Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n =18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with `malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n =26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n =17) designated LCT; and cytologically malignant (n =9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n =13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n =4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases

Background: Pyoderma gangrenosum (PG) is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. There have been a number of reports of PG responding to infliximab, a monoclonal antibody against tumour necrosis factor α. Aim: In the first randomised placebo controlled trial of any drug for the treatment of PG, we have studied the role of infliximab in this disorder. Subjects: Patients 18 years of age or older with a clinical diagnosis of PG were invited to take part. Methods: Patients were randomised to receive an infusion of infliximab at 5 mg/kg or placebo at week 0. Patients were then assessed at week 2 and non-responders were offered open labelled infliximab. The primary end point was clinical improvement at week 2, with secondary end points being remission and improvement at week 6. Results: Thirty patients were entered into the study. After randomisation, 13 patients received infliximab and 17 patients received placebo. At week 2, significantly more patients in the infliximab group had improved (46% (6/13)) compared with the placebo group (6% (1/17); p = 0.025). Overall, 29 patients received infliximab with 69% (20/29) demonstrating a beneficial clinical response. Remission rate at week 6 was 21% (6/29). There was no response in 31% (9/29) of patients. Conclusions: This study has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of PG. Open label treatment with infliximab also produced promising results. Infliximab treatment should be considered in patients with PG.

https://gut.bmj.com/content/gutjnl/55/4/505.full.pdf

Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial

Pyoderma gangrenosum (PG) has four distinctive clinical and histologic variants. Some have morphologic and histologic overlapping features with other reactive neutrophilic skin conditions. PG often occurs in association with a systemic disease, and the specific clinical features of the skin lesion may provide a clue to the associated disease. Management of PG depends on its type and severity and usually requires aggressive local and systemic treatment.

Pyoderma gangrenosum: Classification and management

Pyoderma gangrenosum is a rare but significant cause of ulcerations. It is a diagnosis of exclusion. Herein, we suggest diagnostic criteria and some historical perspectives on the diagnosis of pyoderma gangrenosum.

Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria.

The relative frequencies of cutaneous metastases are similar to those of the primary cancers; breast, colon, and melanoma are the most frequent in women and lung, colon, and melanoma are the most common in men. Cutaneous metastases represent an opportunity to detect a potentially treatable cancer before other evidence of it is present, to modify therapy as appropriate to the tumor stage, or possibly to use the cutaneous lesion as a source of easily accessible tumor cells for specific therapy. Cutaneous metastatic disease as the first sign of internal cancer is most commonly seen with cancer of the lung, kidney, and ovary.

Cutaneous metastatic disease.

The clinical, histologic, and immunofluorescent findings in 86 cases of pyoderma gangrenosum seen at the Mayo Clinic between 1970 and 1983 were reviewed. Males and females were affected in equal numbers. The most frequent site of lesions was the leg. Sixty-seven patients (78 per cent) had associated systemic disease, with arthritis and inflammatory bowel disease being commonest. Cutaneous histopathologic changes varied with the site of biopsy. Lymphocytic vasculitis was predominant in the zone of erythema peripheral to the area of ulceration, while neutrophilic infiltrate and abscess formation were more prominent centrally. In most cases studied, direct immunofluorescence showed immunoglobulins and complement deposited in and around superficial and deep dermal vessels.

Pyoderma gangrenosum: a review of 86 patients.

Sixty-three patients with pyoderma gangrenosum were seen and studied at the Mayo Clinic from 1971 to 1980. Biopsies from the erythematous border or necrotic edge of the pyoderma gangrenosum lesions usually demonstrated a characteristic pathogenic morphologic evolution. The early lesions revealed mild to moderate perivascular lymphocytic infiltrate associated with endothelial swelling. The fully developed lesions demonstrated necrosis in addition to a dense lymphocytic infiltration surrounding as well as involving the blood vessels. Extravasation of erythrocytes and thrombosis sometimes were seen. Ulceration, infarction, and abscess formation were found in the later stages of evolution. Direct immunofluorescence results were positive in the blood vessels of 36 of 65 (55%) specimens. IgM, C3, and fibrin were found in the papillary and reticular dermal vessels. IgG and IgA were only occasionally present. Pyoderma gangrenosum appears to be a reactive process that is manifested as a vasculitis. Biopsy material from the advancing active erythematous border has early characteristic dermatopathologic findings of lymphocytic vasculitis. Cutaneous vascular immune deposits suggest an immune pathogenesis of either an immune complex disease or lymphocytotoxic reaction.

Histopathologic and immunopathologic study of pyoderma gangrenosum

• The records of eight patients with pyoderma gangrenosum and monoclonal gammopathy showed that all patients except one had an IgA paraproteinemia. To date, seven patients have had a benign course and multiple myeloma has developed in one. In seven patients, the onset of the pyoderma gangrenosum preceded the detection of the monoclonal gammopathy. The monoclonal gammopathy did not seem to influence the morphologic findings, course, or therapy of the pyoderma gangrenosum. In the one patient with myeloma, treatment of the myeloma caused accelerated healing of the skin lesions. (Arch Dermatol1983;119:468-472)

Pyoderma gangrenosum and monoclonal gammopathy

Kimura's disease (KD) typically presents as large subcutaneous masses in young Oriental males. It is characterized by deep inflammation with vascular proliferation, lymphocytic nodules with subcutaneous germinal centers, fibrosis, and edema. In comparison, angiolymphoid hyperplasia with eosinophilia (AHLE) occurs in all races and the lesions usually are smaller and more superficial. The causes of these two diseases are debated. We compared histologic features of 4 cases of KD with 22 cases of ALHE and studied expression of endothelial antigens and lymphocyte markers as well as localization of eosinophil, mast cell, and neutrophil granule proteins in lesional tissue. T-cell lymphoid aggregates with well-formed B-cell germinal centers occurred in KD, and nodular and diffuse T-cell infiltration with small B-cell clusters occurred in ALHE. Endothelial proliferation was more pronounced in KD, lacking the atypical histiocytoid endothelial cells characteristic of ALHE. Many intact eosinophils infiltrated lesions in both diseases, although KD had less extracellular granule protein deposition than ALHE. Intact mast cells were seen in both diseases. There was neutrophil elastase staining of occasional scattered intact cells but no extracellular deposition. Compared with KD, ALHE is more varied in its clinical, histopathologic, and immunohistochemical features.

Kimura's disease and angiolymphoid hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins.

We report two cases of microcystic adnexal carcinoma showing extensive sebaceous differentiation. Multiple cellular nests and strands within a moderately sclerotic stroma involving the full thickness of the dermis were observed. Clusters of basaloid cells with extensive sebaceous differentiation were present. Foci of sebaceous ductal differentiation were observed in the more superficial areas. Neither strikingly atypical cells nor mitotic figures were present. Perineural invasion was present in the deep areas of both tumors. Clinically, the lesions were solitary whitish-pink papules with a central dell on the faces of 2 men (aged 78 and 73 years old). We propose a relationship between these tumors and other cytologically bland but locally aggressive adnexal carcinomas. Sebaceous differentiation itself in a poorly circumscribed neoplasm does not indicate conventional extraocular sebaceous carcinoma. We propose a simple classification of locally aggressive adnexal carcinomas that takes into account the full range of adnexal differentiation that can occur in such lesions.

W. P. D. Su

Papers

Pyoderma gangrenosum: a review of 86 patients.

Histopathologic and immunopathologic study of pyoderma gangrenosum

Pyoderma gangrenosum and monoclonal gammopathy

Kimura's disease and angiolymphoid hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins.

Microcystic adnexal carcinoma with extensive sebaceous differentiation.