Lipoid proteinosis: in vivo and in vitro evidence for a lysosomal storage disease.

Tissue and cultured fibroblasts derived from one patient with the classical findings of lipoid proteinosis have been used to examine pathologic mechanisms in the disease. Ultrastructural examination of the skin revealed not only extracellular deposits of finely granular, moderately electron dense material, but in addition the dermal fibroblasts characteristically demonstrated marked cytoplasmic vacuolization. Phase contrast microscopy of the cultured skin fibroblasts also showed strikingly abnormal cells with many inclusions, which by electron microscopy were delimited by a single membrane. Membranous lamellar material was also increased in these cells. Biochemical analysis of the fibroblasts revealed a 3- to 4-fold elevation in intracellular hexuronic acid. These morphologic and biochemical findings suggest certain similarities with known storage diseases and support the postulate that lipoid proteinosis may represent a lysosomal storage disease.

Decreased collagenase production by regional fibroblasts cultured from skin of a patient with connective tissue nevi of the collagen type.

A 10-yr-old female presented with cerebriform tumors covering the plantar surfaces of both feet. Histologically, the lesions consisted of thick collagen fibers and the content of collagen per surface area of skin was increased about 8-fold. Examination of the collagen by SDS-polyacrylamide gel electrophoresis, after limited pepsin proteolysis, showed that the lesions consisted almost exclusively of type I collagen, the predominant collagen type in human skin. Thus, a diagnosis of connective tissue nevi of the collagen type was made. Fibroblast cultures were established from the affected and normal-appearing areas of the skin, and examined for the rate of collagen synthesis, production of collagenase and growth kinetics of the cells. Cell cultures derived from the lesion and from control skin synthesized procollagen at the same rate and in a normal type I/type III procollagen ratio. However, the production of enzymatically active and immunologically detectable collagenase was reduced by 70-82% in the cultures derived from the lesion as compared to controls (p less than 0.005). Fibroblasts derived from the lesions also displayed a mean population doubling time of 1.17 +/- 0.08 days compared to 1.83 +/- 0.24 and 1.92 +/- 0.09 days for control cell strains and cells derived from normal skin of the patient, respectively (p less than 0.025). These results suggest that the excessive deposition of collagen in this case may have resulted from decreased local degradation of collagen. Enhanced proliferative capacity of the regional fibroblasts may have contributed to the accumulation of collagen in these lesions.

Biochemical and ultrastructural demonstration of elastin accumulation in the skin lesions of the Buschke-Ollendorff syndrome.

The Buschke-Ollendorff syndrome is an association of cutaneous lesions, dermatofibrosis lenticularis disseminata, with osteopoikilosis. This condition is inherited in an autosomal dominant pattern. In order to clarify the biochemical nature of the skin lesions, we have examined 12 patients with the Buschke-Ollendorf syndrome, representing 2 unrelated kindreds. Histologically, the lesions were characterized by excessive amounts of unusually broad, interlacing elastic fibers in the dermis. Digestion of skin secretions with pancreatic elastase completely removed these fibers. Electron microscopy of the dermis further revealed markedly branched elastic fibers without fragmentation. The accumulation of elastin in the skin was also demonstrated by measurements of desmosine employing a radioimmunoassay. The desmosine content of the skin lesions increased 3- to 7-fold when compared to the skin either from healthy controls or from uninvolved skin adjacent to a lesion. The results indicate that the skin lesions of the Buschke-Ollendorff syndrome are connective tissue nevi of the elastin type. Cell cultures from these patients may provide a convenient model to study the control mechanisms involved in elastin metabolism.

Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease.

