Guy Orchard

Non-Langerhans cell histiocytoses : A new unifying concept

Based on our series of 111 cases of non-Langerhans cell histiocytoses, we present a new unifying concept for this rare group of disorders. The common denominator is the monocyte/ macrophage, which presents with various histologic features probably due to the influence of cytokines. Non-Langerhans cell histiocytoses are classified according to the predominant mononuclear (vacuolated, spindle-shaped, xanthomatized, scalloped, and oncocytic) and/or multinucleate (Touton, ground-glass appearance, Langhans, and foreign body) histiocytic cell types. Variable mixtures of these cell types produce common polymorphous patterns with prominence of vacuolated, spindle-shaped, and xanthomatized histiocytes in juvenile xanthogranulomas and of scalloped and oncocytic histiocytes in adult xanthogranulomas. Rarely, unusual monomorphous reaction patterns are observed: mostly vacuolated histiocytes are seen in the mononuclear variant of xanthogranulomas, (early benign cephalic histiocytosis, and generalized eruptive histiocytoma. Xanthomatized histiocytes predominate papular xanthoma and rarely xanthoma disseminatum, whereas spindle-shaped histiocytes are evident in spindle cell xanthogranuloma and progressive nodular histiocytosis, scalloped histiocytes are evident in most cases of xanthoma disseminatum, and finally oncocytic histiocytes are evident in reticulohistiocytoma and multicentric histiocytosis. Immunohistochemical, ultrastructural, and clinical findings can rationally be adjusted to this unifying concept of non-Langerhans cell histiocytoses. The time course of lesions, the age of the patients, and the presence or absence of underlying internal diseases are, or may, at least partially, be related to and thus explain variations on the theme of the non-Langerhans cell histiocytic reaction.

Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients.

Summary Background Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is a rare cytotoxic T‐cell lymphoma of the skin. In the World Health Organization classification of T‐cell and natural killer cell lymphoma it is listed as an example of extranodal lymphoma. In practice, however, it is most likely to present to a dermatologist.

Juvenile and adult xanthogranuloma : a histological and immunohistochemical comparison

Thirteen cases of juvenile xanthogranuloma (JXG) and 13 cases of adult-type xanthogranuloma (AXG) were compared at the light and immunohistochemical levels. Histologically, four main cell types (vacuolated, xanthomatized, spindle-shaped, and “oncocytic”) were seen in variable proportions (from monomorphous to mixed variants) with different types of giant cells (nonspecific, foreign body, Touton, and “ground-glass”). Giant cells were more prominent in AXG than in JXG; oncocytic cells (characterized by an eosinophilic, slightly granular cytoplasm similar to thyroid oncocytic cells) and mostly periodic acid-Schiff (PAS) negative giant cells with a ground-glass appearance (6 of 26) were not observed in classic JXG (i.e., occurring in children <2 years old). Immunohistochemically, JXG and AXG gave similar results: most xanthogranuloma cells labeled strongly with KiM1P and vimentin, while HHF35 and HAM56 stained less intensively. Factor-XIIIa (FXIIIa), KP1 (CD68), and HAM56 stained mostly in the periphery of the lesions. Some markers gave variable results: peanut agglutinin (PA), 60%; α-1-antitrypsin, 50%; lysozyme, 25%; LN3 (HLA-DR), <10% of cells positive. Others were negative: S-100, MAC387 (LI antigen), LeuM1 (CD15), desmin, smooth muscle-specific actin, and QBENDIO (CD34). This profile helps to delineate xanthogranuloma from histological stimulants such as dermatofibroma (which is FXIIIa +, LN3 +, KP1 −, and PA −) and multicentric reticulohistiocytosis (which is FXIIIa, KP1 +, PA−,andHHF35−).

Absence of the t(14;18) chromosomal translocation in primary cutaneous B-cell lymphoma.

Background The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas and in a lower percentage of systemic high‐grade diffuse large B‐cell lymphomas. The translocation results in the juxtaposition of the bcl‐2 gene on chromosome 18 with the immunoglobulin heavy chain joining region on chromosome 14. Bcl‐2 protein prevents apoptosis and the translocation leads to overexpression of a functionally normal Bcl‐2 protein that prevents apoptosis of neoplastic cells.

Outcome in 34 patients with juvenile-onset mycosis fungoides - A clinical, immunophenotypic, and molecular study

Mycosis fungoides (MF) is predominantly a disease of older patients, but occasionally occurs in children. The aims of the current study were to describe the clinical presentation, pathologic features, and disease progression (DP) in patients who developed MF before age 16 years.

CD8‐positive juvenile onset mycosis fungoides: an immunohistochemical and genotypic analysis of six cases

Background Childhood cases of cytotoxic T‐cell lymphoma have not been well described.

