Interobserver reproducibility of histological features in cutaneous malignant melanoma.

AIMS: To assess the interobserver reproducibility of certain histological features proposed for the diagnosis of melanoma. METHODS: In a series of melanomas, 13 histological parameters were analysed: dimension > 6 mm, asymmetry, poor circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, asymmetrical melanin, melanin in deep cells, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis. RESULTS: The agreement (reproducibility) between the nine observers was excellent (kappa > 0.75) for 10 of the 13 examined features (dimension > 6 mm, poor circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, asymmetrical melanin, melanin in deep cells, mitoses, and necrosis). The agreement for asymmetry was very close to excellence (kappa = 0.74), and that for cytological atypia (kappa = 0.65) and dermal lymphocytic infiltrate (kappa = 0.47) was slightly lower, but in the fair to good agreement range. The kappa values obtained by comparison with the majority diagnosis were generally high (> or = 0.85); the mean value of kappa was lower (0.70) for only one parameter (dermal lymphocytic infiltrate). CONCLUSIONS: The parameters investigated showed an overall good reproducibility.

Histological features used in the diagnosis of melanoma are frequently found in benign melanocytic naevi.

AIMS: The histological features used in the diagnosis of melanoma may be present in benign naevi, but quantitative data are not available. The aim of this study was to establish the real prevalence of such features in naevi. METHODS: Ten dermatopathologists, from nine Italian institutions, studied a series of naevi. Eleven histological parameters currently used in melanoma diagnosis were analysed: asymmetry, poor circumscription, predominance of single melanocytes, irregular confluent nests, suprabasal melanocytes, hair follicle involvement, absence of maturation, cytological atypia, dermal lymphocytic infiltrate, mitoses, and necrosis. RESULTS: Ninety one naevi were examined: 22 junctional, 59 compound, and 10 intradermal. None of the studied parameters was seen in 22 of the benign naevi studied. One or more investigated features were found in 69 naevi. Poor circumscription was found in 49 cases, single melanocytic predominating in 42, asymmetry in 41, irregular confluent nests in 16, cytological atypia in 14, suprabasal melanocytes in seven, and hair follicle involvement in seven; absence of maturation, mitoses and necrosis were not found. CONCLUSIONS: The histological features used for the histological diagnosis of melanoma are often present in benign melanocytic naevi. This suggests a critical, non-mechanical use of them in melanoma diagnosis.

[Human equine type melanoma: clinicopathologic study of 4 cases]. / Melanoma di tipo "animale/equino" nell'uomo: studio clinico-patologico di 4 casi.

Four cases of human "equine" melanoma are presented. Two had poor prognosis, evidenced by the presence of metastases, and one of these with a rapidly fatal outcome. Human "equine" melanoma is characterized by an expansive, compact, heavily pigmented, dermal melanocytic proliferation without epidermal involvement. The mitotic index is always low, while minute foci of necrosis are present. The differential diagnosis is discussed, outlining the overlapping of the histological features with those of the malignant blu nevus. The only difference is the possible presence in the latter of areas characteristic of either common blu nevus or cellular blu nevus. With regards to the histogenesis of human "equine" melanoma we found no elements to support a follicular sheath origin and we propose a possible perineurial origin.

Melanocytic nevi of the breast: a histologic case-control study.

