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In inflammatory dermatoses, dermal melanophages (MLP) are ascribed to "pigment incontinence," with melanin "dropping down" from the epidermis. Although this is analogous to the "dropping down" of melanocytic nevus cells (Abtropfung), MLP in ordinary nevi have not been systematically studied-so "pigment incontinence" may not apply to MLP in nevi. A total of 31 childhood nevi identified by pediatricians and family practitioners were evaluated for the distribution of MLP. We tested the hypothesis that a dermal origin of the melanin in MLP is more likely than dropping down from the epidermis. In our cohort, 90.3% (28/31) of childhood nevi had dermal MLP, a significantly higher frequency, compared to 31/60 ordinary adult nevi (P < 0.0001). Superficial dermis was the most common location (P < 0.001). However, only six specimens had MLP restricted to the superficial dermis, significantly less than predicted by the theory that melanin drops down from the epidermis (P < 0.00001). We also evaluated perivascular MLP, since nerves run together with vessels in neurovascular bundles (NVB), and it has been showed that precursors of melanocytes migrate from the neural crest to the skin as nerve sheath stem cells. Superficial NVB MLP correlated with deep NVB bundle MLP (P < 0.05), suggesting that NVB MLP represent "tombstones" for superficial and deep dermal nevus cells. Deep dermal, deep NVB, and deep periadnexal MLP may be valid biological criteria for diagnosis of congenital type (prenatal) nevi. Viewing prenatal nevi in children as a neurocristopathy fits a major principle of pediatric pathology: childhood diseases should be studied and understood based on what happens during tissue development., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nevic corpuscle (NC), a stacked lamellar structure reminiscent of Meissner corpuscle, is frequently observed in dermal melanocytic nevi. Although the heading 'neurotized' is classically used for these nevi, the exact neural nature of NC has been a topic of considerable debate. Neurotized nevi have received little attention in the dental literature, and there was no information on NC in oral melanocytic nevi., Methods: Six cases of oral intramucosal nevi with a significant number of NC (two completely and four partially neurotized nevi) were examined immunohistochemically and ultrastructurally., Results: NC was composed of closely piled laminar cells devoid of visible melanin. NC and associated spindle nevus cells were immunopositive for S-100 protein but negative for HMB-45, myelin basic protein and epithelial membrane antigen. Within NC, no reactivity for neurofilament protein, protein gene product 9.5 or peripherin was evident. Numerous CD34-positive dendritic cells were located between nevus cells and often encircled NC. Ultrastructurally, NC consisted of concentrically layered elongated cells with a slender lamellated cytoplasm rich in thin filaments and pinocytotic vesicles. Their cytoplasmic processes were focally covered by external basal lamina and continuous to spindle nevus cells. Occasional NC cells contained a few melanosomes. There was no interposed axon in NC., Conclusions: Despite the close resemblance to Meissner corpuscle, NC showed no axonal supply. NC cells lacked terminal Schwannian differentiation and appeared to be modified melanocytes with some perineurial ultrastructural characteristics. The presence of CD34-positive cells, presumably corresponding to endoneurial fibroblasts, further supports an organizational relationship of NC and peripheral nerve sheath elements.

Objective: To perform a quantitative analysis to identify which of 7 nuclear morphometry-related variables are of diagnostic value in distinguishing benign from malignant melanocytic skin lesions., Study Design: At the Institute of Pathology, University of Nis, formalin-fixed, paraffin-embedded skin biopsies from 23 cases of benign nevi (18 intradermal and 5 junctional) and 25 cases of primary nodular malignant melanomas were retrieved. Specimens were routinely stained with hematoxylin and eosin and analyzed using a computer-assisted interactive image analysis system. Nuclear area, equivalent diameter, volume of equivalent sphere, perimeter, mean chord, circularity and integrated optical density were estimated after manual editing of binary images., Results: In univariate analysis, 6 features were found to be significantly different between the benign and malignant groups (P < .0001); all measured nuclear variables (except circularity) were higher in malignant melanomas. No significant differences were found among lesions with respect to nuclear shape. Using discriminant function analysis, a correct diagnosis was achieved in 95.8% of benign nevi cases and 84.0% of malignant melanoma cases. The best discriminant variable was nuclear area., Conclusion: Image analysis is diagnostically relevant to the evaluation of melanocytic lesions of the skin. The area of the nucleus appeared to have potential for differentiating benign from malignant tumors and can be estimated in the course of routine histology.