Reticulohistiocytoma and Multicentric Reticulohistiocytosis - Histopathologic and Immunophenotypic Distinct Entities

The clinicopathological and immunohistochemical features of four patients with systemic multicentric reticulo-histiocytosis (MR) were compared with five cases of solitary and one case of multiple reticulohistiocytoma (RH), which were confined to the skin only. The MR cases mostly affected the limbs of older women, while RH affected young male adults without preference to site. Characteristically, both entities consisted of oncocytic mononuclear histiocytes (with granular eosinophilic cytoplasm similar to oncocytic thyroid cells) and multinucle-ated histiocytes with a ground-glass appearance, which appeared to be much larger (>200 um) and bizarre in cases of RH compared with cases of MR (50–100 μm). In RH a variable number of vacuolated, spindle-shaped, and xanthomatized mononuclear histiocytes were also present. Immunohistochemical profiles showed positivity of mononuclear histiocytes with HHF35, factor XIlla, and LN3 (HLA-DR), with a variable number of multinu-cleated histiocytes in RH showing binding with peanut agglutinin. In mono- and multinucleated histiocytes in both entities macrophage markers KPI (CD68), KiMIP, HAM56, lysozyme, and αl-antitrypsin were positive. However, macrophage markers MAC387 (LI antigen) and Leu-Mi (CD15) were negative. Vimentin was universally positive in both conditions, with all other markers (S100, desmin, smooth muscle-specific actin, and QBEnd 10 [CD34]) negative. This study shows that histology supplemented by immunocytochemistry delineates MR from RH and immunohistochemical profiles indicate a cell lineage relationship between RH and adult xanthogranu-loma.

Genetic alterations in primary cutaneous CD30+ anaplastic large cell lymphoma.

Primary cutaneous CD30+ anaplastic large cell lymphoma (C‐ALCL) represents a distinct clinical subtype of CD30+ anaplastic large cell lymphomas. The etiology and underlying molecular pathogenesis of C‐ALCL remain unclear. This study aimed to investigate genetic changes in C‐ALCL. Comparative genomic hybridization (CGH) analysis of 23 DNA samples from 15 C‐ALCL cases identified chromosome imbalances (CI) in 10 samples from eight cases (43%). The mean number of CI per sample was 2.09 ± 3.86, with gains (2.00 ± 3.85) more common than losses (0.09 ± 0.29). The most frequent CI were gains of 1/1p and 5 (50%) and 6, 7, 8/8p, and 19 (38%). Microarray‐based CGH analysis of six DNA samples from five cases with CI revealed genomic imbalances (GI) in all of the cases studied. This included oncogene copy number gains of FGFR1 (8p11) in three cases, and NRAS (1p13.2), MYCN (2p24.1), RAF1 (3p25), CTSB (8p22), FES (15q26.1), and CBFA2 (21q22.3) in two cases. Real‐time PCR analysis of nine DNA samples from eight cases with CI and GI detected amplifications of CTSB and RAF1 in seven cases (88%), REL (2p13p12) and JUNB (19p13.2) in six cases (75%), and MYCN and YES1 (18p11.3) in four cases (50%). Immunohistochemical staining of paraffin sections from six cases demonstrated expression of JUNB protein in five cases and BCL2 in three cases. These results reveal a consistent pattern of genetic alterations in C‐ALCL and provide the molecular basis for further investigation of this disease.

BCL2 and JUNB abnormalities in primary cutaneous lymphomas.

Background  BCL2 is upregulated in nodal and extranodal B‐cell non‐Hodgkins lymphomas, with a consequent antiapoptotic effect. However, loss of BCL2 has also been noted in some malignancies, suggesting a different molecular pathogenesis.

Cutaneous histopathology of Sézary syndrome : a study of 41 cases with a proven circulating T-cell clone

Sézary syndrome is an uncommon variant of cutaneous T‐cell lymphoma (CTCL) characterized by erythroderma, pruritus, adenopathy, and circulating atypical T‐lymphocytes with cerebriform nuclei. The definition of Sézary syndrome can be further refined by including only patients with a circulating peripheral blood population of clonal T‐cells. We have evaluated 79 skin biopsies from such a group of 41 erythrodermic patients with circulating Sézary cells and a clonal population of T‐cells detected by T‐cell receptor‐figene rearrangement on Southern analysis of peripheral blood mononuclear cells. Histopathologic features consistent with chronic dermatitis were observed in 26/79 (33%) skin biopsy specimens, emphasizing that a non‐specific histologic appearance is common. Evidence of CTCL was lacking in 11/41 patients on biopsy of their erythrodermic skin. The survival of these patients was not significantly different from 30/41 patients in whom skin biopsies revealed changes diagnostic of CTCL, such as a dermal lymphocytic band with atypical lymphocytes (18/79, 23%) or a mycosis fungoides‐like infiltrate (30/79, 38%). This study confirms that non‐specific cutaneous hlstopathologic findings are common in Sézary syndrome, even when a circulating T‐cell clone is present. This stresses the need for peripheral blood genetic analysis and for multiple or repeat skin biopsies in erythrodermic patients when there is high clinical suspicion of CTCL.