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BASAL CELL EPITHELIOMAS TREATED BY MOHS CHEMOSURGERY. PRESENTED BY REX A. AMONETTE, MD, RICHARD H. SHEREFF, MD. CASE 1.— A 78-year-old black woman had a large (6.5×5.5 cm) basal cell epithelioma in the postauricular sulcus. Infiltrating tumor extended over the posterior surface of the ear and onto the posterolateral area of the scalp. There was no history of trauma or evidence of scar in this area. The epithelioma was surgically removed using Mohs technique. Seven stages of chemosurgery and 72 frozen tissue sections were required to reach a tumor-free plane. The surgical defect healed by spontaneous granulation. CASE 2.— A 78-year-old white woman had a 1.0×1.0-cm nodule over a 2×2-cm sclerotic area of the right tip of the nose. Biopsy revealed this lesion to be an infiltrating basal cell epithelioma. To remove the entire tumor, a 4.3×3.8-cm surgical defect was created. This required nine stages

• Long-term use of a nylon brush for back scratching by a 53-year-old white woman was associated with the development of typical macular amyloidosis. EKH4 monoclonal antikeratin antibody, which recognizes 50-kd neutral and acidic keratin species, labeled this amyloid. Confirmation of amyloid substance in the lesion included positive staining with Dylon and thioflavin T; immunohistochemical reactions with monoclonal and polyclonal antibodies against elastic fiber microfibrils (NKH1 and anti-P component), immunoglobulins (IgG, IgM, and IgA), and complement (C3); and electron microscopic identification of 6- to 10-nm straight filaments. Type IV collagen staining demonstrated a breakage and/or thickening of the dermoepidermal basement membrane above the amyloid deposition in the papillary dermis. Electron microscopic findings confirmed this phenomenon.(Arch Dermatol 1987;123:633-637)

• A black male newborn delivered by cesarean section developed large bullae on his extremities and in other friction areas soon after birth. No significant family history was obtained. The bullae healed rapidly, leaving hypopigmentation but no scars or milia. Occasional new lesions continued to appear for four months but not after. Reexamination 12 months later showed a normal healthy infant with only residual hypopigmentation in some of the previously involved areas. Histologic and electron microscopic examinations revealed a subepidermal bulla that was ultrastructurally a subbasal lamina separation. Collagenolysis and damage to the anchoring fibrils were found to be responsible for this separation. Perifollicular collagen sheath was also damaged, but periductal collagen of eccrine duct was intact. Keratinocytes in the lower epidermis showed large, dilated rough endoplasmic reticulum (RER), which contained electron-dense stellate bodies. The contents of these RER vacuoles were discharged into the papillary dermis through the rupture of the basal lamina. The number and size of RER vacuoles in the lower epidermis correlated with the severity of collagenolysis in the underlying papillary dermis. The outer root sheath keratinocyte in the upper hair follicle contained RER vacuoles, but the eccrine duct keratinocyte did not. We suspected that the RER vacuoles contained proteolytic enzymes, which were responsible for the collagenolysis.(Arch Dermatol 1985;121:1429-1438)

• We studied a family with dominantly inherited eruptive syringoma. The father and the older daughter had chest and neck as well as eyelid lesions. The chest lesions seemed to develop continuously by new formation of eccrine germlike budding from the epidermis. Monoclonal antikeratin antibody EKH4, which predominantly labels the basal layers of the epidermis, stained positively in the cordlike epithelial structure and peripheral cells of the walls of cystic lesions. Staining with EKH6, which recognizes normal eccrine secretory and ductal structures—particularly luminal borders—was positive along the luminal borders of the cystic lesions; staining with EKH5, which labels eccrine secretory portion, was entirely negative in the lesions. These findings further supported the theory that syringoma of the eyelids and eruptive syringoma, which mainly involves the anterior neck and upper chest, are essentially the same tumor and that these appendage tumors are of eccrine ductal differentiation.(Arch Dermatol 1985;121:756-760)

