Cutaneous histiocytic malignancy. Immunohistochemical re-examination of cases previously diagnosed as cutaneous "histiocytic lymphoma" and "malignant histiocytosis"

True histiocytic lymphoma (THL) and malignant histiocytosis (MH) have been defined by clinical and histologic findings and enzyme histochemistry. We reviewed cases previously diagnosed as cutaneous histiocytic lymphoma (HL) and MH with cutaneous lesions. These cases had been classified as "histiocytic" on the basis of previous enzyme histochemistry profiles of frozen tissue. Cutaneous tumor cells were reevaluated using a panel of immunohistochemical stains in formalin-fixed, paraffin-embedded tissue in correlation with histopathologic examination. The antibodies used in this study were directed against CD45 (leukocyte common antigen [LCA]), CD20 (L26) for B cells, CDS and CD45RO (UCHL-1) for T cells, CD68 (KP-1) and lysozyme for histiocytes, as well as CD30 (BerH2) for Ki-1 positive cells. On re-evaluation, the seven cases originally classified as HL were reclassified as one case of THL with neoplastic cells positive for CD68 (KP-1) and lysozyme, two cases with immunohistochemical features of Ki-1 lymphoma (including one of T-cell lineage), three cases of T-cell lymphoma, and one case of B-cell lymphoma, all associated with variable degrees of reactive histiocytosis. The four cases originally classified as MH were reclassified as two cases of MH and two cases of uncertain lineage. Although rare, histiocytic malignancies do exist. However, the diagnosis of histiocytic malignancy should be made only after careful correlation of atypical tumor cells in histopathologic sections and sections stained immunohistochemically. Erroneous classification of reactive histiocytes as neoplastic histiocytes using only enzyme histochemistry in frozen sections is a pitfall to be avoided.     

Histopathology of necrobiotic xanthogranuloma with paraproteinemia

Fifty-three cutaneous biopsies from 22 patients with necrobiotic xanthogranuloma (NXG) were reviewed. One or more biopsies from each patient displayed a typical pattern of palisading histiocytic xanthogranuloma with bands of hyaline necrobiosis. Multiple foam cells and Touton giant cells were present, and atypical, bizarre-appearing foreign body giant cells were characteristic. Cholesterol clefts were found in 18 specimens, and lymphoid nodules were found in 24, 8 of which had germinal center formation. Twenty-one specimens contained foci of plasma cells, and these were located perivascularly, at the periphery of lymphoid nodules, and, as infiltrates, between dermal collagen bundles. Unique features were xanthogranulomatous panniculitis, often appearing as Touton cell panniculitis, and a rare but distinctive palisading cholesterol cleft granuloma. The cytoplasm of giant cells and histiocytes contained PAS-positive, diastase-resistant polysaccharide. Examination of 3 cases by electron microscopy revealed dendritic cells in the epidermis and vacuolated dermal histiocytes. S-100 antibody was negative in 3 cases. Leukocyte monoclonal antibody studies in 6 patients showed predominantly T-helper lymphocytes within the granuloma. NXG is a T-helper cell, non-X histiocytic granuloma with a distinctive histopathology.     

Five cases of cutaneous Rosai-Dorfman disease

Rosai-Dorfman disease (RDD), previously known as sinus histiocytosis with massive lymphadenopathy, is a benign, idiopathic histiocytic proliferative disorder. It commonly affects lymph nodes, but any organ of the body may be involved. Histological findings include characteristic large, pale, histiocytic cells (Rosai-Dorfman cells) exhibiting cytophagocytosis. Immunohistochemically, these histiocytes are positive for S-100 protein and CD68, but stain negatively for CD1a. On electron microscopy, Birbeck granules are absent. RDD limited to the skin is rare, less than 30 cases having been reported to date. We present five further cases of purely cutaneous RDD. Three presented as solitary nodules and one as a large, well-circumscribed plaque. The fifth patient, who was HIV positive, had a rosacea-like facial eruption.     