BACKGROUND: Melanocytic nevi in the genital, acral, and flexural sites often display clinical and histologic features that may simulate melanoma. We verified whether this is the case also for nevi of the breast. METHODS: Eleven dermatopathologists, from nine Italian Institutions, collected the specimens of melanocytic lesions from the breast and other body sites, excluding the acral, genital, and flexural areas, as controls. Cases and controls were matched for sex and age. All nevi were observed 'blindly' and simultaneously by all participants. For each lesion, 10 histological parameters were analyzed: asymmetry, absence of lateral demarcation of melanocytes, lentiginous proliferation, nested and dyshesive pattern, intraepidermal melanocytes above the basal layer, involvement of the hair follicle, absence of maturation of dermal melanocytes, melanocytic atypia, fibroplasia of the papillary dermis, and lymphocytic dermal infiltrate. Each parameter was scored 2 when present and 1 when absent or not valuable. A total score was calculated for each lesion. Results were statistically analyzed by the chi-square test and the Mann-Whitney U-test. RESULTS: One hundred and one nevi came from the breast area and 97 from elsewhere. Breast nevi exhibited significantly more atypical features than nevi from other sites. In particular, breast nevi with intraepidermal melanocytes, melanocytic atypia, and dermal fibroplasia were significantly more numerous. We did not find any sexual difference. CONCLUSIONS: To avoid undue concerns, dermatopathologists should be aware that melanocytic nevi of the breast may show a high degree of atypical features.

Expression of CD30 ligand and CD30 receptor in normal thyroid and benign and malignant thyroid nodules.

Because the CD30 ligand (CD30L)/CD30 receptor (CD30) system is expressed in certain malignancies, but has not been studied in thyroid nodules, we investigated its immunohistochemical expression in 6 normal thyroids (NT) and 131 thyroid nodules: 28 colloid nodules (CN), 45 adenomas (15 oncocytic [OA], 30 follicular [FA]) and 58 carcinomas (15 follicular [FTC], 1 insular [ITC], 6 anaplastic [ATC], 30 papillary [PTC], and 6 medullary [MTC]). NT and CN expressed neither CD30L nor CD30 (CD30L-/CD30-). Forty percent of OA and 20% of FA showed epithelial coexpression of CD30L and CD30, and interstitial expression of CD30L, which was also observed in the surrounding normal tissue. Within malignancies, epithelial coexpression of CD30L and CD30 was observed in 7% of FTC, 33% of ATC, 67% of PTC, and 67% of MTC. Only PTC and MTC showed epithelial expression of CD30L in the perinodular tissue with similar frequency (80% PTC, 75% MTC). PTC and MTC had the highest proportion of CD30L+ or CD30+ cells, and together with OA, a thus far unreported nuclear location of CD30L. In PTC, the proportion of CD30L+ cells and the prevalence of nuclear location of CD30L correlated inversely and directly, respectively, with aggressiveness. In conclusion, CD30L/CD30 signaling is activated only past the colloid nodule stage, most frequently in an autocrine fashion.

Rubinstein-Taybi syndrome with epidermal nevus: a case report.

We describe an 8-year-old boy with Rubinstein-Taybi syndrome, a multiple congenital anomaly/mental retardation syndrome characterized by broad thumbs and great toes, peculiar facies, and mental retardation caused by mutations in the transcriptional coactivator CREB binding protein (CBP). He had on his right side yellowish papular lesions organized in narrow bands according to Blaschko lines, later confirmed by histology as an epidermal nevus. Epidermal nevus syndrome has been ruled out because the patient failed to meet the criteria for inclusion under this designation. This association may be coincidental.

Standardized AgNOR analysis in actinic keratosis.

To assess if the quantity of silver-stained nucleolar organizer region (AgNOR) proteins predicts the behavior of actinic keratosis (AK), we performed a standardized AgNOR analysis on 51 cases of AK; in addition, 10 cases of squamous cell (SCC) and 10 cases of basal cell (BCC) carcinomas and 10 normal skin samples were also studied. AgNOR analysis was performed on formalin-fixed and paraffin-embedded sections according to the guidelines of the Committee on AgNOR Quantification (1995), evaluating the mean area (microm(2)) of AgNORs per nucleus (NORA). A highly significant P value (< 0.001) was found in the comparison among NORA values of normal skin (1.869 microm(2); SD + 0.332), AK (3.988 microm(2); SD + 0.914), BCC (3.044 microm(2); SD + 0.254), and SCC (5.286 microm(2); SD + 0.920). In AK, a progressive increase of mean NORA values was observed moving from Stage I (3.161 microm(2); SD + 0.600) to Stage II (3.455 microm(2); SD + 0.562), Stage III (4.360 microm(2); SD + 0.295), and Stage IV (5.168 microm(2); SD + 0.694); highly significant differences (P < 0.001) were noted when Stages I or II were compared with Stage III or Stage IV or between these latter stages. The AgNOR quantity may identify AKs with high proliferative activity and increased tendency to develop into invasive SCC.