Background: Telomere length is correlated with cellular ageing and immortalization processes. In some human cancers telomere length measurement has proved to be of diagnostic and prognostic value. Results comparable with the traditional terminal restriction fragment length determination by Southern blotting have been obtained in metaphase and interphase cells in some studies by fluorescence in situ hybridization (FISH) analysis; FISH additionally allows for the quantification of telomeres at the cellular level., Objectives: In this study, 32 melanocytic lesions were analysed by FISH, aiming at investigating possible telomere differences among various benign and malignant lesions and correlation with telomerase activity (TA) level., Methods: FISH was performed on paraffin sections from six common naevi, eight Spitz naevi, 12 melanomas, six melanoma metastases and nine control samples of normal skin. Telomere mean maximum diameter (Feret max), area and number per nuclear area were calculated by image analysis on fluorescent images elaborated through KS400 and in situ imaging system (ISIS) for FISH analysis programs. Mean TA level was also calculated in all lesions and correlated with telomere parameters., Results: Telomere number per nuclear area was significantly lower in melanomas and metastases than in benign common and Spitz naevi and in control skin (7 small middle dot24 +/- 3.3; 6.11 +/- 3 vs. 14.46 +/- 5.6; 16.92 +/- 7.8; and 12.59 +/- 3.4, respectively; P < 0 .001). No significant differences were found for the other telomere parameters. In common and Spitz naevi, telomere number was positively correlated with Feret max (P = 0.046 and P < 0.0001, respectively). TA was significantly higher in melanomas and metastases than in the other groups (70.18 +/- 25.2; 105.07 +/- 30 vs. 2.16 +/- 2.4; 2 .99 +/- 2.1; 2 +/- 1.2, respectively; P< or = 0. 001) and it was inversely correlated with telomere number per nuclear area in melanomas (P = 0.0041). No other significant correlations were found., Conclusions: Encouraging results have been obtained from quantitative telomere evaluation in the diagnosis of melanocytic lesions, although an analysis of a larger number of cases would be necessary to provide more reliable data. An extreme shortening of some telomeres probably results in the decrease of telomeric signals and the lower mean number of detectable telomeres in melanomas and metastases. In melanomas, telomere number per nuclear area is also inversely correlated with TA levels. Quantitative FISH of melanocytic lesions could give more specific information at the cellular level in telomere and telomerase fields of investigation.

We report a rare hair follicle nevus that occurred in a three-month-old Japanese boy with mild frontonasal dysplasia. It had been present since birth. Histologically, numerous tiny vellus hair follicles were found within the dermis. The constituent cells of these follicles showed the features of follicular germ cells under the electron microscope. The fibroblasts around the follicles were active and merged with the colloid substance. Many myofibroblasts were found in a collagenous stroma in the atrophic lesion of the frontonasal dysplasia.

In a previous study, we showed by immunohistochemical analysis that basic fibroblast growth factor (bFGF) is expressed strongly and homogeneously in naevus-cell naevus (NCN), while that in malignant melanoma (MM) is heterogeneous and sometimes non-existent. In order to elucidate the role of bFGF in these pigmented tumours, the expression of its receptors must be determined. In this study, we performed an immunohistochemical analysis of FGF receptors 1, 2 and 3 (FGFR-1, FGFR-2 and FGFR-3, respectively) in NCN and MM and compared their expression and localization with those of bFGF. The expression of bFGF and its three receptors was also examined in melanoma cell lines. None of the 10 NCN that showed strong, homogeneous staining for bFGF expressed FGFR-1 or FGFR-3 proteins; six weakly expressed FGFR-2 protein. Ten primary and 10 metastatic MM showed heterogeneous expression for the three receptors, with larger populations of FGFR-3-negative cells in the primary than in the metastatic tumours. Western blot analysis showed homogeneous expression of bFGF protein in all four melanoma cell lines tested, while FGFR proteins had a heterogeneous distribution in the different cell lines. Cultured NCN and normal melanocytes showed no immunoreactive band for FGFR-1 protein, the only protein tested. Our results suggested that tumour-derived bFGF is involved in melanoma formation through an autocrine mechanism, but is involved mostly through a paracrine or other mechanisms in NCN.