A Case of Cutaneous Ki-1 Positive Anaplastic Large Cell Lymphoma in a Hemodialysed Patient

A 66-year-old woman who suffered from chronic glomerulonephritis had been undergoing hemodialysis for about 10 years. A reddish papule on her waist developed gradually into a nodule (1.9 × 1.4 cm). Histopathological findings showed that the tumor cells had oval to reniform nuclei; multinucleated neoplastic cells and erythrophagocytosis were also present. Immunohistochemical analyses revealed that the membranes of the tumor cells stained for Ber-H2 (Ki-1) and epithelial membrane antigen (EMA), Vimentin was partially positive, but keratin, S-100, chromogranin, leukocyte common antigen (LCA), UCHL-1, MT-1, L-26, MB-1 and C3D-1 were all negative. Anti-human T-cell leukemia virus-1 (HTLV-1) was also negative. No gene rearrangement of the T-cell receptor β-, γ- and δ-chain could be detected. From these results, we diagnosed cutaneous Ki-1 anaplastic large cell lymphoma (ALCL), but the origin could not be determined. The relationship between lymphoma and chronic renal failure and/or hemodialysis was far from clear.     

Giant cell rich histiocytic dermatitis/panniculitis associated with thrombocytosis

An unusual histiocytic dermatitis associated with a lymphoplasmacytic and histiocytic panniculitis appears to represent a previously undescribed disease process. A 56-year-old woman presented with a 5 year history of a violaceous, maculo-papular rash primarily on her legs. It began approximately 8 months before therapy for thrombocytosis. The rash subsequently progressed to form confluent patches and plaques on her torso and arms. The clinical impression was of disseminated granuloma annulare, but multiple biopsies from different sites did not confirm this. Histologic examination revealed a diffuse proliferation of histiocytic cells in the dermis, without well-formed granulomas or necrobiosis. The cells had large, focally irregular nuclei with prominent nucleoli, and were associated with scattered, often bizarre multinucleate giant cells. Immunohistochemistry demonstrated the histiocytic cells to be positive for S100 and CD68 and negative for CD1a. Perivascular siderophages as well as a lymphoplasmacytic and histiocytic panniculitis accompanied the process. The striking cutaneous changes are of unknown etiology but appear to be previously undescribed.     

Is CD30 (Ki-1) immunostaining in cutaneous eruptions useful as a marker of Th1 to Th2 cytokine switching and/or as a marker of advanced HIV-1 disease?

CD30 is a member of the tumour necrosis factor/nerve growth factor receptor superfamily, which is expressed on CD4 + and CD8 + T-cell clones which produce T helper (Th) 2-type cytokines. It has been proposed that disease progression in HIV-1 is associated with Th1 to Th2 cytokine switching. In 70 cutaneous biopsies from HIV-1 positive patients in different stages of disease, we performed a battery of immunohistochemical stains. These included antibodies to CD3, UCHL-1, OPD-4, L-26, KP-1 and CD30 (Ki-1). In addition, we used a similar battery of stains on cutaneous biopsies of HIV-1 negative patients with inflammatory dermatoses which are established as Th1 or Th2 dominant, e.g. polar leprosy. CD30 + cells were rarely present in early stages of HIV-1 disease, but commonly present in later stages of disease. However, there were cases of late HIV-1 disease which did not contain CD30 + cells. Increased numbers of CD30 + cells were more commonly seen in later stages of HIV-1 disease. However, the expression of CD30 appeared to be better in predicting other established Th2 cutaneous infiltrates in HIV-1 negative patients than in predicting a Th2 cutaneous cytokine pattern in advanced HIV-1 disease.     

Subcutaneous panniculitic-like T-cell lymphoma and other primary cutaneous lymphomas with prominent subcutaneous tissue involvement

The concept of subcutaneous T-cell lymphoma defines a reduced group of primary cutaneous lymphomas characterized morphologically by a prominent or exclusive subcutaneous tissue involvement. Subcutaneous panniculitic-like T-cell lymphoma is a rare subtype of primary cutaneous T-cell lymphoma clinically mimicking panniculitis. The clinical course is usually protracted with recurrent cutaneous lesions but rarely with early extracutaneous dissemination. The clinical, histopathologic, immunophenotypic, and evolutive features of this heterogeneous and rare group of primary cutaneous lymphomas are reviewed.     