Several points can be made from analysis of the published cases of cutaneous mycobacteriosis and those in our series: 1) mycobacterial cutaneous infections are probably more common than is reported-we collected 34 cases over a 10-year period; 2) most patients with cutaneous infections caused by nontuberculous mycobacteria have significant underlying disease; 3) there is a relative lack of classic histologic features in patients with cutaneous mycobacteriosis, and there appear to be diverse forms of clinical presentation; 4) a high index of suspicion is needed in evaluating patients with possible cutaneous mycobacteriosis, and appropriate cultures must be done to establish the diagnosis. In attempting to provide a practical classification of cutaneous mycobacteriosis which includes infection by nontuberculous mycobacteria, we propose the following grouping, which uses simple terms, avoids confusing nomenclature, and incorporates pathophysiologic descriptions and prognostic information: 1) Mycobacteriosis caused by inoculation from an exogenous source. 2) Cutaneous mycobacteriosis caused by spread from an endogenous source. Contiguous spread originates most often with osteomyelitis, but also occurs through autoinoculation of the perirectal, oral, or vaginal skin as organisms are passed or expectorated from pulmonary or genitourinary tuberculosis. 3) Cutaneous mycobacteriosis caused by hematogenous spread. This group includes lupus vulgaris, nodules and abscesses, and acute disease with hemorrhagic pustules. Some mycobacterioses will be difficult to classify when inoculation or hematogenous spread cannot be ruled out. However, the system of classification we have proposed should help clinicians understand and diagnose the diverse forms of cutaneous mycobacterial infections.

Cutaneous inflammatory pseudotumor. Lesions resembling "inflammatory pseudotumors" or "plasma cell granulomas" of extracutaneous sites.

This report describes four cases of a previously undocumented circumscribed idiopathic inflammatory fibrosclerotic lesion of the skin. The lesions occurred in two black women and two white men; they had been apparent from months to a year. The nodules were solitary; two were located on the arm, one on the calf, and one on the posterior neck. The clinical diagnoses included nodules, keratinous cyst, pilar tumor, pilomatricoma, vascular leiomyoma, dermatofibroma, and metastatic carcinoma. The lesions were grossly white, homogeneous, and circumscribed; one was located in the superficial subcutis and three in the reticular dermis. Histologically, they were sharply circumscribed and surrounded by a dense peripheral rim of lymphocytes and plasma cells. Peripheral germinal centers were noted in two cases. All cases had variable amounts of fibrosis centrally, giving them the low-power appearance of lymph nodes; however, no subcapsular or medullary sinuses were found. In the center of the lesions, the mononuclear infiltrate was accompanied by eosinophils and neutrophils. Virtually imperceptible vasculature was noted in portions of three lesions; in the fourth lesion, high endothelial venules were seen in the lymphoid portions, and "targetoid" perivascular sclerosis was seen in the central portions. There appears to be a transition from the early, mostly inflammatory, lesions to the sclerotic ones. The process seems to be reactive in nature. No obvious local or systemic etiology was found in our series, and follow-up of 2 to 5 years has been noncontributory. These mixed-cell proliferations resemble the extracutaneous masses that have been described in numerous viscera--particularly the lung--as "inflammatory pseudotumors" or "plasma cell granulomas." In our opinion, these lesions also bore a superficial resemblance to cutaneous lymphoid hyperplasia secondary to insect bites. Other differential diagnostic considerations include dermatofibroma, nodular fasciitis, Kimura's disease, epithelioid (histiocytoid) hemangioma, and reactive lymph nodes.

Anaplastic Paget's disease.

Six cases of a distinct, histologically anaplastic variant of mammary Paget's disease are described. Patients ranged in age from 40 to 85 years. All patients had scaling erythematous lesions confined to the nipple; none had palpable breast masses. Histologically, the lesions had features resembling Bowen's disease, including full-thickness epidermal atypia, loss of nuclear polarity, and marked cytologic anaplasia. Intraepidermal acantholysis was a distinctive feature in all cases. In some biopsies, small groups and single typical Pagetoid cells were seen within the areas of confluent Bowen-like change. Immunohistochemically, carcinoembryonic antigen (CEA) was positive in three of six patients; epithelial membrane antigen (EMA) in five of six patients, and cytokeratin AE1/AE3 in three of six patients. Mucicarmine stains were uniformly negative. In our series, anaplastic Paget's disease was associated with concomitant invasive ductal carcinoma in three of six patients (50%). This percentage is significantly higher than that previously reported for patients with Paget's disease and without palpable breast mass. Histologic features that are helpful in distinguishing between anaplastic Paget's disease and Bowen's include cleft-like acantholysis, absence of dyskeratotic cells, and persistence of basal cell layer. More rarely, but very helpful when present, are underlying ductal carcinoma, intracellular lumina, and associated conventional Paget's disease. Immunohistochemistry results were variable and of relative value. Our study suggests that a nipple lesion histologically resembling Bowen's disease is likely to represent anaplastic Paget's disease.

