Clinical Significance of Serum Adenosine Deaminase Activity in Patients with Mycosis Fungoides

Adenosine deaminase is one of the key enzymes in purine nucleotide degradation. This enzyme exists in most of the human tissues and the activity is high in lymphatic tissues, especially in T lymphocytes. Elevated adenosine deaminase activity in T cell leukemia has been reported, and its inhibitor, deoxycoformycin, has been developed as an antitumor agent. In some types of leukemia, serum adenosine deaminase activity increases in accordance with the severity of the disease. Although mycosis fungoides rarely involves peripheral blood, tumor cells do invade the skin. In order to evaluate the clinical significance of adenosine deaminase in mycosis fungoides, adenosine deaminase activity was measured in sera of 15 patients with mycosis fungoides at various stages. The mean enzyme activity was 23.2 IU/l, which was high with statistical significance compared with healthy controls (P<0.001). Nine of twelve patients in the plaque stage (T2N0M0, IB) showed higher adenosine deaminase activity than did the normal population. The mean adenosine deaminase activity in sera in the patients in the plaque stage (T2N0M0, IB) was as high as 19.0 IU/l (range 13.7–21.4) with statistical significance compared with healthy control (P<0.001). Three tumor stage patients without visceral involvement (T3N0M0, IIB) showed higher levels of adenosine deaminase activity (19.7, 21.5, 24.4 IU/l). An erythrodermic patient (T4N0M0, III) also had a high adenosine deaminase activity 28.4 IU/l. Two tumor stage patients with organ involvement (T3N0M1, IVB) exhibited extremely high adenosine deaminase activity (60.9, 32.2 IU/l). The adenosine deaminase activity in sera showed a tendency to become higher with the extension of the stages. From the results obtained in this study, it is suggested that serum adenosine deaminase activity may reflect the tumor progress in mycosis fungoides.     

Adenosine deaminase activity in sera of patients with psoriasis, mycosis fungoides and adult T cell leukemia.

Adenosine deaminase activities in sera were measured in 18 psoriatic patients, 8 mycosis fungoides patients, and 9 patients with adult T cell leukemia. Adenosine deaminase activity in the sera of the psoriatic patients showed no significant increase. An elevated adenosine deaminase activity was observed in 7 of the 8 patients with mycosis fungoides and 8 of the 9 patients with adult T cell leukemia. After chemotherapy, adenosine deaminase activity in serum of acute adult T cell leukemia was reduced. Adenosine deaminase activity in the sera of 2 patients with smoldering adult T cell leukemia was more elevated, with exacerbation of the disease. It is difficult to grade the extension of the tumors in plaque stage mycosis fungoides and smoldering adult T cell leukemia. To know the progression of the disease is critical in determining its management. These results indicate that adenosine deaminase activity in serum is one of the reliable indicators for the grading of mycosis fungoides and adult T cell leukemia.     

TWO FORMS OF ADENOSINE DEAMINASE IN PIG EPIDERMIS (II)

Using pure pig skin epidermis, we investigated the biochemical nature of adenosine deaminase, Two different (large and small) forms of adenosine deaminase were separated by a gel filtration technique using Sephadex G-150 column chromatography. The molecular weight of the large form was 300,000 to 350,000 and that of the small form was 30,000 to 40,000. The kinetics of the two enzymes were quite similar, in terms of Km values for adenosine, substrate specificity, pH optima, temperature sensitivity, isoelectric points, and inhibition by coformycin, a tight-binding inhibitor of adenosine deaminase.     

ADENOSINE DEAMINASE ACTIVITY IN PERIPHERAL LYMPHOCYTES OF PSORIASIS AND SÉZARY'S SYNDROME

Adenosine deaminase (ADA) activity in peripheral lymphocytes were measured in 15 normal subjects, 15 psoriatic patients, and one patient with Sézary's syndrome. No significant differences were found in ADA activity between normal and psoriatic lymphocytes. A significant increase in ADA activity was observed in lymphocytes from the patient with Sézary's syndrome. The increased ADA activity in Sézary's syndrome was not accompanied by a change in the Km value for adenosine. The possible significance of the elevation of ADA activity in T-lymphocyte dysfunction was discussed.     