To investigate the role of c-KIT receptor in melanocytic tumour development and progression, we analysed the expression and localization of c-KIT by immunohistochemistry and Western blotting. In contrast to the positive staining shown by melanocytes and naevus cells in the epidermis of common naevi (n=20), all dysplastic naevi (n=13) were negative, as were dermal melanocytic cells of blue naevi (n = 4) and common naevi (n = 26). Three out of four superficial spreading melanomas lost c-KIT expression both in the epidermal and dermal parts, while nodular melanomas showed no expression of c-KIT except in partially positive cells, and six out of seven metastatic melanomas were negative. In acral lentiginous melanomas (n = 8), in contrast to other types of melanoma, all cases with melanoma cells growing basally in the epidermis showed strong c-KIT positivity, but melanoma cells growing at the upper layers of the epidermis and vertically into the dermis lost c-KIT expression. Using the Western blot method on cultured pigment cells, human epidermal melanocytes, junctional naevus cells and one out of three metastatic melanoma cell lines showed 125 and 145 kDa bands corresponding to c-KIT, whereas dermal naevus cells did not. These results suggest that dysplastic naevi are distinct from ordinary naevi in terms of c-KIT expression and that basally growing cells in acral lentigenous melanomas could be at an initial stage of tumour progression, before c-KIT loss occurs.

To identify possible ultrastructural markers of melanocytic atypia, a quantitative ultrastructural study was made of melanocytes found at the dermal-epidermal boundary of normal skin and in benign, premalignant, and malignant melanocytic lesions. There was a significant increase (p < 0.05) in the number of melanosomes per melanocyte in the premalignant and malignant lesions compared with the number observed in the benign lesions. There was a significantly higher number (p < 0.05) of abnormal melanosomes (with irregularities in the laminar matrix or with a granular or clumpy matrix) in the premalignant and malignant lesions, which suggests that the presence of a high percentage of abnormal melanosomes might act as a useful ultrastructural marker in the diagnosis of melanocytic atypia.

Background: Many skin disorders are characterized by a mosaic pattern, often with alternating stripes of affected and unaffected skin that follow the lines of Blaschko. These nonrandom patterns may be caused by a postzygotic mutation during embryogenesis. We studied the genetic basis of one such disorder, epidermal nevus of the epidermolytic hyperkeratotic type. Epidermolytic hyperkeratosis is an autosomal dominant blistering skin disease arising from mutations in the genes for keratin (K) 1 and 10. The offspring of patients with epidermal nevi may have generalized epidermolytic hyperkeratosis., Methods: We studied the K1 and K10 genes in blood and in the keratinocytes and fibroblasts of lesional and nonlesional skin from three patients with epidermal nevi and four of their offspring with epidermolytic hyperkeratosis., Results: In the patients with epidermal nevi, point mutations in 50 percent of the K10 alleles of epidermal cells were found in keratinocytes from lesional skin; no mutations were detected in normal skin. This mutation was absent or underrepresented in blood and skin fibroblasts. In the offspring with epidermolytic hyperkeratosis, the same mutations as those in the parents were found in 50 percent of the K10 alleles from all cell types examined., Conclusions: Epidermal nevus of the epidermolytic hyperkeratotic type is a mosaic genetic disorder of suprabasal keratin. The correlation of mutations in the K10 gene with lesional skin and the correlation of the normal gene with normal skin provide evidence that genetic mosaicism can cause clinical mosaicism.

Comparison of argyrophilic nucleolar organizer region (AgNOR) counts has been found to yield statistically significant differences between benign and malignant conditions albeit with considerable overlap. In this study we compared the size of AgNORs and the nuclear areas, as well as the AgNOR count in 23 benign melanocytic lesions and 9 melanomas. Of these parameters, the ratio AgNOR area/nuclear area was found to be the main discriminating factor between melanoma and all the other benign groups studied, with p values of < 0.01 and no overlap. Next to it was the nuclear area, which in our study gave significant differences between the groups evaluated. The total AgNOR area and the largest AgNOR gave results comparable to the simple AgNOR counting in all groups studied, except in Spitz nevus, in which the AgNOR counts were less significant than the other parameters (p = 0.0420). We conclude that the ratio AgNOR area/nuclear area discriminates benign from malignant melanocytic lesions better than AgNOR counts or other parameters studied.