• A patient with eosinophilic granuloma, with extensive oral mucous membrane involvement, was treated with intralesional triamcinolone acetonide injections. Although radiation therapy had failed, this treatment resulted in remission. The biopsy specimen from the patient's lesion contained a predominance of OKT6-positive cells, which were shown by electron microscopic analysis to be mostly indeterminate cells and a small percentage of Langerhans' cells, with characteristic L-cell granules; there was also 5% eosinophils. Many L-cell granules were being produced between cell membranes of the same as well as neighboring L cells. It was thought that in this condition, as in other proliferative conditions of L cells, cell membranes are extremely adhesive and that such adhesion areas of L cells form L-cell granules. This occurs in a similar fashion as the adhesive areas of epithelial cells form desmosomes.(Arch Dermatol 1985;121:770-774)

• A chronic brawny edema developed in the shoulder and arm ipsilateral to the site of a previous mastectomy in a 68-year-old woman. Bluish nodules and telangiectasia admixed with more superficial papules and plaques developed subsequently. Histologically, many of these lesions showed angiocentric clusters of large hyperchromatic tumor cells, often with lumina in the center. It was difficult to differentiate two possibilities, ie, postmastectomy angiosarcoma in lymphedema (Stewart-Treves syndrome) and nodulotelangiectatic metastasis of the original breast carcinoma. Monoclonal anti-keratin antibody and anti-desmosome antibody identified keratin and desmosomes in the tumor cells, whereas staining with factor VIII-related antigen yielded negative results. Electron microscopy revealed, in addition to keratin filaments and desmosomes, typical secretory cells and lumen formation. A combined use of specific monoclonal and polyclonal antibodies is helpful in the determination of tumor origins.(Arch Dermatol 1985;121:742-746)

• A clinicopathologic study was made of 35 patients with primary eccrine adenocarcinoma diagnosed in the past 20 years from among 450,000 consecutive skin biopsy specimens. Histologically the following four distinct variants were identified: eccrine porocarcinoma (18 cases), syringoid eccrine carcinoma (12 cases), mucinous eccrine carcinoma (three cases), and clear cell eccrine carcinoma (two cases). Overall, eccrine adenocarcinomas are destructive lesions with a tendency to local recurrence. The syringoid histologic variant appears to be well differentiated and may have a benign clinical course; the lesion remained localized to the skin in our 12 cases. Regional lymphatic and distant metastasis, however, occurred in two patients with eccrine porocarcinoma.(Arch Dermatol 1983;119:104-114)

• A 24-year-old woman noted a depigmented halo around a pigmented lesion that had been present on her abdomen since birth. The halo and the central pigmented zone showed no change during the following year. Light and electron microscopic studies disclosed an uninflamed nevus extending to the deep reticular dermis; peripherally, the basal layer of the epidermis was depigmented. These findings indicate that a halo may develop about an uninflamed nevus that does not involute, and that the nevus may show the specific histopathology of congenital nevus.(Arch Dermatol 113:1572-1575, 1977)

Specimens from one case each of acquired and congenital cutis laxa were examined by electron microscopy. Elastic fibers of the dermis and subcutaneous arteries and veins were found to have similar changes. Elastin was diminished and microfilaments were visible throughout the entire fiber. Electron-dense, amorphous or granular layers that alternate with relatively electron-light layers were deficient. This electron-dense substance was unevenly aggregated within or in the vicinity of elastic fibers. In the congenital case, the aggregation and deposition of the electron-dense substance was often pronounced. In the vein, deficient deposition of elastin and admixture of microfilaments and amorphous substance were also found. Such admixture was often encircled by fibroblasts or smooth muscle cells. In the artery, multiplication of basal lamina was seen. Collagen fibers and anchoring fibrils of the skin were normal.