Increased succinate dehydrogenase activity of lymphocytes in eczema.

Succinate dehydrogenase activity has been studied in the peripheral blood lymphocytes from controls and patients with a variety of skin and other diseases. Increased activity has been found in eczematous dermatitis and dermographism, and also in one patient with chronic lymphatic leukemia. Normal levels were found in psoriasis. The enzyme activity is broadly correlated with the extent and activity of the disease process.     

Adenosine deaminase activity in leprosy

Adenosine deaminase (ADA) activity was studied in serum and peripheral blood lymphocytes of leprosy patients and healthy controls. Serum ADA levels were found to be elevated in tuberculoid as well as lepromatous cases compared to control subjects. Serum ADA activity was significantly higher in tuberculoid cases than in the lepromatous group. Lymphocyte adenosine deaminase activity showed a similar trend. These results suggest that, since the overall activity of the enzyme is not deficient in leprosy, the cellular immune abberation seen in the different types of leprosy may be due to abnormal proliferation of different subsets of lymphocytes in response to M. leprae.     

Crusted (Norwegian) scabies in a patient with smoldering adult T-cell leukemia

Crusted (Norwegian) scabies is described in a patient with smoldering adult T-cell leukemia (ATL). The patient is an 84-year-old Japanese woman who presented with widespread scaling over the trunk and limbs and crusted lesions on the scalp and ears. Microscopical examination of scrapings from the scalp and ears showed extraordinarily large numbers of scabies mites. The white blood cell count was 5.1 x 10(9)/L with 6% abnormal lymphocytes with mature nuclei that showed convolution and lobulation. Anti-HTLV-I antibodies were positive. Southern blot analysis revealed that the cellular DNA extracted from this patient's peripheral blood cells, digested with Pst I, showed the same pattern of provirus genome as the DNA from ATL patients. A diagnosis of crusted scabies with smoldering ATL was made. It is possible that crusted scabies could be an opportunistic infection and a pre-diagnostic sign of ATL.     

Treatment of cutaneous T cell lymphoma with 2'-deoxycoformycin (pentostatin)

2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered to three patients with cutaneous T cell lymphoma refractory to multiple treatment modalities. Patient 1, who received 5 mg/m2/day for 3 days at 35- to 71-day intervals, has achieved a complete remission greater than 16 months in duration. Patient 2 had progressive disease despite two courses of 2'-deoxycoformycin at a dose of 5 mg/m2/day for 3 days at 28-day intervals. The third patient, who was treated with 4 mg/m2 2'-deoxycoformycin weekly to biweekly, had an initial response, but the disease progressed after eight treatments. Only one patient had any side effects: Patient 1 developed reversible episcleritis, mild elevation of liver enzymes, and persistent nausea and vomiting. In red blood cells of all patients, there was near complete inhibition of adenosine deaminase (91% to 96%) and S-adenosylhomocysteine hydrolase (89% to 95%) activities with treatment. In peripheral blood lymphocytes, adenosine deaminase was inhibited by 85% to 98% and S-adenosylhomocysteine hydrolase by 51% to 88%. The deoxyadenosine triphosphate level, reflected by the total cellular adenine deoxyribonucleotide measurement in erythrocytes, was noted to be modestly elevated during treatment, with the highest level in the patient who demonstrated the only complete response and the only toxic effects. Low-dose 2'-deoxycoformycin appears to be safe but may be an insufficiently intensive regimen to treat refractory cutaneous T cell lymphoma. With proper biochemical monitoring, higher doses may be both safe and more effective.     

Distribution of natural killer cells and lymphocyte subclasses in Jessner's lymphocytic infiltration of the skin and in cutaneous lesions of discoid and systemic lupus erythematosus

We studied the cell infiltrates in biopsies from lymphocytic infiltration of the skin (LIS), with six monoclonal T cell antigen-specific antibodies and compared the reactivity pattern with those in biopsies from discoid and systemic lupus erythematosus skin lesions and allergic contact skin reactions. A newly described antibody (NK₉) recognizing natural killer (NK) cells and activated cytotoxic T lymphocytes was included, and the numbers and activity of circulating NK cells was determined. Immunohistochemical staining revealed that the numbers of NK₉-positive cells were highest in LIS. The distribution of T lymphocytes (OKTii + ve), helper T cells (OKT₄+ ve), suppressor T celts (OKT8 + ve), Langerhans cells (OKT6 + ve) and activated T cells (anti-Tac + ve) in LIS differed from those in DLE, SLE and allergic contact reactions. However, the number of circulating NK cells (large granular lymphocytes) and the NK activity in peripheral blood were normal in LIS. We conclude that in LIS a distinct type of T cell activation occurs; the cause of this remains to be determined.     

