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PURPOSE: This phase II study was undertaken to assess the efficacy and toxicity of the addition of continuous low-dose interferon alfa-2a (IFN) to fludarabine in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS). PATIENTS AND METHODS: Thirty-five patients were treated with fludarabine 25 mg/m2 intravenously (IV) on days 1 to 5 every 28 days along with IFN 5 x 10(6) U/m2 subcutaneously three times per week continuously for up to eight cycles. IFN doses were escalated to 7.5 x 10(6)/m2 at day 29 if constitutional toxicities were less than grade 3. Twenty-one patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), and 10 of these had received prior deoxycoformycin (pentostatin; DCF) and intermittent high-dose IFN; seven had received only topical therapies, and seven were untreated. RESULTS: Four patients achieved a complete response (CR) and 14 achieved a partial response (PR) for an overall response rate of 51% (95% confidence interval, 35% to 70%). Four of 11 patients with visceral involvement responded. The median progression-free survival duration of the patients who responded was 5.9 months, and three of the complete responders are in unmaintained response after 18 to 35 months. Grade 3 or 4 hematologic toxicity occurred in 21 patients, including two who developed persistent bone marrow aplasia. Eighteen patients developed infections during therapy, including five with herpes zoster, one with Pneumocystis carinii, one with extrapulmonary tuberculosis, and two with disseminated toxoplasmosis. CONCLUSION: The combination of fludarabine with continuous low-dose IFN is an active regimen in patients with advanced MF/SS, including patients with visceral involvement and patients who progressed after prior therapy with DCF and IFN. This regimen has induced unmaintained remissions in a small subset of patients.

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PURPOSE: This phase II study was undertaken to assess the efficacy and toxicity of alternating administration of pentostatin (deoxycoformycin [DCF]) and interferon alfa-2a (IFN) in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS). PATIENTS AND METHODS: Forty-one patients underwent therapy with alternating cycles of DCF 4 mg/m2 intravenously (IV) days 1 through 3 and IFN 10 million U/m2 intramuscularly (IM) day 22, and 50 million U/m2 intramuscularly (IM) days 23 through 26. Twenty-nine patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), six had not responded to topical therapies, and six had no previous treatment. RESULTS: Two patients achieved a complete response (CR) and 15 achieved a partial response (PR), for an overall response rate of 41% (95% confidence interval, 26% to 58%). No responses were observed in the seven patients with visceral involvement. The median progression-free survival of patients who responded was 13.1 months. IFN-related constitutional symptoms were reported in 39% of patients; severe toxicities included cardiomyopathy in one patient, acute and chronic pulmonary dysfunction in four, and reversible mental status changes in two. Seven patients developed herpes zoster during therapy and six had staphylococcal bacteremia. CONCLUSION: These results suggest that the combination of DCF and IFN is an active regimen in MF patients without visceral involvement.

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We investigated the correlation between the detection of clonal rearrangement of the T-cell antigen receptor gene (TCRR) in lymph node tissue with histopathologic lymph node classification in 33 patients with mycosis fungoides with and without the Sezary Syndrome. We analyzed DNA extracted from lymph nodes that were histologically uninvolved (LN1-2), dermatopathic nodes with clusters of atypical cells (LN3), and nodes effaced with lymphoma (LN4) and found TCRR in none of five LN1-2 nodes, 8 of 17 LN3 nodes, and 10 of 11 LN4 nodes. Further, the detection of TCRR correlated with presence of palpable adenopathy (P2 less than .0001) and was associated with a worse survival (P2 = .0024). Within the subgroup of patients with LN3 nodes, there was a trend (P2 = .14) toward inferior survival if nodes were involved by TCRR, irrespective of extent of skin disease. We conclude that detection of TCRR in nodes from mycosis fungoides patients is an objective and reliable means of assessing tumor infiltration of lymph node and is associated with an inferior survival.

