclei, as assessed by a group of pathologists.     

Leiomyoma with atypical cells (atypical leiomyoma) in the larynx

AIMS: To report and confirm the identity of laryngeal leiomyoma with many atypical cells, which has not been described previously. CASE DETAILS: A 53-year-old man was found to have a polypoid tumour in the larynx. The tumour was excised and the patient has shown no evidence of recurrence over a 5-year period. The tumour tissue comprised intersecting fascicles of spindle-shaped tumour cells with blunt-ended nuclei. Many of the tumour cells showed marked atypia. Mitotic activity in the tumour cells was low, and no atypical mitoses were found. Immunohistochemically, the tumour cells were positive for smooth muscle actin and desmin. p53 overexpression was identified in many tumour cells; the p53 labelling index of the tumour cells was 45%. DNA from tumour cells showed loss of heterozygosity on chromosomes 3p, 5q, 8p, 9p, 10q, 17p and 18q. We diagnosed this case as leiomyoma with atypical cells (atypical leiomyoma) based on the clinical course and pathological and genetic findings. CONCLUSION: This is the first report of atypical leiomyoma in the larynx. The clinical course and pathological findings indicate that although laryngeal atypical leiomyoma contains numerous atypical cells, it is a benign neoplasm.     

Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma

This study concerns the significance of aberrant (nuclear/cytoplasmic) expression of beta-catenin in pancreatoblastoma (PBL). On immunohistochemistry, all seven PBLs examined showed nuclear/cytoplasmic expression of beta-catenin, predominantly in the squamoid corpuscles (SCs). In areas with acinar/ductular differentiation, few tumour cells displayed nuclear/cytoplasmic expression of beta-catenin and more than half of the tumour cells showed membranous expression. Two out of five (40%) tumours examined showed missense mutations in codons 33 and 37 of exon 3 of the beta-catenin gene. No mutation of the adenomatous polyposis coli (APC) gene was detected in two of the remaining three tumours. Amplifiable DNA for APC analysis was not obtained from the one other tumour. Immunoreactivity for cyclin D1, one of the nuclear targets of beta-catenin, was found predominantly in the SCs of the seven tumours. In contrast, the Ki-67 labelling index was 2-4% (median 3%) in the SCs and 8-18% (median 12%) in the other areas, indicating a negative correlation with nuclear cyclin D1 reactivity. These results imply that in PBLs, nuclear/cytoplasmic accumulation of beta-catenin and overexpression of its target gene cyclin D1 are not associated with the induction of tumour cell proliferation. Nuclear/cytoplasmic accumulation of beta-catenin may be related to the morphogenesis of the SCs that are considered most characteristic for PBL.     

Flat epithelial atypia (DIN 1a, atypical columnar change): an underdiagnosed entity very frequently coexisting with lobular neoplasia

AIMS: Flat epithelial atypia of the breast [FEA; synonyms: ductal intraepithelial neoplasia (DIN) 1a, atypical columnar change] is increasingly recognized by pathologists and shows distinct genetic alterations. The aim of this study was to determine its biological significance as an incidental finding in breast biopsy specimens. METHODS AND RESULTS: On the assumption that both FEA and lobular neoplasia (LN) derive from progenitor cells in the terminal ductal-lobular unit, we investigated the association between FEA and LN semiquantitatively in 111 excisional breast biopsy specimens which contained LN, but did not contain ductal carcinoma in situ (DCIS) or invasive carcinoma. Ninety-six cases (86.5%) revealed coexistence of LN and FEA (P < 0001). The distribution of LN was focal in 41 cases (37%), multifocal in 50 (45%) and extensive in 20 (18%) cases. FEA was identified as focal, multifocal and extensive in 29 (26%), 42 (38%) and 25 (23%) cases, respectively. Distribution patterns of LN and FEA showed no statistically significant correlation. CONCLUSIONS: Due to the striking association between LN and FEA in our material, one may speculate that these two lesions are biologically related and that FEA is an early but non-obligate precursor lesion similar to LN. Based on this assumption, regular clinical and mammographic follow-up of patients with FEA would be prudent.     

Clinical impact (cost-effectiveness) of qualifying atypical squamous cells of undeterminate significance (ASCUS) in cases favoring a reactive or dysplastic process

The cost-effectiveness of qualifying ASCUS cases into two different subcategories, favoring a reactive (ASCUS-R) or dysplastic process (ASCUS-S), was evaluated at the Centro per lo Studio e la Prevenzione Oncologica of Florence in a prospective study. The study determined the positive predictive value (PPV) for histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2) or more (CIN>) severe lesion of the two ASCUS subgroups. ASCUS-S had a PPV (10.78%) comparable to low-grade squamous intraepithelial lesions (LSIL) (11.40%). For ASCUS-R cases, the recommendation of 6-mo repeat cytology prompting colposcopy in cases of persistent ASCUS or more severe cytology was also effective, as it selected a subgroup with a relatively high PPV (10.34%). The cost-effectiveness of a protocol based on ASCUS qualification was compared with two other possible options for nonqualified ASCUS cases: immediate colposcopy and colposcopy in persistent ASCUS at 6-mo repeat cytology. The detection rate of CIN2> was substantially higher using ASCUS qualification (35.9 vs 14.8 or 17.1). The cost per ASCUS subject was euro 24.99, 27.11, or 25.14 and that per CIN2> detected was euro 697, 1,831 or 1,470 for the three options, respectively. The evidence that ASCUS detection option implies a higher detection rate of CIN2> and subsequently a lower cost per CIN2> detection must be considered with caution and deserves confirmation by other comparative studies.