Adult T cell leukemia accompanied by annular elastolytic giant cell granuloma

We report a 74-year-old Japanese patient with adult T-cell leukemia who concurrently developed annular elastolytic giant cell granuloma. Initially, itchy granulomatous lesions developed on his face, nape of the neck and dorsa of the hands, but gradually erythematous plaques appeared on the back and lower limbs. The histology of the granulomatous lesions revealed coexistence of an epithelioid cell granuloma with giant cells that phagocytosed elastic fibres in the dermis and Pautrier's microabscesses in the overlying epidermis. Subsequent sequential histological studies of an erythematous plaque revealed the development of granulomatous changes in pre-existing lymphomatous lesions. Laboratory data revealed the presence of antibody to human T cell leukemia/lymphoma virus I and 14,200 white cells/mm3 in the peripheral blood with 2% atypical lymphocytes which eventually amounted to 30%, one month before his death.     

Erythema multiforme-like lesions associated with lesional infiltration of tumor cells occurring with adult T-cell lymphoma/leukemia

A 66‐year‐old Japanese woman visited our hospital with a complaint of multiple papules on her trunk and extremities. She had a past medical history of appendicitis and blood transfusion 40 years earlier. For the last 10 years, she had noticed multiple, gradually enlarging papulonodular lesions with surrounding erythema on her trunk and extremities. Physical examination revealed multiple, violaceous papules or nodules, less than 10 mm in diameter, with surrounding erythema on her trunk and extremities ( Fig. 1 ). The results of routine laboratory examinations, including blood count, liver function, renal function, serum calcium, and lactate dehydrogenase, were within the normal range. The peripheral blood picture showed a small population of atypical lymphocytes below 1% of the total white blood cells. Human T‐cell lymphotropic virus type I (HTLV‐I) serology was positive. A microscopic examination of a biopsy specimen from a nodule on the abdomen demonstrated diffuse infiltration of large pleomorphic T cells in the upper and middle dermis, although highly atypical lymphocytes, so‐called flower cells, could not be recognized. Infiltrating lymphocytes were positive for CD2, CD3, CD4, CD5, CD7, and CD45, but negative for CD8 and CD20, immunohistologically. Bone marrow biopsy also demonstrated the infiltration of lymphocytes expressing CD2, CD3, CD4, CD5, and CD7, but not CD25. Southern blot analysis of the infiltrating cells in the skin revealed an integration of HTLV‐I proviral DNA in T cells. Clonal T‐cell receptor γ gene rearrangement was detected in skin and bone marrow biopsies. No abnormal mass or bone defect was detected by chest or abdominal computed tomographic scanning, systemic gallium‐67 citrate scintigraphy, or chest radiography. On the basis of these data, the patient was diagnosed with smouldering‐type adult T‐cell lymphoma/leukemia.

Figure 1 Open in figure viewer PowerPoint Clinical features of adult T‐cell lymphoma/leukemia (ATL) skin lesions. Crusted, target‐like, dark‐red plaques on the lower legs     

Detection of HTLV-I proviral DNA in sarcoidosis

'Sarcoidosis-lymphoma syndrome' is known as an association of sarcoidosis with malignant lymphoma. We report a 56-year-old woman with systemic sarcoidosis who was seropositive for antibody against human T cell lymphoma/leukemia virus type I (HTLV-I). This patient showed integration of HTLV-I proviral DNA within cutaneous sarcoid nodules, but not in peripheral blood mononuclear cells. Neither atypical lymphocytes nor a T cell receptor beta1 gene rearrangement were observed in peripheral blood mononuclear cells or in cutaneous nodules, indicating that the patient did not have a smouldering type of adult T cell lymphoma/leukemia. Detection of integration of HTLV-I proviral DNA in cutaneous sarcoid nodules could suggest that the sarcoid nodules might have been generated as a protective response to chronic stimuli of HTLV-I.     