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Mycosis fungoides is a T-cell lymphoma that arises in the skin and progresses at highly variable rates. Nonradomized studies have suggested that early aggressive therapy may improve the prognosis in this usually fatal disease. We studied 103 patients with mycosis fungoides, who, after complete staging, were randomly assigned to receive either combination therapy, consisting of 3000 cGy of electron-beam radiation to the skin combined with parenteral chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine (n = 52) or sequential topical treatment (n = 51). The prognostic factors were well balanced in the two groups. Combined therapy produced considerable toxicity: 12 patients required hospitalization for fever and transient neutropenia, 5 had congestive heart failure, and 2 were later found to have acute nonlymphocytic leukemia. Patients receiving combined therapy had a significantly higher rate of complete response, documented by biopsy, than patients receiving conservative therapy (38 percent vs. 18 percent; P = 0.032). After a median follow-up of 75 months, however, there was no significant difference between the treatment groups in disease-free or overall survival. We conclude that early aggressive therapy with radiation and chemotherapy does not improve the prognosis for patients with mycosis fungoides as compared with conservative treatment beginning with sequential topical therapies.

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STUDY OBJECTIVE: To determine the optimal staging evaluation at the time of initial diagnosis of mycosis fungoides or the Sézary syndrome. DESIGN: Retrospective review of a uniformly staged inception cohort. SETTING: Single-institution tertiary care center. PATIENTS: 152 consecutive patients who had mycosis fungoides with or without the Sézary syndrome within 6 months of the initial definitive diagnosis. INTERVENTION: A detailed staging evaluation including physical examination, routine laboratory studies, chest roentgenogram, lymphangiogram, peripheral blood smear, lymph node biopsy, bone marrow aspirate or biopsy, and liver biopsy in selected patients. MEASUREMENTS AND MAIN RESULTS: Univariate adverse prognostic features at initial diagnosis in patients with mycosis fungoides included (P less than 0.01) one or more cutaneous tumors or generalized erythroderma, adenopathy, blood smear involvement with Sézary cells, lymph node effacement, eosinophilia, and visceral involvement. Important, independent prognostic factors in a multivariate analysis are the presence of visceral disease and type of skin involvement. CONCLUSIONS: A staging system based on histopathologic evaluation of skin, lymph nodes, blood, and visceral sites provides more comprehensive prognostic information than clinical evaluation of skin disease and adenopathy. Patients may be divided at initial presentation into three prognostic groups: good-risk patients, who have plaque-only skin disease without lymph node, blood, or visceral involvement (median survival, greater than 12 years); intermediate-risk patients, who have cutaneous tumors, erythroderma, or plaque disease with node or blood involvement but no visceral disease or node effacement (median survival, 5 years); and poor-risk patients, who have visceral involvement or node effacement (median survival, 2.5 years).

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Peripheral blood lymphocyte morphology was evaluated prospectively by light microscopy of blood smears and E rosette preparations in 160 patients with cutaneous T cell lymphoma (CTCL). Blood involvement was related to the type of cutaneous T-stage, being present in 90% of patients with erythroderma (T4), 27% of those with cutaneous tumors (T3), 9% of those with generalized (T2), and 0% of those with limited skin plaques (T1). Untreated patients with blood involvement (38 of 105) had a higher frequency of CTCL in lymph nodes and viscera and survival inferior to that of patients with normal or nondiagnostic lymphocyte morphology (P less than .001). Multivariate analysis showed skin stage and age to be the most important pretreatment risk factors for survival. Although blood involvement was not an independent risk factor for the entire group, it appeared to have some adverse influence in the T2/T3 subsets (P = .051). Both lymphocytosis and size distribution of the circulating CTCL cells at initial diagnosis influenced survival. Patients with "mixed cell" cytology (greater than 20% large [greater than 11 microns] CTCL cells), had a worse survival than those with predominantly small circulating CTCL cells (P = .009). The former were more likely to have aggressive features, including lymph node effacement by tumor (P less than .001) and visceral disease (P = .074), than were "small cell" patients. Our data indicate that detailed review of the blood lymphocyte morphology in patients with diagnosed or suspected CTCL is helpful in predicting extent of disease and prognosis.