The histogenesis of malignant melanoma with particular reference to the role of melanocytic nevus is still controversial in oncological pathology. In order to differentiate between the proliferative activity of malignant melanomas and benign melanocytic tumors, immunohistochemical analysis was carried out. We used monoclonal antibody PC10 to identify the Proliferating Cell Nuclear Antigen (PCNA), a highly conserved 36 KD acidic nuclear protein which correlates with cell proliferation, and the AgNOR method to stain the Nucleolar Organizer Regions (NORs) whose number and configurations may reflect protein synthesis activity. 47 cases of primary melanoma, 63 metastatic melanoma lesions, and 23 cases of nevi are included in this study. Spitz nevi showed a higher index of cell proliferation compared with other common benign nevi but a much lower index compared with malignant melanoma cells. The metastatic lesions of malignant melanomas had a higher index of proliferation and activity of cells than the primary lesions. Skin-metastatic lesions had higher indexes of cell proliferation and NOR activity than lymph node-metastatic lesions. These results support the idea that metastatic melanoma cells are derived from a more advanced stage of tumor progression. These data suggest that the combination of PCNA and AgNOR is an useful marker for differentiating benign melanocytic tumors from malignant melanomas.

Because the differential diagnosis of melanocytic tumors is sometimes difficult, we performed a morphometric analysis of 20 benign nevi, 20 malignant melanomas, and 10 Spitz's nevi. The nuclear pleomorphism and the maturation to the depth of the tumor were quantified by measuring nuclear area and nuclear density at serial levels of the tumor (every 220 microns of thickness). Data obtained were analyzed statistically. Linear regression was used to represent the variation of nuclear area to the depth, and the standard deviation of nuclear areas reflected nuclear pleomorphism. We attempted to separate different tumors from each other using the Jacknife procedure and morphometric data. Using the Jacknife procedure rather than the usual histological procedures, we were able to distinguish benign nevi from Spitz's nevi and malignant melanoma in as many as 92% of cases, but we distinguished Spitz's nevi from malignant melanoma in only up to 60% of cases. In conclusion, we found it difficult to distinguish between Spitz nevi and melanoma using nuclear morphometric parameters. Other studies using new morphometric parameters are needed in order to improve our ability to make this discrimination.

A 75-year-old Japanese man developed a tubular apocrine adenoma (TAA) (tubulopapillary hidradenoma with apocrine differentiation, a rare skin tumor), within a long-standing organoid nevus on the parietal area of his scalp. Histologically, the tumor consisted of dilated ductlike areas with some atypism and apocrine glandlike areas surrounded by myoepithelial cells. The superficial part of the tumor was connected to the epidermis and showed some of the characteristics of syringocystadenoma papilliferum (SCAP). The close relationship between TAA, SCAP, and papillary eccrine adenoma (PEA) is discussed. According to 19 reported cases of TAA, SCAP might occur together with TAA when they are preceded by an organoid nevus, and they might represent a spectrum of disease. Although TAA and PEA may represent another spectrum (designated as tubulopapillary hidradenoma), the relationship to SCAP should be considered in understanding and diagnosing an intermediate case.

Multiparametric image cytometry was applied to 10 examples each of malignant melanoma and common, Spitz, and dysplastic nevus. DNA index, area, and 21 parameters describing chromatin texture were measured for 50 nuclei in each lesion. Linear discriminant analysis was used to derive discriminant functions based on the measured parameters. The analysis demonstrated that chromatin texture provides more diagnostic information than either DNA index or nuclear area. The discriminant functions allowed 68% of nuclei to be accurately classified among the four groups, and allowed 37 of the 40 lesions to be accurately classified as nevus or melanoma.