Panniculitis. Part II. Mostly lobular panniculitis

The second part of our review of panniculitis summarizes the clinicopathologic features of the mostly lobular panniculitides. Erythema induratum of Bazin (nodular vasculitis) represents the most common variant of lobular panniculitis with vasculitis, although controversy persists about the nature of the involved vessels. Mostly lobular panniculitides without vasculitis comprise a series of disparate disorders. These include sclerosing panniculitis that results from chronic venous insufficiency of the lower extremities; panniculitis with calcification of the vessel walls such as calciphylaxis and oxalosis; and inflammatory diseases with crystals within the adipocytes such as sclerema neonatorum, subcutaneous fat necrosis of the newborn, and poststeroid panniculitis. Connective tissue diseases, such as systemic lupus erythematosus and dermatomyositis, pancreatic diseases, and alpha(1)-antitrypsin deficiency may also show a mostly lobular panniculitis with characteristic histopathologic features. Lobular panniculitis may also be an expression of infections, trauma, or factitial causes involving the subcutaneous fat. Lipoatrophy refers to a loss of subcutaneous fat due to a previous inflammatory process involving the subcutis, and it may be the late-stage lesion of several types of panniculitis. In contrast, lipodystrophy means an absence of subcutaneous fat with no evidence of inflammation and often the process is associated with endocrinologic, metabolic, or autoimmune diseases. Finally, cytophagic histiocytic panniculitis is the term that has been used to describe two different processes: one is inflammatory, a lobular panniculitis, and the other one is neoplastic, a subcutaneous T-cell lymphoma. The only common feature of these two different processes is the presence of cytophagocytosis in the lesions. (J Am Acad Dermatol 2001;45:325-61.) Learning objective: At the completion of this learning activity, participants should be familiar with the pathogenesis, clinical manifestations, histopathologic findings, and treatment options for the most frequent variants of the lobular panniculitides.     

Value of immunohistochemistry in the diagnosis of leukemia cutis: study of 54 cases using paraffin-section markers

A grave prognosis is usually associated with leukemic skin infiltrates (leukemia cutis). However, some leukemic skin infiltrates are clinically similar to reactive non-leukemic infiltrates in patients with leukemia; thus it is of great importance to distinguish them. Fifty-four cases which were thought clinically to be leukemia cutis underwent immunophenotyping with a panel of nine T, B, monocytic, and macrophage markers using paraffin sections. Immunohistochemistry helped identify 44 cases with leukemia cutis and 10 with reactive infiltrates. In all cases of leukemia cutis, the staining patterns of skin infiltrates were concordant with cell type in the bone marrow. Furthermore, the panel of markers was usually helpful in distinguishing reactive from leukemia infiltrates, especially in cases with chronic lymphatic leukemia. Immunohistochemistry is a valuable adjunct in histopathologic differentiation of skin infiltrates in most cases of leukemia. With formalin-fixed, paraffin-embedded biopsies, we recommend that CD45 (LCA), CD45RO (UCHL-1), CD3, CD20 (L-26), CD43 (Leu-22), CD68 (KP-1), lysozyme, and chloroacetate esterase be considered in cases of systemic leukemia with cutaneous papules and nodules that prove difficult to interpret with routine section.     

皮肤恶性T细胞性淋巴瘤伴反应性噬血组织细胞增生症的临床病理研究

报道6例皮肤T细胞性恶性淋巴瘤伴噬血组织细胞增生症.病变局限于真皮和皮下脂肪组织,灶性的肿瘤性T淋巴细胞浸润和分化良好的噬血组织细胞增生伴各种炎症细胞浸润.4例表现为病情进行性恶化、复发或死亡.并探讨其发病机理、诊断标准及鉴别诊断.     

Erythrophagocytosis in the skin: case report

A 68-year-old male with a myelodysplastic syndrome developed a bulla on his right thigh. A skin biopsy revealed a subepidermal cleavage containing fibrin and a mononuclear cell infiltrate exhibiting prominent erythrophagocytosis. Erythrophagocytosis by mononuclear cells was present, to a lesser extent, throughout the dermis and in the subcutis. Immunoperoxidase studies with anti-lysozyme and anti-alpha-l-chymotrypsin confirmed the histiocytic nature of the phagocytic cells. Only a few prior reports of cutaneous erythrophagocytosis exist in the literature. In contrast to the generally grave clinical manifestations of the patients described in previous publications documenting erythrophagocytosis, this patient lacked a concomitant hematologic deterioration or serious systemic illness.     

Subcutaneous T-cell lymphoma: report of two cases

We have seen two patients, a 24-year-old man and a 15-year-old girl, with subcutaneous nodules and fever. The histo-pathological findings in both cases showed a lobular, histiocytic panniculitis with 'bean bag' cells and lymphoid cells identified as immature T-cells. This picture was consistent with subcutaneous T-cell lymphoma associated with cytophagic histiocytic panniculitis. The girl died after 5 months of disease with florid hemophagocytic syndrome; the man was subjected to a course of treatment (CHOP; cyclophosphamide/doxorubicin/vincristine/prednisone) and after 6 months observation his symptoms of nodules and fever disappeared.     