Cellular angiolipoma.

Three examples of cellular angiolipoma are presented. They occurred as part of multiple, occasionally painful, subcutaneous nodules on the extremities and trunk of healthy men. There was no familial tendency. Grossly, the cellular angiolipomas were small lesions, approximately 1 cm. Histologically, dense cellular angiomatous tissue comprised more than 95% of the lesions. Much of this component contained prominent spindle cells. Lesser degrees of involvement in the other subcutaneous nodules illustrated the continuum of histology between cellular angiolipomas and more typical angiolipomas. The differential diagnosis of cellular angiolipomas includes spindle cell lipoma, Kaposi's sarcoma, and other vascular tumors. The most important distinguishing features are encapsulation, intravascular fibrin thrombi, septation, association with other more typical angiolipomas, and occurrence in healthy individuals.

Synovial metaplasia of the skin.

Synovial metaplasia has been described in bone or soft tissues following surgical procedures or under experimental conditions. Three cases in which skin biopsies showed synovial metaplasia of the dermis are herein reported. The metaplastic foci were associated with cyst formation and transepidermal fistulae. All patients had a history of previous surgical procedures in the area, and in all, the lesions clinically resembled suture granulomas. Microscopically, the lesions bore a striking resemblance to hyperplastic synovium. The immunohistochemical studies showed strong staining with vimentin and scattered positivity with alpha-1-antichymotrypsin (alpha-1ACT) and lysozyme. No basement membrane antigens or elastic fibers were demonstrated. We believe that the name "metaplastic synovial cyst" is an appropriate pathologic designation for this entity. An increased awareness of its occurrence will help to establish its true incidence.

Cutaneous lymphadenoma.

Thirteen cases of a unique cutaneous tumor are presented. The lesions presented as single, nondescript, skin-color nodules. Eleven were located on the head and two were on the legs. The male/female ratio was 8:5. The age at diagnosis ranged between 21 and 55 years (mean: 39). The duration of the lesions was from several months to more than 20 years. All tumors were excised and did not recur. The tumors typically presented as well-circumscribed nodules with scant or no epidermal connections. (One example, however, had a plate-like configuration amply connected with the basal layers of the epidermis.) The proliferation consisted of multiple, rounded lobules of basaloid cells with some degree of peripheral palisading, immersed in a dense, fibrous stroma. There was an intense infiltrate of small lymphocytes within the lobules, with some spillage into the stroma. No clear adnexal differentiation was noted except for rare isolated cells showing apparent sebaceous differentiation within the tumor lobules. Areas of central keratinization were also present. Numerous cells with ample amphophilic cytoplasm, large vesicular nuclei, and prominent nucleoli were also seen. Immunohistochemistry confirmed the presence of keratin within tumor cells. Common leukocytic antigen highlighted the intense intralobular lymphocytic component. Vimentin not only highlighted the stromal fibroblastic component, but also stained scattered intralobular cells. Epithelial membrane antigen was positive within some of the large intraepithelial cells. S-100 protein was extensively positive within dendritic intralobular and stromal cells. Lymphocytic markers demonstrated a polyclonal B and T population. This unique tumor appears to represent a form of adnexal neoplasm with basaloid features, possibly immature pilosebaceous differentiation.

Deep juvenile xanthogranuloma. Subcutaneous and intramuscular forms.

Juvenile xanthogranuloma occurring in soft tissue is rare and has received little attention. This report describes cases of deep juvenile xanthogranuloma occurring in the soft tissues of three children. Each tumor was a solitary lesion that arose, respectively, in the superficial skeletal muscles of an 8-month-old girl, the subcutis of the scalp of a 3-month-old boy, and the subcutis of the forehead of a 10-year-old girl. Two lesions were grossly firm, tan-yellow, and homogeneous. Histologically, the subcutaneous lesions were relatively circumscribed; the third lesion infiltrated muscle and contained widely separated skeletal muscle fibers. All lesions showed sheets of uniform amphophilic or acidophilic cells with occasional eosinophils and rare Touton giant cells. In two cases and in cutaneous controls, positive immunoperoxidase stains (HAM-56, HHF-35, and vimentin) supported macrophagic-myofibroblastic differentiation. S-100 protein, MAC-387, and factor XIIIa were negative. Electron microscopy in one case also supported macrophagic-myofibroblastic differentiation. Langerhans granules were absent. Follow-up of 7, 6, and 5 years indicated no recurrences. The differential diagnosis includes deep fibrous histiocytoma and cellular subcutaneous neural tumors.

