Dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma.

BACKGROUND: The risk of malignant melanoma associated with histologically dysplastic naevi (HDN) has not been defined. While clinically atypical naevi appear to confer an independent risk of melanoma, no study has evaluated the extent to which HDN are predictive of melanoma. OBJECTIVES: To estimate the risk of melanoma associated with HDN. Secondarily, the risk associated with number of naevi and large naevi is estimated. METHODS: We enrolled 80 patients with newly diagnosed melanoma along with 80 spousal controls. After obtaining information on melanoma risk factors and performing a complete cutaneous examination, the most clinically atypical naevus was biopsied in both cases and controls. Histological dysplasia was then assessed independently by 13 dermatopathologists (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, severe dysplasia). The dermatopathologists were blinded as to whether the naevi were from melanoma subjects or controls. Multivariate analyses were performed to determine if there was an independent association between the degree of histological dysplasia in naevi and a personal history of melanoma. RESULTS: In persons with naevi receiving an average score of > 1 (i.e. naevi considered to have greater than mild histological dysplasia), there was an increased risk of melanoma [odds ratio (OR) 2.60, 95% confidence interval (CI) 0.99-6.86] which persisted after adjustment for confounders (OR 3.99, 95% CI 1.02-15.71). Very few dermatopathologists reliably graded naevi of subjects with melanoma as being more dysplastic than naevi of control subjects. Among the entire group, the interobserver reliability associated with grading histological dysplasia in naevi was poor (weighted kappa 0.28). CONCLUSIONS: HDN do appear to confer an independent risk of melanoma. However, this result may add more to our biological understanding of melanoma risk than to clinical assessment of risk, because HDN assessed by a single pathologist generally cannot be used to assess risk of melanoma. Future studies should be directed at establishing reproducible, predictive criteria for grading naevi.

The utility of cytokeratin 5/6 in the recognition of cutaneous spindle cell squamous cell carcinoma.

BACKGROUND: Cutaneous spindle cell squamous cell carcinoma (SSCC) is a challenging diagnosis since it may be difficult to distinguish from spindle cell melanoma, leiomyosarcoma and atypical fibroxanthoma. Furthermore, it may be difficult to demonstrate epithelial differentiation by a traditional immunohistochemical panel. We performed an expanded immunohistochemical evaluation of ultrastructurally documented SSCC to assess its utility in diagnosing this entity. METHODS: We identified 16 cases of SSCC that were composed predominantly of spindle-shaped cells and with ultrastructural evidence of epithelial differentiation (i.e. at least rudimentary cell junctions). Immunohistochemical analysis using antibodies to a variety of cytokeratins (AE1/3, K903, CK5/6) and S-100 protein was performed. The extent of immunostaining was graded on a scale of 0 to 4+ (0: no staining; 1+: < or =25%; 2+: 26-50%; 3+: 51-75%; 4+: >75%). RESULTS: Of the 16 cases, 6 expressed AE1/3 (38%), 8 expressed K903 (50%) and 11 (69%) expressed CK5/6. Six cases were positive for all three CK markers and two cases were positive for both K903 and CK5/6 but negative for AE1/3. Three cases (19%) stained for CK5/6 without any staining for AE1/3 or K903. Five cases (31%) were negative for all epithelial markers. The extent of CK5/6 staining was either similar to or greater than K903 staining in 7 of 8 cases that stained with both markers. All 16 cases were negative for S-100 protein. CONCLUSIONS: Including CK5/6 in the initial battery of immunostains performed on a cutaneous spindle cell neoplasm can help demonstrate epithelial differentiation in SSCC, even in the absence of AE1/3 or K903 staining. However, some cases of cutaneous SSCC can only be confirmed ultrastructurally, as up to one-third may not show evidence of epithelial differentiation using an expanded immunohistochemical panel.

Analysis of therapeutic and immunologic effects of R(24) anti-GD3 monoclonal antibody in 37 patients with metastatic melanoma.

BACKGROUND: Antitumor effects of antibodies against ganglioside antigens of melanoma have been reported, but neither optimal doses nor mechanisms have been established. METHODS: This Phase IB trial of the murine immunoglobulin IgG(3) monoclonal antibody R(24) against disialoganglioside GD3 was conducted with 37 patients to define better the dose-response relation and mechanism of action of R(24) in patients with metastatic melanoma. RESULTS: Dose-limiting toxicity consisted of a pulmonary capillary leak syndrome in 3 of 5 patients in the 80 mg/M(2)/day dosage tier. Serial blood and tumor biopsy samples were obtained prior to therapy and on Days 5, 9, and 22 following R(24) infusion. Tumor biopsy-infiltrating lymphocytes were enumerated in peritumoral, endotumoral, and perivascular compartments: endotumoral CD4(+) and CD8(+) T cells and HLA-DR(+) T cells increased over time on R(24) antibody. Endotumoral CD4 lymphoid infiltrate activation (DR expression) and antibody-dependent cytotoxicity were the greatest in the one patient who achieved a complete response. CONCLUSIONS: Clinical response was associated with depression in natural killer (CD56(+) and CD56(+)DR(+)) blood cells (P = 0.03) and was associated with R(24) dosage (P = 0.01). A complete response that lasted 2 years and a partial response that lasted 2 months occurred at a dose of 1 mg/M(2)/day. The limited number of clinical responses observed in this trial hampered the correlation of antitumor and immune parameters but provided a rational foundation for the future evaluation of antiganglioside antibodies.

Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.

The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.

A multiobserver, population-based analysis of histologic dysplasia in melanocytic nevi.

BACKGROUND: Nevi that are clinically atypical and histologically dysplastic have been associated with increased melanoma risk. There are few reproducibility studies or population-based studies of nevus histology. OBJECTIVE: Our purpose was to quantify concordance in histologic diagnosis of melanocytic lesions among a diverse group of pathologists, to assess intraobserver concordance by comparing readings of the same slide as well as of adjacent recuts from the same block, to correlate histology with nevus appearance and melanoma risk, and to estimate the range of prevalence of histologic dysplasia. METHODS: Histologic slides were prepared from 149 tissue blocks of pigmented lesions from melanoma cases, relatives, and controls. Six dermatopathologists independently evaluated the lesions for histologic dysplasia, without prior agreement on criteria. RESULTS: According to kappa statistics, intraobserver reproducibility was substantial, and interobserver concordance was fair, despite differences in criteria. The estimated prevalences of histologic dysplasia for the six pathologists ranged from 7% to 32%. Histologic dysplasia was correlated with nevus size for most observers, confounding the observed correlation between nevus appearance and histology. CONCLUSION: Although experienced dermatopathologists use different diagnostic criteria for histologic dysplasia, their usage is consistent. Histologic changes ascribed to melanocytic dysplasia are prevalent in the white population for all pathologists. The term nevus with histologic dysplasia should be used in preference to dysplastic nevus.

Flow cytometric DNA content analysis of a case of pilomatrix carcinoma showing multiple recurrences and invasion of the cranial vault.

Pilomatrix carcinomas are rare neoplasms of the skin that may be locally aggressive or metastatic. The differentiation of these tumors from benign pilomatrixomas depends on a constellation of microscopic features, some of which may be equivocal or absent in individual biopsy specimens. We encountered a tumor with distinct pilomatrix differentiation (lobulated nests of basaloid cells, ghost cells, focal calcification) that recurred multiple times and ultimately invaded the cranial vault. Despite this aggressive behavior, the tumor was difficult to separate from benign pilomatrixoma on morphologic grounds. Because DNA content flow cytometry has proved useful in the prediction of aggressive behavior in various solid tumors, we analyzed this neoplasm by flow cytometry. Neither aneuploid peaks nor a high proliferative fraction were seen in this example of pilomatrix carcinoma.

Histopathologic characteristics of dysplastic nevi. Limited association of conventional histologic criteria with melanoma risk group.

Studies of dysplastic melanocytic nevi (DMN) have suggested that lesions from patients with a personal or family history of malignant melanoma are histologically more atypical than are those from control populations without such histories. To evaluate this possibility, we examined histologic sections of DMN that had been removed from patients in three groups. Group A consisted of 17 subjects with a past history of melanoma; group B comprised 79 subjects with DMN and a family history of melanoma in first-degree relatives; group C consisted of 64 subjects who were unrelated spouses of members of groups A and B. For each group, sections of DMN were initially selected on the basis of architectural atypia as defined by the National Institutes of Health Consensus Conference. All biopsy material was then further evaluated for four histologic features suggested to be discriminatory for DMN associated with increased melanoma risk; the features are degree of junctional activity, irregularity of melanocytic nests, presence of dusty melanin, and size of melanocytic nuclei. A subjective rating was given for each on a 0 to 3 scale of increasing severity. Three pathologists individually rated the specimens without knowledge of the patient group. The means of the individual observer cumulative scores of the four histologic criteria for each biopsy specimen and the average of these means from the three observers exhibited a trend to increasing values from groups C to A, but none of the differences reached statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison study of two methods of peanut agglutinin staining with S100 immunostaining in 29 cases of histiocytosis X (Langerhans' cell histiocytosis)

Staining with peanut agglutinin (PNA) and with polyclonal antibody to S100 protein have both been recommended as aids in the diagnosis of histiocytosis X (Langerhans' cell histiocytosis). Although a large body of literature attests to the utility of S100 staining in this condition, the few published studies that involve PNA staining have employed varying methods of radically different results. We studied formaldehyde solution-fixed, paraffin-embedded tissue from 29 cases of histiocytosis X by using standard avidin-biotin immunostaining for S100 protein, as well as two published methods of PNA staining. All cases stained positively for S100 protein. By utilizing prior trypsinization and a three-step procedure, all cases also stained with PNA. With a two-step PNA-staining procedure, however, 9 cases failed to stain with PNA, and 3 cases showed a diffuse staining pattern that was not considered characteristic of Langerhans' and histiocytosis X cells. We concluded that both the S100 and the three-step PNA procedures are sensitive methods for the diagnosis of histiocytosis X.