Seven new cases of dermatofibrosarcoma protuberans were studied. Most tumors were asymptomatic, multinodular, protuberant masses; five were on the trunk or abdomen and two on a thigh. Clinical diagnoses included dermatofibrosarcoma protuberans, dermatofibroma, metastasis, and lymphoma. Histologic examination showed a cartwheel or storiform pattern in each lesion; short fascicles of spindle-shaped tumor cells coursed in various directions and intersected at different angles. Melanocytes were present deep in one lesion. Electron microscopically, the tumor cells showed extensive cytoplasmic processes, moderately dense cytoplasmic matrix, elaborately convoluted nuclei, few profiles of rough-surfaced endoplasmic reticulum and Golgi lamellae, spotty basal laminalike material, and fibrous long-spacing collagen; conspicuously absent were intracellular lysosomes and lipid, and prominent cytoplasmic filamentation. The findings are sufficiently distinctive to be of diagnostic utility and suggest origin from a modified neural supporting cell, such as the endoneural or perineural cell.

• Studies of early progressive vitiligo, Vogt-Koyanagi syndrome, and incontinentia pigmenti achromians were made by electron microscopy. At the periphery of the depigmented lesions, the melanocytes had several subcellular abnormalities, ie, vacuolization of the cytoplasm, aggregation of melanosomes, autophagic vacuoles, fatty degeneration, pyknosis or homogeneous cytoplasmic degeneration, and others. Numerous nerve endings were seen in close contact with the basal lamina of the epidermis or even within the epidermis. Direct continuities between Schwann cell basal lamina of nerve endings and the basal lamina of the melanocytes were observed. Nerve endings could be associated with either normal or abnormal melanocytes.(Arch Dermatol 113:755-766, 1977)

• Angiokeratoma corporis diffusum (Fabry disease) is an X-linked recessive disease. We had an opportunity to examine a heterozygous female patient with angiokeratoma and cornea verticillata. The patient's serum α-galactosidase activity was reported to be about 50% of normal. Skin lesion biopsy specimens were stained with electron microscopic acid phosphatase (ACP), with proper controls. Acid phosphatase activity was demonstrable within membrane-bound inclusions of cutaneous vascular endothelial cells. This suggested that the accumulation of abnormal glycolipids in the vascular cells occurs in the lysosomes.(Arch Dermatol 112:1416-1423, 1976)

• Psoralen-ultraviolet light (PUVA)-treated psoriatic lesions were studied for ultrastructural changes. In early stages of treatment, sunburn cells in the epidermis and bizarre giant cells in the dermis were more frequently observed. When clinical improvement was apparent, these changes had subsided. Dermal abnormality in long-term therapy consisted of a thick perivascular coat of amorphous substance. No abnormality was found in the epidermal keratinocytes in long-term therapy, except a clustering and giant cell formation of melanocytes, a heavy melanization of keratinocytes, and hyperkeratosis. Low-dose initiation and slow increment of both 8-methoxypsoralen and UVA is probably a reasonable regimen for benign dermatoses such as psoriasis because it will allow enough time for the skin to become more protected, while the therapeutic results are as satisfactory as in a high-dose schedule.(Arch Dermatol 114:711-722, 1978)

Two new cases of colloid milium were studied by several methods to examine if collagen is the source of colloid. Woundhealing experiments in the lesion revealed that colloid is reproduced de novo with possible interaction with epidermal cells. Unfixed, native colloid did not contain collagen and salt extraction did not alter the ultrastructure of colloid. Tissue culture of colloid fibroblasts produced colloid-like substance. These results suggest that colloid is not a degeneration product of collagen. Disc electrophoresis of extracted colloid produced a distinct band, which is absent in the normal skin control. Amino acid analysis of colloid suggests that colloid may contain the recently described class of glycoprotein, called "structural glycoprotein" that is not related to collagen because it does not contain hydroxyproline and hydroxylysine and contains only a small amount of glucose. These biochemical data support the conclusion reached in electron microscopical studies.