Sebaceous carcinoma of the eyelid following radiation therapy.

This paper reports a case of a 12-year-old boy with fatal sebaceous carcinoma originating from the eyelid. The carcinoma developed 11 years after curative radiation therapy for bilateral retinoblastoma. Sebaceous carcinomas associated with previous irradiation are uncommon, and only five such cases have been published. Three of the patients were treated for benign disorders and the two other cases followed radiation therapy for bilateral retinoblastoma. Second malignant neoplasms in patients with bilateral retinoblastoma are thought to be related to a genetically inherited predisposition to the development of second malignant tumors. Radiation therapy is claimed to be an inducing factor in many cases but malignant neoplasms are also found in areas distant from the portals of irradiation as well as in patients not irradiated. Most of the secondary tumors were sarcomas, and usually osteogenic sarcomas.

Epithelioid cell histiocytoma. A report of 10 cases including a new cellular variant.

Epithelioid cell histiocytoma is a recently recognized lesion that is considered to be a variant of cutaneous fibrous histiocytoma (dermatofibroma). Ten cases are presented, including their light microscopic, immunohistochemical, and ultrastructural features. Eight of the cases are similar to those previously reported, presenting as elevated nodules arising on the extremities and composed of epithelioid histiocytes with overlying epidermal effacement. Two of the cases were composed of cells with the same morphologic and immunohistochemical characteristics as typical epithelioid cell histiocytoma, including factor XIIIa positivity, but these arose in the reticular dermis and exhibited prominent cellularity.

Sclerosing sweat duct (syringomatous) carcinoma.

This report describes 20 sclerosing adnexal carcinomas of the skin that recapitulate the sweat duct and share certain microscopic features with benign syringoma. Clinically, the neoplasms were slow-growing, indurated nodules or plaques. Sixteen were located on the face, including five on the upper lip. Three were situated in the axilla, and one involved the buttock. Twelve of the tumors (group 1) were composed primarily of cords and nests of whorled squamous cells with clear cell change and variable keratinization. Lumens consistent with ductal differentiation were few and isolated in some of these lesions, but others had more numerous and complex ducts. The remaining eight neoplasms (group 2) contained large numbers of small, uniform ducts, and exhibited little keratinization. Each neoplasm in the series infiltrated subcutaneous tissue or deeper tissues and was accompanied by sclerotic, fibrous stroma. Sixteen of the lesions (80%) exhibited perineural growth. One tumor involved an underlying lymph node, probably by direct extension. Cytologic atypicality was mild or lacking, and mitotic figures were sparse. Seven of 15 tumors (47%) with follow-up recurred, in some instances many years after primary excision. Tumor-free margins in the initial excision specimen appeared to be a favorable prognostic factor. The most aggressive lesion in the series showed increased cytologic atypicality in recurrences.

The histologic spectrum of the cutaneous mycobacterioses.

The authors examined the histopathology of cutaneous involvement in 31 cases of nonleprous mycobacterial infection. Cases include three patients with Mycobacterium kansasii infection, two with M. fortuitum infections, and one each with M. marinum and M. chelonei infections, as well as 18 with M. tuberculosis infections. In the remainder, species were not identified. The histopathologic picture was variable and often did not suggest mycobacterosis. The authors identified seven basic pathologic patterns of skin involvement: 1) abscess, 2) well-formed (tuberculoid) granulomas, 3) diffuse histiocytic infiltration, 4) panniculitis, 5) nonspecific chronic inflammation, 6) naked (sarcoidal) granulomas, and 7) rheumatoid-like nodules. Intermediate forms were also found. Some cases showed adnexal or epidermal involvement, while others showed variably distributed dermal infiltration. The results indicate that a wide variety of cutaneous, clinical, and histologic guises may be assumed by mycobacterial infections in normal and immunocompromised hosts.