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Thirty-nine patients with cutaneous T cell lymphoma (CTCL; including mycosis fungoides or the Sezary syndrome) with no previous treatment other than topical therapy or oral corticosteroids, received total skin electron beam irradiation (TSEB) and either sequential or simultaneous systemic chemotherapy. Median follow-up, measured from the time of initiation of therapy to the time of analysis, is in excess of 6 years and extends to 100+ months. Thirteen patients with stage I disease (limited to skin with no adenopathy) received 3,000 rad total skin electron beam irradiation followed by three 2-week courses of daily intravenous (IV) mechlorethamine. Twenty-six patients with advanced disease (stage II-IV) received 2,400 rad of TSEB and simultaneous chemotherapy with two alternating three-drug regimens: vinblastine, doxorubicin, and bleomycin (VAB) alternating with cyclophosphamide, methotrexate, and prednisone (CMP) administered over 54 weeks. The overall response rate was 92% with 16 of 39 patients (41%) achieving a histologically documented complete response (CR). Stage I patients had a significantly increased CR rate (77%) compared with stage II-IV (P less than .01). The overall 6-year survival was 92% for stage I patients and 26% for stage II-IV patients (23%) (P less than .001). Among ten completely responding stage I patients, six remain alive and disease-free in excess of 72 months. The median disease-free survival is 26 months for completely responding stage II-IV patients (P = .04), but none are continuous disease-free survivors after protocol treatment. We conclude that combined modality treatment can be safely administered and produces prolonged disease-free survival in some stage I patients, but not in more advanced stage patients.

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Mycosis fungoides and the Sézary syndrome share common cutaneous histopathologic features, and this spectrum of malignant disease is referred to here as cutaneous T-cell lymphoma (CTCL). A method (LN classification) for describing the histopathologic features of lymph nodes in CTCL is presented. In this system, lymph node biopsy specimens are scored according to the number of atypical lymphoid cells in T-cell-dependent paracortical zones and the preservation or distortion of the lymph node architecture. Lymph node architecture is preserved in lymph nodes scored LN1 to LN3, and these nodes may have coexistent dermatopathic change. LN1 nodes have single infrequent atypical lymphocytes in paracortical T-cell regions. LN2 nodes have small clusters of paracortical atypical cells. LN3 nodes have large clusters of atypical cells. LN4 nodes are partially or totally effaced by atypical cells. This system was used to classify 96 lymph node biopsy specimens obtained within six months of the initial diagnosis of CTCL; no LN1 nodes, 37 LN2, 44 LN3, and 15 LN4 nodes were found. The LN class was significantly correlated with the extent of skin, blood, and visceral involvement, as well as with survival. Patients with LN2 lymph nodes have an estimated five-year survival of 70 per cent, while patients with LN3 and LN4 nodes have estimated five-year survivals of 30 and 15 per cent, respectively. The survival differences between the LN subgroups were all significant (P less than 0.05). The LN classification system was clearly shown to be reproducible among experienced pathologists. The LN system for the histopathologic classification of lymph nodes in CTCL is of prognostic value and should be used to assess lymph node biopsies in patients with CTCL.

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A prospective pretreatment staging evaluation was done on 49 consecutive patients with mycosis fungoides or the Sézary syndrome to study patterns of disease spread and prognostic factors. Routine staging procedures included complete blood count, blood chemistries, chest roentgenogram, lymphangiogram, radionuclide scans, bone marrow aspiration and biopsy, liver biopsy, and lymph node biopsy. Special evaluations included cytogenetic analysis, electron microscopy, and T-cell cytology. Extracutaneous lymphoma was documented by light microscopy in 51% of patients and by the three special procedures in 88%. Extracutaneous lymphoma was most frequent in blood and lymph nodes; 18% of patients had visceral involvement. Patients with generalized erythroderma had a higher frequency of extracutaneous disease than did patients with cutaneous plaques and tumors by both light microscopy and special studies. Survival was directly related to the type of skin involvement and the presence or absence of extracutaneous disease. Systemic dissemination of cutaneous T-cell lymphoma is frequent, generally asymptomatic, and develops early via the circulation. These findings may explain why cutaneous therapies are associated with a high frequency of relapse.