An ultrastructural study of the mononuclear cell infiltrate of mycosis fungoides and poikiloderma atrophicans vasculare

Tissue from twenty-five patients with mycosis fungoides and three patients with poikiloderma atrophicans vasculare was examined ultrastructurally. Characteristic abnormal lymphoid cells were conspicuous in all biopsies comprising 30–60% of the cutaneous infiltrate. These cells possessed irregular nuclear outlines presenting a spectrum from mild indentation to grossly cerebriform shapes. The other prominent cell type was the histiocyte which occasionally appeared abnormal. Bizarre histiocytic cells resembling the interdigitating reticulum cell of lymph node T cell areas were also observed. In the epidermal infiltrate, abnormal lymphoid cells were seen singly infiltrating between keratinocytes and less frequently in groups, forming Pautrier microabscesses, or in close apposition to histiocytes. Langerhans cells appeared in normal numbers and were usually isolated but were occasionally seen in contact with lymphoid cells.     

Cytophagic histiocytic panniculitis. Systemic histiocytosis presenting as chronic, nonhealing, ulcerative skin lesions

Systemic histiocytosis was found in a patient who presented with chronic, nodular, and ulcerative skin lesions. The patient's hospital course was complicated by persistent fever, thrombocytopenia, severe neutropenia, and coagulation abnormalities. Treatment consisted only of splenectomy and supportive care. Postoperatively, the patient's skin lesions and the fever, pancytopenia, and coagulopathy resolved. Marked proliferation of histologically benign macrophages was observed in dermal, splenic, hepatic, and lymphoid tissues; leukophagocytosis and erythrophagocytosis were clearly demonstrated. This illness is most consistent with cytophagic histiocytic panniculitis, a newly described syndrome.     

Unusual expression of S-100 protein in histiocytic neoplasms

Twenty-nine cases of histiocytic neoplasms, some resembling juvenile xanthogranuloma (JXG) and others resembling reticulohistiocytoma (RH), were evaluated. Immunohistochemical stains were performed. In this series, seven cases were identified that expressed S-100 protein positive cells. The S-100 positive cells were predominantly large mononuelear and multinucleated histiocytes with eosinophilic cytoplasm, but also in some cases xanthomatous cells and Touton giant cells. These cells also expressed a positive reaction for vimentin, KP-1, and Factor XIIIa. There was no reactivity observed for monoclonal antibody 010(CD1a). A positive reaction for S-100 protein is conventionally accepted as a useful differentiating feature between histioeytosis X and non-X histiocytosis such as JXG and RH. The conflicting results of the immunohistochemical stains in the lesions we studied could be potential pitfalls in diagnosing histiocytic neoplasms.     

Lethal T- and NK-cell lymphomas mimicking granulomatous panniculitidies: a clinicopathologic study of three cases

An infiltrate mimicking subcutaneous panniculitis associated with a granulomatous response represents an uncommon histopathologic presentation of lymphoma. We report three cases, comprising one case each of nasal-type extranodal NK/T-cell lymphoma, cutaneous γ/δ T-cell lymphoma and human T-lymphotropic virus-I associated adult T-cell leukemia/lymphoma, which based on initial histopathologic and/or clinical presentation were thought to represent systemic lupus erythematosus, sarcoidosis and psoriasiform dermatitis, respectively. Excisional biopsies of indurated lesions performed at our institute; however, in each case showed an atypical subcutaneous lymphohistiocytic infiltrate associated with a variable number of granulomas. Extensive immunophenotypic characterization, in conjunction with histomorphologic and molecular analysis, established the diagnosis of lymphoma in all instances. All patients had a rapidly progressive clinical course and death was attributable to complications of lymphoma shortly after diagnosis. These cases highlight the importance of using a multimodality diagnostic approach to distinguish lymphomas masquerading as granulomatous panniculitis from inflammatory or reactive disorders associated with such histopathologic patterns.     