Pseudopseudohypoparathyroidism and pseudohypoparathyroidism have been thought to represent variants of the same disease process, Albright hereditary osteodystrophy. A 31-year-old woman with the characteristic features of pseudopseudohypoparathyroidism, such as shortened metacarpals and metatarsals, round facies, and normal serum calcium values, was studied. Underdeveloped metacarpal and metatarsal heads produced an important diagnostic sign, Albright dimpling sign, which dermatologists can use to make the correct diagnosis. The presence of this sign, together with roentgenographic evidence, will usually exclude other diagnostic possibilities. Our patient had a normal response to parathyroid hormone infusion, including increased urinary adenosine 3′,5′ cyclic monophosphate excretion. Radiological, light microscopic, and electron microscopic studies of the mandible showed fibrous dysplasia, a disease commonly reported to be present with hyperparathyroidism, but, to our knowledge, never before reported in association with any variant of hypoparathyroidism.

One case of congenital, multicentric reticulohistiocytoma of the skin was followed up for more than a year. All lesions disappeared within 31/2 months, and there was no recurrence. Electron microscopic examination revealed typical histiocytic proliferation. Characteristically, the majority of the tumor cells contained numerous dense bodies, many of which showed myelin-like laminations. About 10% of the tumor cells contained Langerhans' cell granules. Some of these cells also contained myelinated dense bodies. These features, which are not commonly seen in Langerhans' cells of histiocytosis X, and the benign course of the disease were emphasized as differentiating points of this entity from histiocytosis X. No cell exhibited a resemblance to ganglioneuronal cells.

The cellular envelope of the human toenail cell becomes twice as thick as the original cell membrane of the matrix cell. It was found that this thickened envelope, ie, the marginal band, was not formed by the coating of the original cell membrane by discharged contents of the membrane coating granules (MCGs). Instead, it was produced by the precipitation of proteinaceous material on the cytoplasmic side of the cell membrane. Keratohyaline granules do not seem to contribute to the formation of the marginal band, since the nail cells keratinized by accretion of tonofibrils without the formation of keratohyaline granules.

Skin and muscle lesions of nine patients with clinically and histologically typical dermatomyositis were studied for the paramyxovirus-like inclusions previously described in several other connective tissue and autoimmune diseases. The detection rate of the inclusions correlated well with the degree of disease activity. The inclusions were cytoplasmic in small vessels of the skin lesion and could also be perinuclear in large vessels of the muscle. Tubules composing the inclusion budded from the wall of the endoplasmic reticulum or from nuclear membrane. No budding through the plasma membrane was observed. Uranyl acetate used in tissue block staining increased the tubular density and ribonuclease disintegrated, though not completely, the tubules. An increased number of lysosomes in the inclusion-positive cells was associated with the vascular damage. Tissue culture studies and serological tests for several paramyxoviruses were negative.

Lanthanum permeates the intercellular spaces, including cell-to-cell junctions such as desmosomes and tight junctions. It penetrates into small invaginations of the cell membrane, but does not go through the cell membrane. Lanthanum, therefore, stains intracellular organelles only when they are communicating with the extracellular spaces. Also, lanthanum combines with the cell-surface coating substance. When the epidermal Langerhans' cells were treated with lanthanum, it was found that some Langerhans' cell granules completely enclosed within the cytoplasm were stained, indicating that one end of these granules were open to the extracellular spaces at some level different from that of the section. The contents of such closed granules and of those open to the extracellular spaces were heavily stained with lanthanum, suggesting that they contained the cell-surface coating substance. This finding supports an endocytotic origin of Langerhans' cell granules.