The apocrine nevus (AN) is a rare tumor occurring in the upper chest and the axilla. We report a case of a AN in a 33-year-old female occurring unilaterally. The presenting complaint related to tenderness and swelling in the right axilla. The initial impression was hidradenitis suppurativa. The gross specimen revealed the presence of irregular thickening just beneath the dermal subcutaneous interface. Microscopically the lesion was composed of mature apocrine glands with apical snouts. The glands were arranged in lobules divided by thin fibrous septa. Immunohistochemical studies revealed the following profile in the glandular epithelium: positive low molecular weight cytokeratin, epithelial membrane antigen, and gross cystic disease fluid protein reactivity and negative high molecular cytokeratin and S-100 protein reactivity. Carcinoembryonic antigen reactivity was found in the duct epithelium. Ultrastructural studies revealed cells lining the lumen of the glands with a concentration of granules in the apical region and light and dark granules. These findings support the previously described light microscopic observations and provide unreported ultrastructural studies in this rare tumor.

The selector was used to make an unbiased estimation of nuclear size variability in one benign naevocellular skin tumour and one cutaneous malignant melanoma. The results showed that the estimates obtained using the selector were comparable to those obtained using the more time consuming Cavalieri-disector approach. Employing 'optical sections,' the selector was found to be between five and ten times more efficient than the Cavalieri-disector method when using physical sections.

An unusual case of isolated exophytic elastic tissue nevi in the scrotal region of a 64-year-old man is described. The histological and ultrastructural findings were those of abundant abnormal elastic fibers and increased reticulin in the dermis. This hamartomatous lesion possesses clinical and histological features previously undescribed in connective tissue nevi.

Prompted by the well-known difficulties of reliable and objective histologic differentiation between initial malignant melanoma (MM) and benign nevocytic nevi (NN), ultrastructural high-resolution image and multivariate analyses were evaluated for their diagnostic efficiency. Thirty-seven different features describing morphometry (area, circumference, and shape factor), amount of heterochromatin and euchromatin, chromatin homogeneity, and presence of smaller dark chromatin aggregations were determined by a MICROVAX 3500 computer in each of 1840 intraepidermal melanocytic nuclei of 17 MM and 20 NN. A strategy for the classification of cases based on the identification of markedly atypical melanocytic cells (MACS) was developed. MACS, selected in multivariate analysis with a linear combination of the eight most important features for cell classification, were found in 39.4% of the melanoma cells, but only in 0.3% of nevocytic nevus cells. The presence of MACS allowed a clear differentiation between MM and NN. All cases of MM had more than four MACS, whereas 17 cases of nevocytic nevi were MACS negative, and in each of the remaining three cases only one MAC was present. The percentage of MACS detected within intraepidermal parts of MM by using computerized high-resolution image analysis was found to be a highly efficient diagnostic marker. The new classification strategy has the potential of saving considerable time in subsequent studies, because preselected sampling and the calculation of only a few criteria have proven sufficient for correct classification of malignant melanomas.

There is considerable variation in the quoted mean numbers of AgNORS per nucleus for benign melanonaevi and malignant melanomas. This is partly attributable to different approaches to AgNOR counting. This study summarizes our experience in devising an optimal technique for counting AgNORs. We show that it is essential to count intra-nucleolar AgNORs in addition to those lying outside the nucleolus to obtain clear separation of naevi from melanoma. Although this seems an onerous task, we further demonstrate that a maximum of only 30 nuclei need to be counted to obtain a mean AgNOR count per nucleus which is representative of the whole lesion. This compares with the arbitrary figure of 100 nuclei chosen by most workers. Only by optimizing and standardizing all aspects of the AgNOR technique including fixation, staining, and counting will mean AgNOR counts per nucleus become a useful quick, reproducible method which can be applied to lesions which pose diagnostic problems such as borderline melanocytic lesions.

Skin lesions of three patients with inflammatory linear verrucose epidermal naevus (ILVEN) were examined. Histologically, orthokeratosis and parakeratosis were alternately seen in the acanthotic epidermis. By N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide staining, the horny cells in the parakeratotic epidermis showed a cytoplasmic SH pattern and a weak membranous SS pattern. The orthokeratotic epidermis revealed an increased involucrin expression, whereas the parakeratotic epidermis showed almost no involucrin expression. Ultrastructurally, in the parakeratotic epidermis, the living keratinocytes had prominent Golgi apparatuses and vesicles in the cytoplasm. In the intercellular spaces in the upper spinous layer through to the lower horny layer, an electron dense, homogeneous substance was deposited. The cytoplasm of the horny cells was filled with keratin filaments and contained remnants of nucleus and cytoplasmic membrane structures, and some lipid droplets. The marginal band formation was incomplete. Most of these ultrastructural abnormalities were not found in the orthokeratotic epidermis. There are both similarities and differences in histopathogenesis of the parakeratotic epidermis between ILVEN and psoriasis. A unique finding was the lack of involucrin expression in the ILVEN parakeratotic epidermis.