Lupus erythematosus panniculitis (lupus profundus): clinical, histopathological, and molecular analysis of nine cases

BACKGROUND: The diagnosis of lupus erythematosus panniculitis (LEP) may be very difficult in cases in which involvement of the subcutaneous fat is the only manifestation of the disease. The main differential diagnosis is subcutaneous panniculitis-like T-cell lymphoma (SPTCL). METHODS: We performed a retrospective study reviewing the histopathologic features of 11 biopsy specimens from nine patients with LEP (M : F = 2 : 7; median age: 48 years; range: 20-71 years). RESULTS: Histopathologically, all biopsies revealed a lobular panniculitis, with concomitant septal involvement in 82% of them. Dermal changes included the presence of superficial and deep infiltrates (82%) and mucin deposition (73%). The majority of cases (73%) presented also some form of epidermal involvement. The subcutaneous infiltrate was composed of lymphocytes in all cases, admixed with plasma cells in 91% of cases. Lymphoid follicles with reactive germinal centers were detected in 45% of cases. Immunohistochemistry showed a predominance of alpha/beta-T-helper and cytotoxic lymphocytes in 80% of cases admixed with B lymphocytes. The polymerase chain reaction analysis of the T-cell receptor (TCR)-gamma gene showed a polyclonal smear in all cases. CONCLUSIONS: Our study shows that the most useful histopathologic criteria for distinguishing LEP from SPTCL are the presence of involvement of the epidermis, lymphoid follicles with reactive germinal centers, mixed cell infiltrate with prominent plasma cells, clusters of B lymphocytes, and polyclonal TCR-gamma gene rearrangement.     

Fatal cytophagic panniculitis and haemophagocytic syndrome

We present two fatal cases of cytophagic panniculitis (CP) and haemophagocytic syndrome (HPS). In the first of these, there was an underlying T-cell lymphoma but in the second no associated disease was found. HPS is a frequently fatal disorder of immune regulation, characterized by fever, histiocytic haemophagocytosis, hepatosplenomegaly, pancytopenia, hypertriglyceridaemia and coagulopathy; CP is a less common manifestation. A number of benign and malignant conditions may present with HPS, the clinical findings and investigations aiding in determining an underlying disorder. Therapy is both supportive and directed at any associated illness, but often very difficult as diagnosis is delayed.     

Malignancy-associated multicentric reticulohistiocytosis: a clinical, histological and immunophenotypic study

The clinical, histopathological, and immunophenotypic characteristics of four cases of malignancy associated multicentric reticulohistiocytosis (MMR) and one case each of diffuse cutaneous reticulohistiocytosis (OCR) and isolated reticulohistiocytoma (IR). are reviewed. In all four cases of MMR the cutaneous lesions and joint manifestations were judged to be concurrent with the diagnosis of malignancy. Malignancies observed included one case each of pancreatic adenocarcinoma, squamous cell carcinoma of the lung, metastatic melanoma and intraperitoneal grade 4 mucinous adenocarcinoma of uncertain origin. Histologically, all six cases demonstrated the typical changes of a diffuse histiocytic and multinucleated giant cell infiltrate with ground-glass cytoplasm, predominantly in the upper dermis. Immunohistochemical investigation revealed strong cytoplasmic staining with KP-1 (CD68) in all six cases. Prominent membrane staining was noted with leucocyte common antigen (CD45) in four cases (three MMR and one fR), and CD3 in four cases (three MMR and one IR). Weak membrane staining with Leu 22 (CD43) was noted in two MMR cases. UCHL-1 (CD45RO), L26 (CD20), S-100 and BerH2 stains were all uniformly negative. A prominent number of perilesional factor XIIIa-positive dermal dendrocytes were noted in the single case of IR, in contrast with the other five cases. We conclude that MMR, DCR and IR are histopathologically and immunohistochemically similar. The pattern of immunoreactivity observed is consistent with a monocyte-macrophage origin of the infiltrating tumour cells. We emphasize the paraneoplastic association of multicentric reticulohistiocytosis, which we have observed in four of 13 such cases (31%) evaluated at our institution.     

Follow-up study on cytophagic histiocytic panniculitis with abnormal immunologic findings

A 41-year-old patient suffering from multiple subcutaneous nodules of 9 years' duration subsequently left a well-demarcated region of atrophy. Histiocytic panniculitis was observed in biopsy specimens with cytophagocytosis. Histiocytosis was found in the bone marrow. These histiocytes were positive for lysozyme and platelets. He later developed fever and hepatomegaly. Laboratory examination revealed leukocytopenia, mild anemia, and liver disfunction as well as abnormal immunologic findings such as positive LE test and ANA, and an increase of serum IgA and complement levels. The patient was successfully treated with systemic administration of prednisolone and azathiopurine++.