Ruthenium red staining demonstrated the intercellular cement substance more distinctly and specifically than staining with uranyl acetate and lead citrate. The intercellular cement substance was seen in direct contact with the outer leaflet of the plasma membrane. In the acantholysis of pemphigus vulgaris the cement substance underwent dissolution first in nondesmosomal areas and later in desmosomal areas and at intermediate junctions where the cement substance was present as a thicker layer and appeared condensed. Occluding zonules persisted even in degenerated acantholytic cells, indicating a high degree of resistance against separation. In separated desmosomal areas and separated intermediate junctions, the trilaminar structure of the plasma membrane remained intact. In early acantholyzed cells, the attachment plaques and tonofilaments appeared normal. Thus, acantholysis in pemphigus is initially an extracellular phenomenon.Fine fibrillar structures were found crisscrossing the space between the basal plasma membrane of the basal cell and the basal lamina. The presence of these fibrils partially explained why acantholysis does not occur in this space.

Tubular structures similar to paramyxoviruses were observed in the skin lesions of ten consecutive patients with discoid lupus erythematosus. Two lesions from each case, one representing the most recently developed and the other the oldest one, were examined. Fifty dermal blood vessels consisting of arterioles, capillaries, venules, and small veins were examined in each lesion, totaling 100 blood vessels from each case. The detection rate of paramyxovirus-like inclusion or inclusions in either endothelial cells, perivascular histiocytes, or fibroblasts was 100% in new lesions (defined as up to six months' duration), whereas in old ones (older than six months) the mean detection rate was 70% on average. Very old scarred lesions did not contain the structure. Similar structures have been found also in dermatomyositis, scleroderma, and the congenital rubella syndrome. Since these inclusions were found mostly in so-called autoimmune disorders and, with the exception of congenital rubella syndrome, not in other groups, we hypothesized that, if proven to be a virus, they may be causally related to these diseases or, if not, they may represent a common reaction pattern in the autoimmune responses of tissue.

Electron microscopic examination showed varying numbers of typical Langerhans cells in the dermis in normal human skin, pityriasis rosea, reticulum cell sarcoma, and Letterer-Siwe disease as well as among the stromal and parenchymal cells of several benign appendage tumors. Langerhans cells were observed crossing the basement membrane and an epidermal Langerhans cell in mitosis was seen. These findings suggest that Langerhans cells are not directly related to epidermal melanocytes and may constitute a self-perpetuating "intraepidermal phagocytic system" to which histiocytes from the dermis are added from time to time.

Biopsy specimens of cutaneous lesions from two patients with histiocytosis X of the infantile type (Letterer-Siwe disease) were examined with the electron microscope. More than one half of the dermal macrophages in both specimens contained organelles identical to epidermal Langerhans' cell granules. These organelles appear to arise during the process of endocytosis of extracellular material and are ultimately found in various stages of degradation within Iysosomelike granules.The ultrastructural identity of these dermal macrophages to epidermal Langerhans' cells supports the hypothesis that the epidermal Langerhans' cell is a macrophage.

Eruptive hidradenoma, a rare type of syringoma, was studied histologically, histochemically, and electron microscopically in two patients. In spite of its peculiar clinical differences, such as occurrence of numerous lesions with limited distribution to anterior surfaces of the body, it showed features identical to the eyelid type syringoma. Direct connections were found between the lesions and epidermis and between individual lesions, but not between the lesions and underlying eccrine secretory segments. Also, cystic or tubular spaces were lined with an "immature eccrine intra-epidermal type" of epithelium which possessed a periluminal tonofilament band, lysosomes, keratohyaline granules, and often underwent complete keratinization. No secretory epithelium was found in the lesion. Dermal histiocytes with typical Langerhans cell granules and collagen fiber bundles were seen in parenchyma. It seemed that the lesion was undergoing constant destruction and regeneration.

Clear cell hidradenoma was found to be composed of two main types of cells: (1) a fusiform, dense cell located at the periphery of the tumor strands contained a large number of tonofilaments and a small amount of glycogen; and (2) a large and "clear" cell, differentiated from the former toward the center of the tumor strands, was filled with glycogen but poor in tonofilaments. Ail tumor cells were positive for enzymes present in normal eccrine glands in a higher concentration than in normal apocrine glands. The luminal spaces were lined by one of four types of epithelium, ie, embryonic epidermal, dermal, transitional, or secretory. Some tubular lumina were found to be very similar to the unopened secretory coil of immature embryonic eccrine gland. The majority of the clear cell tumors of the skin represent an immature eccrine sweat gland tumor.