HTLV-I-associated myelopathy in a patient with adult T-cell leukemia

Disseminated erythematous papules and plaques developed in a 60-year-old man 3 years before the appearance of neurologic manifestations. A biopsy specimen of the plaque revealed Pautrier's microabscess and a dense mononuclear cell infiltration with atypical convoluted nuclei in the papillary dermis. These cells were helper/inducer T lymphocytes that expressed the interleukin 2 receptor. The patient's white blood cell count was normal, but 1% atypical lymphocytes and a high titer of anti-human T-lymphotropic virus (HTLV)-I antibody were detected in his serum. A smoldering type of adult T-cell leukemia was diagnosed. While he was being treated with PUVA, a gait disturbance developed. A high titer of anti-HTLV-I antibody, characteristic of HTLV-I-associated myelopathy, was demonstrated in his cerebrospinal fluid.     

Cutaneous lymphocyte antigen expression in benign and neoplastic cutaneous B- and T-cell lymphoid infiltrates

Background: Cutaneous lymphocyte‐associated antigen (CLA) is expressed in resident cutaneous T lymphocytes, high endothelial venules, peripheral monocytes, granulocytes and a small percentage of memory B cells. It has been postulated to be an important factor in homing of lymphocytes to the skin because of its function as a ligand for E‐selectin expressed on cutaneous endothelial cells. Design: We investigated the expression of CLA using the HECA‐452 antibody on paraffin‐embedded, formalin‐fixed tissue in a variety of reactive, neoplastic and preneoplastic cutaneous lymphoid infiltrates of T‐ and B‐cell derivation. Results: CLA was expressed at high levels in various types of inflammatory dermatoses with the exception of lupus erythematosus. High levels of CLA expression were seen in epidermotropic T‐cell dyscrasias and epidermotropic T‐cell lymphomas including mycosis fungoides (MF) and adult T‐cell leukemia/lymphoma (ATCLL). A loss of CLA in tumors normally positive for CLA was a feature of disease progression best exemplified by tumor‐stage MF and acute ATCLL. There was a lack of CLA expression in those lymphocytic infiltrates manifesting subcutaneous localization including lupus profundus, panniculitis‐like T‐cell lymphoma and atypical lymphocytic lobular panniculitis. CLA expression was not only observed in primary cutaneous anaplastic large cell lymphoma but also seen in cases of nodal anaplastic large cell lymphoma secondarily involving the skin and was negative in cases of nodal anaplastic large cell lymphoma without any established skin involvement. An oligodot pattern defined a novel reaction pattern in those aggressive systemic dyscrasias with a proclivity to involve the skin. CLA was negative in the majority of B‐cell lymphomas. Conclusions: CLA plays a role in the pattern of T‐cell lymphocyte migration in the skin and subcutis in both reactive and neoplastic states. An alteration in the expression of this marker, whether it is in the context of the acquisition of expression in a cell that is normally CLA negative or its loss of expression, may define a key event in determining cutaneous and extracutaneous hematopoietic cell distribution.     

Adult T‐cell leukemia–lymphoma associated with follicular mucinosis

Follicular mucinosis (alopecia mucinosa) is often associated with malignancies including mycosis fungoides and Sézary syndrome, but not adult T‐cell leukemia–lymphoma (ATLL). We report a 49‐year‐old male patient who had pruritic follicular papules and erythemas clinically, and follicular and perifollicular infiltrates and follicular mucin deposition histopathologically. The patient showed 11% of flower‐shaped atypical lymphocytes in blood examination and positive human T‐cell leukemia virus type 1 antibody in serology, consistent with the chronic type of ATLL. This case seems to be a very rare association of follicular mucinosis and chronic ATLL, suggesting that malignant T cells may have a feature of folliculotropism as well as epidermotropism.     