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A 54-year-old male with diabetes, weight loss, glossitis and Candidiasis presented with the typical cutaneous eruption of necrolytic migratory erythema. The suspicion of pancreatic glucagonoma was confirmed by an elevated plasma glucagon level. Surgical removal of the pancreatic alpha cell tumor resulted in a complete disappearance of all symptoms. The importance of the recognition of the skin eruption of necrolytic migratory erythema as a clue to the presence of pancreatic glucagonoma is emphasized.

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Cytology of peripheral blood and lymph node lymphocytes from a group of unselected patients with cutaneous T cell lymphoma (CTCL) was studied by light microscopy. Twenty of 45 patients had circulating lymphocytes with convoluted nuclei recognized in routine Wright-Giemsa-stained peripheral blood smears. Cytocentrifuge preparations of E-rosetted lymphocytes showed that greater than 10% of the T cells had convoluted nuclei in each of 16 patients with positive blood smears and in six of 17 whose blood smears were negative or inconclusive. Peripheral blood involvement with greater than 10% convoluted T cells was most frequent in patients with erythroderma (100%) including those with normal of decreased lymphocyte counts, and was not uncommon in patients with mycosis fungoides in the plaque or tumor phase (42%). The light-microscopic morphology of the abnormal cells found in the patients with the plaque or tumor phase of mycosis fungoides was not distinguishable from that of the erythrodermic patients. Increased percentages (less than 15%) of T cells having convoluted nuclei were also found in the lymph node cell suspensions from CTCL patients with adenopathy (18 of 25 patients). These results suggest that a high frequency of extracutaneous involvement occurs in patient with CTCL, the clinical significance of which remains to be determined.

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This is an interim report of a double-blind multi-institutional study to examine the effect of chemotherapeutic agents applied topically to patients with mycosis fungoides. To date, 41 patch tests have been completed using 15 drugs. Five of the drugs produced some improvement, four were highly irritating, and six had no effect. This patch-testing study is a prelude to more extensive therapy trials.

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The history of occupational, environmental, and/or iatrogenic exposure to potential carcinogenic agents was obtained at the time of onset of skin disease in 43 of 44 patients with cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome) entering a National Cancer Institute therapeutic trial. A history of multiple exposures to these agents was common, the two most frequent being chemicals (91% of patients) and drugs (86%). Mean duration of expsosure was 13 years for chemicals and 18 years for drugs. The most common chemicals were air pollutants (39%), pesticides (36%), solvents and vapors (30%), and detergents and disinfectants (14%). Increased severity of disease was seen with increaed duration of chemical exposure in stage V cutaneous T-cell lymphomas only. The most frequent drugs besides tobacco (86%) were analgesics (20%), tranquilizers (18%), and thiazides (14%). Second cancers occurred in four patients, including two renal cell carcinomas, and a family history of cancer was present in 11. Fourteen of 22 patients questioned had recurrent herpes simplex. Patients with chronic skin disease who have long-term exposure to combinations of chemicals, physical agents, and biologic agents, are heavy smokers, or have recurrent herpes simplex appear to be prime candidates for developing mycosis fungoides or the Sézary syndrome.

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A case of documented Sézary syndrome, a cutaneous T-cell lymphoma, with gastrointestinal lymphocytic infiltration is presented. The symptom of diarrhea waxed and waned with the course of the disease process. Radiographic studies were normal, and no evidence of malabsorption was elicited. The diagnosis was established by endoscopic and biopsy techniques, with light and electron microscopy of colonic and small bowel biopsies demonstrating extensive infiltration with typical Sézary cells. To our knowledge this is the first reported case of gastrointestinal involvement in the Sézary syndrome.

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