Histiocytoid endothelial cells in a malignant schwannoma.

Unusual vascular lining cells within a malignant schwannoma prompted a comparative study of these cells and the endothelial cells in cases of histiocytoid hemangiomas. The endothelial cells in all cases showed similar morphologic and immunohistochemical features. Such endothelial cells were not found in the capillaries of a pyogenic granuloma or in those of developing rat skin. It is postulated that these distinctive endothelial cells may be more widely distributed than was previously thought and that morphologic changes associated with these cells may be induced by vasoactive substances.

Mucin-like changes in keloids.

Six of 125 keloids of the earlobe demonstrated a peculiar accumulation of mucinous material within their stroma. The six patients had all received prior injections of a corticosteroid compound. The histopathologic picture is characterized by irregularly contoured pools of amorphous eosinophilic material surrounded by a variable granulomatous response of multinucleate giant cells and bubbly histiocytes. Histochemical studies demonstrated that the material is different from the hyaluronic acid-rich substances of the usual forms of cutaneous mucinoses. The lesion is similar to but distinct from that previously described to occur in nasal mucosa injected with corticosteroids. Its recognition and correlation with clinical history should prevent confusion with other entities.

Adenomatoid metaplasia of prostatic urethra.

Adenomatoid metaplasia, or so-called nephrogenic metaplasia, is an uncommon alteration of urothelium associated with prior trauma and/or chronic infection. Although the majority of reported cases of adenomatoid metaplasia have involved the urinary bladder, two cases of patients in whom the metaplastic changes were present in tissue from prostatic resections are presented. The fact that both patients had undergone prior transurethral resections of the prostate further supports the association between adenomatoid metaplasia and trauma. Confusion of adenomatoid metaplasia with prostatic ductal carcinoma in one of the cases emphasizes the importance of the recognition of this lesion. The distinction of adenomatoid metaplasia from ductal carcinomas and from other benign proliferative lesions in the prostatic urethra is discussed.

Verruciform xanthoma of the vulva. Report of two cases.

Two cases of verruciform xanthoma of the vulva are described. This rare lesion, previously reported to occur only in the oral cavity, is characterized by a verrucous epithelial proliferation accompanied by xanthoma cells distributed exclusively in the papillary dermis. The histologic features of the lesion are diagnostic and include (1) regular acanthosis in which the rete pegs extend to a uniform level into the dermis; (2) hyperkeratosis with parakeratosis often extending deep into the rete pegs and manifesting a massive neutrophilic infiltrate; (3) hyalinization of the collagen and infiltrates of xanthoma cells that are restricted to the papillary dermis between the rete pegs. Additionally, a lichenoid inflammatory infiltrate is seen at the periphery of the verrucous lesions, and in one case this has the pattern of classic lichen sclerosus. Verruciform xanthoma must be differentiated from verruca vulgaris, condyloma acuminatum, granular cell tumor with pseudoepitheliomatous hyperplasia, and verrucous carcinoma.

Cholesterotic fibrous histiocytoma. Its association with hyperlipoproteinemia.

A 63-year-old woman with fibrous histiocytomas showed cholesterol deposition in the setting of type IIB hyperlipidemia. The two lesions involved the left leg and right thigh. One had typical features of a fibrous histiocytoma including changes of the overlying epidermis. The other was essentially replaced by cholesterol deposits and could not be differentiated from a tuberous xanthoma. This case illustrates the histiocytic response of fibrous histiocytomas to a hyperlipoproteinemic microenvironment.

Dermal thymus. A light microscopic and immunohistochemical study.

Two rare cases of distinctive thymic remnants occurring in the skin are described. The lesions were present at birth, and involved the side of the neck. One child had a complete cleft lip and palate. The other had multiple congenital anomalies consistent with a rare syndrome entitled branchio-oculo-facial syndrome. Microscopically, lobular foci were present in the dermis and consistent with both prethymic and thymic remnants. Immunohistochemical studies using antibodies to T cells and B cells showed a distribution similar to that seen in normal thymus. Dermal thymus appears to be a distinct entity and may be associated with other faciobranchial defects.