In congenital naevocytic naevi (CNN), the ultrastructure of melanosomes has been demonstrated only in a few case reports. In the present study, five defined skin levels were systematically compared by electron microscopy in five giant and seven medium-sized CNN. The ages of the patients ranged from 5 days to 29 years. Six common acquired naevocytic naevi (ANN) served as controls. Melanosomes were classified morphologically into several groups. Epidermal melanosomes were normal in all cases. In 10 of the 12 patients, the morphology and size of dermal melanosomes corresponded well with those in ANN, although in four young children (up to 4-years-old) a few enlarged or atypical forms were found. On the other hand, two new-born babies showed rather different, grossly enlarged dermal melanosomes of various shapes and some unusual internal features. They were seen focally even in lower dermal layers and in naevus cells in subepidermal sweat ducts. We conclude that dermal naevus cells in CNN of new-borns, at least in some cases, may contain melanosomes with unusual morphological variations. This does not necessarily indicate malignant transformation.

Fourteen nevi with neuroid zones were examined and compared with nine nevi without neuroid structures. At light microscopic level, nevus cells from the neuroid nevi and the control nevi show the same staining pattern with polyclonal antibodies against S-100 protein. Around the cells of the neuroid zones is a more intensive immunoreactivity with monoclonal antibodies against laminin and collagen type IV than around the nevus cells in the upper dermis and the nevus cells in the control nevi. Also, the Gordon-Sweet stain for reticulin shows a dense network around the cells of the neuroid zones. No immunoreactivity in the neuroid zones was found with monoclonal antibodies against myelin-basic protein, myelin-associated protein, and glial fibrillary acidic protein. At the electron microscopic level, nevus cells from the neuroid zones show stacks of elongated cytoplasmic processes surrounded by basal lamina material. This pattern explains the presence of the abundant cytoplasm seen at light microscopy. Because no features of neural or neurolemmal differentiation could be found, the exactitude of the term neurotization can be questioned.

Although the term "nevus cell" was introduced nearly a century ago and is used daily in the parlance of general pathology and dermatopathology, writings about the subject indicate that agreement has yet to be reached about the nature of these cells. On the basis of all of the evidence about "nevus cells," morphological and biochemical, that has been accumulated to date, we conclude that they are simply melanocytes.

Eleven dysplastic melanocytic naevi with various degrees of dysplasia, as judged by light microscopy, were studied by transmission electron microscopy, and their intra-epidermal melanocytes compared with those of five superficial spreading melanomas and seven common benign naevocellular naevi. Intra-epidermal melanocytes in dysplastic naevi exhibited signs of cellular atypia, which were most pronounced in the dysplastic naevi with histological high-grade dysplasia. A correlation between the degree of dysplasia at the light microscopic level and the degree of cytological atypia at the ultrastructural level was noted, and melanocytes in dysplastic naevi with a high degree of dysplasia had ultrastructural features similar to the melanocytes in superficial spreading melanomas. Our observations support the concept that dysplastic naevi fill the biological gap between benign naevocellular naevi and malignant melanomas and suggest that at least some of the dysplastic naevi must be regarded as potential precursor lesions of malignant melanoma, particularly those exhibiting a high degree of histological dysplasia.

We describe a 33-year-old man with an unusual epidermal naevus that followed the lines of Blaschko. There were filiform hyperkeratoses, large cutaneous horns and lesions that resembled giant comedones and linear hyperkeratotic plaques. All of these lesions showed acantholysis without dyskeratosis. As the disorder is characterized by multiple small or large horn-like processes, we propose the term 'naevus corniculatus'.