A new family with Papillon-Lefèvre syndrome: effectiveness of etretinate treatment.

Papillon-Lefèvre syndrome is characterized by the association of palmoplantar hyperkeratosis, severe periodontitis, and early loss of deciduous and permanent teeth. We report two patients from the same family, aged 21 and 30 years, who were unaware of their pathology; one was successfully treated with etretinate.

Loss of heterozygosity of the long arm of chromosome 7 in follicular and anaplastic thyroid cancer, but not in papillary thyroid cancer.

Papillary thyroid cancer (PTC), but neither the follicular nor the anaplastic histotype [follicular thyroid cancer (FTC), anaplastic thyroid cancer (ATC)], overexpresses simultaneously the protooncogene HGF (hepatocyte growth factor) and its receptor HGF-R (or c-met). Because 1) HGF and c-met map to chromosome 7q21 and 7q31, respectively, 2) FTC loses genetic material at multiple loci with a frequency much higher than PTC, and 3) loss of heterozygosity (LOH) on 7q has been previously found in various tumors, we tested the hypothesis that both FTC and ATC, but not PTC, could harbor LOH in segments of 7q encompassing the loci for HGF and c-met. We screened 6 normal thyroids, 10 colloid nodules, 10 follicular hyperplasias, 10 oncocytic adenomas, 10 follicular adenomas (FA), 10 FTC, 6 ATC, 12 PTC using two microsatellite markers for HGF, and two for c-met. LOH for all 4 markers was found in 100% of FTC, 100% of ATC, and (for only 1 or 2 markers) in 10-29% of FA. This is the first demonstration of an LOH that separates both FTC and ATC from PTC, in the best possible manner: 100% vs. 0%. Clearly, each of the two segments we have probed contains at least one tumor suppressor gene, whose inactivation is crucial for the establishment of the FTC (and ATC) phenotype. This loss of genetic material explains why FTC and ATC, but not PTC, fail to express both HGF and c-met. Our findings may also have immediate diagnostic application, in the context of assisting pathologists in the often difficult task of distinguishing FA from FTC.

Primary cervical melanoma with brain metastases. Case report and review of the literature.

Primary intramedullary melanoma is a very rare tumor that occurs most frequently in the middle or lower thoracic spinal cord. The authors present a case of primary cervical cord melanoma that developed in a 62-year-old man who was surgically treated and subsequently underwent radiation therapy. Clinical and histogenetic features of this neoplasm and results of chemo-. radio-, and immunotherapy are reported. Both "dysembryogenetic" and "mesodermal" hypotheses on the origin of primary spinal melanoma are discussed.

An intriguing case of LEOPARD syndrome.

We report a 9-year-old boy affected by LEOPARD syndrome, who also had ichthyosis, axillary freckling, two café au lait spots, and one neurofibroma. The diagnosis of LEOPARD syndrome has been made on clinical grounds, whereas the ichthyosis and neurofibroma have been histologically confirmed. The analogies between LEOPARD syndrome and neurofibromatosis have been discussed. Finally, we maintain this case is an example of the multiple lentigines syndrome/LEOPARD syndrome spectrum.

Expression of the hepatocyte growth factor and c-met in normal thyroid, non-neoplastic, and neoplastic nodules.