Eleven new patients with macular amyloidosis were observed during one year. Areas involved included the thighs, shins, arms, upper back, breasts, and buttocks. Typical cases exhibited moderately pruritic, symmetrically distributed, brown, rippled macules. Amyloid deposits in the papillary dermis were quantitatively and qualitatively similar to those found in lichen amyloidosus. The differential feature was a lack of epidermal hyperplasia in macular amyloidosis. Ultrastructurally, the amyloid was the same as that described in other forms of amyloidosis. Islands of amyloid were present in the papillary dermis and extended to the dermoepidermal junction. Many of these aggregates were surrounded by fibroblasts. The association of macular and lichenoid elements in some patients, and features that are similar on examination with both the light and electron microscope, suggest that macular amyloidosis and lichen amyloidosus represent the same basic disease.

Colloid milium exhibited histochemical reactions similar to those of lichen amyloidosus. Colloid in this condition was composed of an amorphous material and filaments of various sizes, whose characteristics were distinctly different from the amyloid in lichen amyloidosus. There was evidence that some parts of the amorphous substance and thin filaments were derived from decomposition of preexisting collagen fibers, but the major portion was believed to have been produced by fibroblasts in the lesion. The fibroblasts in the lesion showed dilated cisternae of rough-surfaced endoplasmic reticulum, pinching off of peripheral cytoplasm, and extracellular formation of fine filaments in their vicinity, which indicated an active fibrillogenesis. Various forms of junctional devices and half-desmosome-like structures were commonly observed among these fibroblasts. Elastic fibers, normal or showing actinic elastosis, were few.

With the use of new material, lichen amyloidosus was reexamined with improved techniques. Island formation of amyloid in a close spatial relation to fibroblasts and absence of amyloid in perivascular spaces were reemphasized. As new findings, segregation of cytoplasmic material of fibroblast by budding and ballooning of the peripheral cytoplasm, desmosome-like and half-desmosome-like structures of fibroblasts, intracellular amyloid of dermal fibroblasts, and amyloid-like intracellular filaments of keratinocytes were described.

Intradermally injected peroxidase was found in the Langerhans' cell granules of the epidermal Langerhans' cells. As time elapsed, the number of stained granules increased, reaching the maximum at 22 hours, and tended to concentrate near the Golgi zone. Since the peroxidase molecule does not cross the plasma membrane, this suggested (1) ingestion of peroxidase by the Langerhans' cell granules at the cell periphery and (2) migration of such granules into the cell interior. At the cell periphery various types of close apposition of the plasma membrane with gap distance ranging from 30 Angstroms (gap junction) to 350 A (Langerhans' cell type) were found. They too migrated into the cell interior. This suggested that the so-called Langerhans' cell granule is just one type of plasma membrane apposition or invagination which this cell can produce.

HISTOCHEMICAL .ISTOCHEMICAL and electron microscopic investigations have been useful in the determination of the histogenesis of many appendage tumors for two reasons. First, the immature cells of appendage tumors, like immature cells of cutaneous appendages of the human embryo, contain certain enzymes that are quite specific for each cutaneous appendage. Second, the electron microscopic examination of the appendage tumors reveals details which are not recognizable on examination with the light microscope. With these new methods, many conventional viewpoints of the light microscopist have been confirmed, whereas, some were disproved.1-4In this review, the histogenesis of eccrine poroma, syringoma, eccrine spiradenoma, cylindroma, and calcifying epithelioma will be discussed. MATERIALS AND METHODS All histochemical methods and materials used were the same as those used previously.5-12 Original electron micrographs used for Fig 2, 3, 6, 8, and 10 were taken with a high resolution electron microscope (Hitachi HU-11C) at accelerating voltage