A silver staining technique which demonstrates the nucleolar organiser region (NOR) was used in paraffin sections of iris naevi and melanomas. The technique shows argyrophilic NOR associated proteins (AgNORs) which are seen in nuclei as black dots. In nine iris naevi the AgNOR count ranged from 1.54 to 3.82 (mean 2.73), in 21 melanomas from 1.89 to 8.31 (mean 4.67). Mean AgNOR counts greater than four dots per nucleus were only seen in malignant lesions, thereby differentiating between benign and malignant tumours, whenever high AgNOR counts were found. We subsequently examined three tumours in the intermediate group of aggressive naevi, Jakobiec group 6: there were counts averaging 4.08 but with a wide standard deviation of counts indicating that the behaviour of this group of aggressive tumours is likely to depend on the percentage of cells bearing the higher numbers of NORs, which may represent mitotic potential or increased metabolic rate.

Unlabelled: Hereditary dysembryoplasia, the B. R. B. N. (Bean, 1958) is a variety of bluish nevus of the skin, associated with angioma of the gastrointestinal tract with serious bleeding, and sometimes of liver, spleen, bones, brain, marrow. The angiomas of the skin may occur in 3 forms: large cavernous angiomas; blood sac looking like a blue rubber nipple, they can be emptied; irregular blue mark, sometimes with puncted blackish spots, they may not blanch on pressure. They are painful., Histology: glomus-like angioma cavernous angioma. Ultrastructure: cavity with endothelial cells and one to four coats of smooth muscle cells. The angiomas arose in the submucous cellular tissue, projected into the cavity of the bowel, sometimes bleeding. Hematemesis and melena may be observed as in the Rendu-Osler disease. They nver spontaneously involve but they don't degenerate. The prognosis depends essentially on the bleedings and anemia. It is possible to cut out the skin angiomas.

The light and electron micrscopic findings in an eye enucleated from a 38-year-old woman with iris naevus (Cogan-Reese) syndrome are presented. The clinical manifestations of this disease, namely, iridic stromal matting, iridic nodule formation, and unilateral angle-closure glaucoma, appear to be secondary to an endothelial membrane on the anterior surface of the iris. The iris naevus syndrome is now thought to represent one end of the clinical spectrum of an iridocorneal endothelial syndrome which also includes those clinical entities classified previously as Chandler's syndrome and essential iris atrophy.

Uncontrolled unilateral glaucoma developed in the right eye of a 24-year-old woman. It was caused by the diffuse growth of a nonpigmented nevus of the iris into the anterior chamber angle. Histologically, the nonpigmented nevus cells in the angle were distinguishable from a proliferation of corneal endothelium. Clinically, there was no heterochromia, and a tumor was not suspected as the cause of the glaucoma.

Frequency of malignant transformation arising in giant congenital nevi is considered to be 4%-5%. More than a half of the patients in which malignant melanoma developed in giant congenital nevi were under the age of 10. It may be hypothesized that dermabrasion of giant congenital nevus may provoke malignant transformation. Some of the cell groups in giant congenital nevus are potentially malignant. Some groups of nevus cells were larger in size than those of other portions of nevus. Electron microscopic observation revealed that nuclei of these larger nevus cells were significantly indented, and melanization of melanosomes was irregular. Coexistence of alpha-like actin with beta- and gamma-actins in giant congenital nevus cells and disappearance of alpha-like actin in malignant melanoma cells were noted.

The occurrence, location and intensity of the basement membrane (BM) components collagen IV and laminin in benign and malignant pigment cell tumors was studied by immunohistochemical methods. The results seemed to establish the following findings: junctional nevi display varying continuity of BM; nevus cells in the dermis display more continuous and thicker BM superficially (associated with epithelial type nevus cells); superficial spreading melanoma displays discontinuity of BM, and nodular melanoma and metastatic melanoma display variable BM around tumor aggregates. The variable expression of BM components in this study showed an apparent relationship to tumor cell type and laminin and collagen IV production, partly related to clinical behaviour.

A case of naevus comedonicus on the palms and soles and scalp is reported. A similar case was previously reported by Leppard. The rare localization of this folicular hamartoma is commented.

A classification of peripheral nerve sheath tumors in the skin is based on analysis of light-, electron microscopy, immunohistochemistry and cellular composition of the different tumor types. Not only Schwann cells, but also perineurial cells and fibroblasts may be involved in tumor formation. Schwann cell rich and connective tissue cell rich tumors are distinguished. Generally all tumors show low proliferating activity as investigated by H3-Thymidine autoradiography. Only in few connective tissue cell rich tumors higher labelling indices can be demonstrated. These findings are correlated with the clinical course and prognosis of the different tumor types. The question remains, whether connective tissue cell rich tumors are at higher risk for malignant transformation.