We have examined the coexpression of hepatocyte growth factor (HGF) and its receptor (HGF-R or c-met) in an archival series of 63 paraffin-embedded thyroid specimens plus one lymph node metastasis. By immunocytochemistry, we found undetectable expression of both the ligand and the receptor in 10 normal thyroids and 9 nonpapillary malignant nodules [5 follicular carcinomas, 1 poorly differentiated (insular) carcinoma, 3 undifferentiated (anaplastic) carcinomas]. Of 10 non-neoplastic nodules (colloid nodules) and 17 benign neoplastic nodules, 3 of 10 colloid nodules, 2 of 10 follicular adenomas, and 2 of 7 oncocytic adenomas showed a weak but distinct staining (1+ score in a scale from 0 to 4+) of both HGF and c-met in a modest proportion of cells (1% to 3%). In these 7 cases, expression of HGF was always stromal and expression of c-met limited to the membrane of the follicular cells. Of 3 malignant nodules derived from aberrant growth of the parafollicular C cells (medullary thyroid cancer or MTC), 2 were positive (6% of cells). In these 2 cases, the expression of HGF (3+) was not stromal, but in both the membrane and cytoplasm of the parafollicular cells, while that of c-met (3+) was restricted to the membrane. In contrast to all of the above, of 14 papillary carcinomas (PTC) encompassing 5 histological variants (conventional; follicular; oncocytic; with foci of solid growth; diffuse sclerosing) plus 1 neck lymph node metastasis of 1 conventional PTC, 12 (86%) expressed HGF, and 13 (93%) expressed c-met. With the exception of 2 negative cases, HGF was detected in 15% to 46% of the cells. The highest percentage (46%) pertained to conventional PTC cases with abundant peritumoral lymphocyte infiltration, indicating that some lymphokine(s) may recruit PTC cells for HGF expression in a paracrine fashion. With the exception of one negative case, c-met was found in 43% to 80% of the cells, both at levels from intense (3+) to very intense (4+). The immunostaining for HGF was stromal in 25%, membranous in 8%, cytoplasmic in 8%, and both membranous and cytoplasmic in 59% of the PTC-positive cases. The immunostaining for c-met was membranous in 43% and both membranous and cytoplasmic in 57% of the PTC-positive cases. In the lymph node metastasis and in the diffuse sclerosing variant of PTC (the most aggressive variant), the coexpression of HGF/c-met was lost, in that only c-met was expressed on membranes in both cases. We conclude that the HGF/c-met system is activated (by overexpression of both components) in the vast majority of PTC. In most PTC the interaction of HGF and its receptor (c-met) is autocrine, not paracrine.

White fibrous papulosis of the neck in three Sicilian patients.

Three patients, two females and one male, presented with white fibrous papulosis of the neck. This condition is characteristically located on both sides of the neck; however, it also appears on the upper sternal region, with a necklace-like configuration, in the two female patients, aged 72 and 78 years, respectively. A differential diagnosis was carried out with respect to other dermatoses that show a similar skin aspect, and to the pseudo-xanthoma elasticum-like papillary dermal elastolysis. This is because this condition, as well as fibrous papulosis, can be interpreted as a clinical-histological variant of the same process of cutaneous ageing. However, environmental factors can play a role in the aetiopathogenesis of fibrous papulosis in the Sicilian population.

Milia-like idiopathic calcinosis cutis: an unusual dermatosis associated with Down syndrome.

We describe two boys affected by Down syndrome (DS), who showed milia-like idiopathic calcinosis cutis (MICC). The clinical diagnosis was confirmed by histological examination. All reported cases are reviewed and compared. Syringeal structures play a significant part in the pathogenesis of this dermatosis. MICC appears to be a poorly recognized condition which, rarely, is associated with DS.

Perforating milia-like idiopathic calcinosis cutis and periorbital syringomas in a girl with Down syndrome.

An 11-year-old girl with Down syndrome had whitish, milia-like lesions on the acral areas of the limbs, and periorbital syringomas. Calcium deposits were the histologic counterparts of the milia-like lesions. This is the first European report of this feature in Down syndrome.