Flow-cytometric DNA content of histiocytosis X (Langerhans cell histiocytosis).

Retrospective DNA-content analysis was performed by flow cytometry on formalin-fixed, paraffin-embedded tissue from 36 patients with histiocytosis X (Langerhans cell histiocytosis). Included were 17 patients with solitary bone lesions, 4 patients with multiple bone lesions, 2 patients with solitary extraosseous lesions, 1 patient with congenital self-healing histiocytosis, and 12 patients with disseminated disease. The diagnosis was in each case verified by review of the clinical history and histopathologic material. None of the cases displayed significant cytologic atypia. DNA content analysis failed to reveal additional G0-G1 peaks or "shoulders" suggestive of aneuploid subpopulations in any case. Full-peak coefficients of variation ranged from 3.8 to 8.0. Our data suggest that despite a prior report of a single aneuploid case of histiocytosis X, DNA content analysis may not be useful in predicting clinical stage and outcome in this disease.

Clinical, ultrastructural immunohistochemical and DNA content analysis of lymphomas having features of interdigitating reticulum cells.

Interdigitating reticulum cells (IRC) are dendritic, nonphagocytic histiocytes found in thymus-dependent areas of lymphoid tissues. We report two cases of large cell lymphoma having features of IRC in patients 13 and 17 years old. In each case the diagnosis was suggested by light and electron microscopic features, positive immunoperoxidase staining for S-100 protein, and additional immunoperoxidase findings. Both patients presented with aggressive lymphomas and were treated with intensive combination chemotherapy. Each patient achieved a complete clinical remission, then rapidly relapsed and died with disseminated disease 3 and 9 months after presentation. Novel findings included strong staining of specimens with an antibody to epithelial membrane antigen, staining of one specimen with peanut agglutinin in the pattern previously described in normal IRC, and a DNA content analysis that showed aneuploid stem cell lines in both patients.

Hyperplastic acral keratoses--association with invasive squamous cell carcinoma.

We have observed hyperplastic epidermal lesions in sun-damaged skin on the backs of the hands, wrists, and forearms that, in some examples, contain foci of invasive squamous cell carcinoma. Atypia in these lesions is focal or absent. Because of their bland histology, physicians are likely to interpret small or superficial biopsies as indicating a benign lesion. However, careful clinical correlation and follow-up are recommended, as residual tissue may contain invasive carcinoma or its precursor.

Epithelial membrane antigen staining patterns of histiocytic lesions.

Epithelial membrane antigen (EMA) appears to be a marker of activation, proliferation, and/or neoplasia in some epithelial and nonepithelial cells, including histiocytes. We performed immunoperoxidase stains for EMA on a variety of histiocytic lesion specimens, including specimens from two cases of interdigitating reticulum cell lymphoma, 12 cases of histiocytosis X, seven cases of sarcoidosis, five cases of granuloma annulare, 13 juvenile xanthogranulomas, two reticulohistiocytomas, five xanthelasmas, three dermatopathic lymph nodes, and three foreign body reactions. Only the two cases of interdigitating reticulum cell lymphoma and two of the 12 cases of histiocytosis X exhibited significant EMA positivity. These findings may prove useful in the differential diagnosis of histiocytic lesions.

[Results of using acupuncture and therapeutic physical exercise for preventing the development of arterial hypertension in persons with borderline arterial pressure]. / Rezul'taty primeneniia igloterapii i LFK dlia profilaktiki razvitiia arterial'noi gipertonii u lits s pogranichnym arterial'nym davleniem.

Altogether 63 patients with border-line arterial pressure were followed-up. In 44 of them preventive measures included acupuncture and exercise therapy, in 19 patients-acupuncture only. In 3 yrs after treatment initiation arterial hypertension developed in 6.3% of the patients versus 26.7% in the control group, arterial pressure got back to normal in 42.4% versus 28.3% in the control group. As compared to acupuncture used alone the combination of this method with exercise therapy resulted in lowered diastolic arterial pressure and a prolonged antihypertensive effect.

[Hemodynamic shifts as affected by the physical loading of persons with different blood pressure levels in relation to the blood circulatory type]. / Gemodinamicheskie sdvigi pod vliianiem fizicheskoi nagruzki u lits s raznym urovnem arterial'nogo davleniia v zavisimosti ot tipa krovoobrashcheniia.

Tetrapolar chest rheography was used to study central hemodynamic shifts in response to submaximum physical stress in 29 normal subjects, 26 individuals with marginal hypertensive conditions and 28 patients with labile arterial hypertension. Physical stress tolerance and cardiovascular performance were shown to decline as arterial hypertension developed; differences between individual hemodynamic types, demonstrated at rest, persisted at the peak of exercise; hypokinetic circulation was associated with the poorest cardiovascular performance.