This paper reports a case of malignant Melanoma in a 53 year old man with simultaneous development around the lesion of an acromic area with the characteristics of the so called Halo Navi phenomenon. Furthermore the patient presented lesions in other skin areas not related to apparent nevi. Microscopic tissue examination showed an inflammatory infiltrate in the depigmented zone which tended to surround and to include the melanoma periphery. This supports the conclusions of other publications linking these infiltrates with immunological phenomena tending to eliminate the tumor. A review is made of the new physiopathogenic criteria of the development of vitiligo.

A case of naevoid basal cell carcinoma syndrome with clusters of Langerhans' and lymphoid cells in the inflammatory peritumoral infiltrate, is reported. Electron microscopy shows intercellular contacts between eight to ten lymphoid cells and a single Langerhans' cell. These contacts occur over limited areas of the cell membranes by means of zones of high electron density on the outer edge of the cytoplasm. The functional significance of this finding is discussed, bearing in mind that recent observations have established certain analogies between Langerhans' and interdigitating reticulum cells. The latter might, within the thymus-dependent region of the lymph nodes, contribute to the formation of a micro-environment favourable to certain immunological activities of T-lymphocyte populations.

We have studied the ultrastructural organization of nucleoli in benign naevi and malignant melanomas. In benign naevus cells the nucleoli displayed a compact ribonucleoprotein distribution, with one or two large fibrillar centres. In malignant melanoma cells the nucleoli were large with an irregular, nucleolonema-like ribonucleoprotein distribution and they exhibited numerous, small fibrillar centres. Statistical evaluation of the size of fibrillar centres indicated a mean value of 0.482 micron 2 +/- 0.136 SD for naevi and 0.221 micron 2 +/- 0.128 SD for malignant melanomas. These features, together with the more dispersed chromatin pattern of malignant melanoma nuclei compared with those of benign naevus cells, are proposed as diagnostic parameters which differentiate benign naevi from malignant melanomas at the ultrastructural level.

We studied the fine structure of benign, premalignant and malignant melanocytic lesions induced in Dunkin-Hartley guinea pigs by means of topical application of 7,12-dimethyl-benzanthracene (DMBA). The most noteworthy characteristics of the atypical melanocytes (melanocytic dysplasia and melanomas) were the variable morphology and structure, and, in particular, the aberrant character of the melanosomes. The melanocytes presented irregularity of nuclear outlines with frequent lobulation. The heterochromatin was usually found in thick clumps reinforcing the nuclear membrane, and the nucleoli were usually multiple. The melanosomes were ellipsoidal and spherical with a pattern that was lamellar, concentric, incomplete, and even microgranular and microvesicular. The melanization was usually in thick, irregular clumps. Melanosome complexes were always present.

We studied 14 biopsies of congenital melanocytic nevi of children up to 1 year of age. In 11 biopsies we found two different types of melanocytic cells. In the reticular dermis, they were small cells. They had small nuclei, little cytoplasm, and no detectable pigment. They did not come in nests, but were scattered between the collagen bundles. The other type of cells was found within the epidermis or closely under it. These cells were large and round, and had abundant cytoplasms and evenly distributed melanin. Sometimes these cells were arranged in nests and in two moles they were also found in the epithelia of follicles. In all of these biopsies (with three exceptions) the superficial, large pigmented cells were separated from the deep, small, nonpigmented ones by a zone of tissue without any melanocytic cell. Early in life both types of cells are clearly separated, and the superficial ones are few. At later ages the superficial large cells are found in increased numbers, whereas the number of the deep ones does not change with age.

In a case of white sponge naevus type congenital buccal keratosis, electron microscopic study revealed severe disturbances in filamentogenesis which was insufficient (pale cells) or on the contrary excessive and anarchic (dark cells) and, to a lesser degree, corneal maturation. This was accompanied by slight abnormalities of the cellular junctions, rarely described in such a condition up to the present time. With regard to the delayed epithelial exfoliation typical of this condition, the manner and causes of its development are discussed in the light of ultrastructural findings.