A membrane protein preferentially expressed by a subpopulation of immature lymphoid cells, epidermal basal keratinocytes, and other epithelial cells

A murine monoclonal antibody, designated EL-1, was raised by immunization with a human malignant T cell line. It reacted specifically with a membrane antigen expressed on T and B lymphoblastoid cell lines, a subpopulation of normal thymocytes and bone marrow lymphocytes, lymphocytes from a subset of patients with non-B, non-T cell acute lymphoblastic leukemia or T cell acute lymphoblastic leukemia and epithelial stem cells. The latter reactivity was especially striking in the skin, where only basal epidermal keratinocytes and epidermal appendages, including eccrine sweat glands, sebaceous glands and hair follicles, stained positively. A human epidermoid carcinoma cell line was also stained by EL-1. Suprabasilar keratinocytes and acellular keratin did not stain. However, in vitro proliferating fetal lung fibroblasts stained positively. Membrane immunoprecipitation analysis demonstrated that the antigen recognized by antibody EL-1 is a single protein of molecular weight 105 kilodaltons which did not change with exhaustive chemical reduction. Metabolic radiolabeling studies demonstrated that this protein is synthesized by the cell and not merely taken up from the culture medium. This antibody can be useful in studying keratinocyte differentiation in epidermal malignancies and normal skin.     

T-cell receptor-gamma/delta bearing lymphocytes in normal and inflammatory human skin

Murine dendritic epidermal T cells (DETC) were recently reported to express T-cell receptor (TCR)-gamma/delta chains. In a search for the human equivalent of these cells, we tested normal and lesional skin with MoAb which react with the TCR-gamma/delta heterodimer. We performed indirect immunofluorescence (IF) on epidermal sheets, and alkaline-phosphatase-anti-alkaline-phosphatase complex (APAAP) on epidermal cell smears. Frozen skin sections from normal skin and various cutaneous lymphocyte infiltrates were also studied. A few CD3+ T lymphocytes were consistently found in normal epidermis. Most of these cells appeared to be TCR-alpha/beta +, and some CD4+ or CD8+. On epidermal sheets and cell smears, only a very small TCR-gamma/delta + cell population was visualized (less than 0.1% of the total). On normal skin sections, we observed 0 to 3 gamma/delta + cells per section. When present, they were often located in the epidermal basal layer, and were round or dendritic. Double immunolabeling revealed that gamma/delta + cells differed from CD1+ Langerhans cells, and that they had a similar phenotypic pattern as gamma/delta + peripheral lymphocytes (PBL): CD2+, CD3+, CD4-, and CD8-. Immunostaining from various inflammatory skin lesions showed that the dermal infiltrates included CD3+ T lymphocytes but virtually no gamma/delta + cells. Only a few gamma/delta + cells were found in some end-evolutive infiltrates. Taken together, these results strongly suggest that normal human epidermis occasionally harbors TCR-gamma/delta complex bearing lymphocytes, which constitute a small fraction of the CD3+ cutaneous T lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monocyte activating factor originally found in sarcoidosis sera. II. Production of a similar factor by a human acute monocytic leukemia cell line (THP-1)

The culture medium of a human acute monocytic leukemia cell line (THP-1) was able to induce normal human monocytes to spread. No such ability was found either in the culture medium of a promyelocytic leukemia cell line (HL-60) nor in that of a diploid human fibroblast cell line (Flow 7000). Gel filtration of the culture medium of THP-1 cells on a size exclusion column (TSKgel G3000SW) revealed that the most obvious monocyte spreading activity was found in the fraction eluted at the position with a molecular weight of about 70,000. This fraction was also able to increase production of angiotensin converting enzyme and Fc receptor sites for IgG on normal human monocytes.     

TWO FORMS OF ADENOSINE DEAMINASE IN PIG EPIDERMIS

Molecular heterogeneity of adenosine deaminase in pig epidermis is reported. Gel filtration of pig skin extracts with Sephadex G-150 revealed the existence of two forms of adenosine deaminase. Molecular weights of the enzymes were around 30,000–40,000 and 300,000–350,000 respectively. Several catalytic properties of these two adenosine deaminases were quite similar: Km value, substrate specificity, pH activity profile, and the effect of coformycin, a strong inhibitor of adenosine deaminase.