Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis.

The clinical course of cutaneous T cell lymphoma (mycosis fungoides and Sezary syndrome) is generally indolent, but in occasional patients becomes fulminant. We found that biopsies from patients with accelerating disease can reveal cytologic transformation from previously observed small, convoluted lymphocytes to large cells that are similar to cells seen in large-cell lymphoma. The cerebriform nuclei characteristic of malignant T cells can only rarely be identified. Of 150 cutaneous T cell lymphoma patients we treated from 1976 to 1984, cytologic transformation was identified in 12 after review of peripheral blood smears and biopsies from skin, lymph nodes, and visceral sites. Patients who developed cytologic transformation were initially characterized by advanced stage (11 of 12), with lymph node effacement (seven of 11) and erythroderma (five of 12). The tumor cell DNA content after transformation was aneuploid (four of four), and the ability to form rosettes with sheep erythrocytes was retained in transformed cells (three of three). The median time from diagnosis of cutaneous T cell lymphoma to cytologic transformation was 21.5 months (range, 4 to 64), and the median survival from transformation was only 2 months (range, 0 to 19+). We conclude that cytologic transformation in cutaneous T cell lymphoma represents a distinct clinicopathologic entity, characterized by an aggressive clinical course.

Calcitriol levels in hypercalcemic patients with adult T-cell lymphoma.

Hypercalcemia is a frequent complication in patients with adult T-cell lymphoma. We measured serum calcitriol (1,25-dihydroxyvitamin D3) levels in five hypercalcemic patients with adult T-cell lymphoma and compared the values with those of five patients with mycosis fungoides, a T-cell neoplasm not associated with hypercalcemia. All five patients with adult T-cell lymphoma had calcitriol levels in or below the normal range. These data show that elevated calcitriol levels are not uniformly elevated in this disorder and may not be the usual cause of hypercalcemia in this subgroup of patients with lymphoma.

Combined modality treatment of cutaneous T cell lymphoma: results of a 6-year follow-up.

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.

Computed tomography of the abdomen and pelvis: documentation of tumor response and progression in disseminated prostate cancer.

Computed tomography of the abdomen and pelvis has been used to stage early prostatic cancer. We investigated its value in monitoring tumor response in more advanced disease. Serial computed tomography of the abdomen and pelvis was obtained along with multiple other staging tests prior to treatment and at 3- to 4-month intervals thereafter in 32 patients with stage D2 tumor treated initially with combination chemotherapy and with hormones at progression. Pretreatment lymphography with follow-up abdominal films was also performed. Initial computed tomography of the abdomen and pelvis showed evidence of node metastases in 35% of patients while lymphography was positive in 54%. Among 19 patients with tumor response and 25 with progression, the results of treatment were objectively documented by improvement or worsening, respectively, in a mean of 5.1 and 5.0 other staging tests, exclusive of computed tomography. Computed tomography of the abdomen and pelvis improved in 85% of responding patients examined. Progression was confirmed by worsening of computed tomography in 32%. Although lymphography was often abnormal prior to treatment, in our hands it was not useful in serial monitoring of tumor status. We conclude that serial computed tomography of the abdomen and pelvis, when initially positive, is a useful test to document objectively tumor response and progression in disseminated prostatic cancer.

Lymphokine-induced monocytic differentiation as a possible mechanism for hypercalcemia associated with adult T-cell lymphoma.

Patients with adult T-cell lymphoma frequently have hypercalcemia. Bone biopsies from these patients show increased numbers of osteoclasts. We hypothesized that substances produced by the malignant T-cell caused these phenomena by increasing the formation and/or activity of osteoclasts. To test this hypothesis, we cultured U937 cells in conditioned media from a clonal T-cell line derived from a patient with adult T-cell lymphoma and hypercalcemia. This conditioned media produced maturational changes in the U937 cells as evidenced by decreased proliferation, increased adherence, increased expression of complement receptors, and formation of multinucleated giant cells. These changes were synergistically enhanced by the addition of 1 alpha, 25-dihydroxyvitamin D3 which is known to promote monocyte differentiation. We also tested interleukin 2 and gamma- and alpha-interferon to see if they were responsible for the maturational changes. Although some effects were seen, these lymphokines could not account for all the changes induced by the T-cell conditioned media. These findings support the above hypothesis and suggest that other unidentified factors may promote the differentiation of osteoclast precursors and be involved in the pathogenesis of the hypercalcemia.

In vitro assays of chemotherapeutic sensitivity.

The concept of designing an in vitro assay to predict in vivo antineoplastic drug activity that would provide the medical oncologist with the necessary data to define beneficial drug regimens is appropriate; however, the optimal assay has been elusive over the last 3 decades. It is hoped that information gained from attempts to design such an assay has provided further refinements that will bring the goal in reach. The initial studies of drug-induced cell cytotoxicity employing changes in cell metabolism or the cell's ability to exclude supravital dye or reduction in the incorporation of radiolabeled precursors into DNA, RNA, or proteins provided the starting point for developing such an assay. Although initial enthusiasm existed with each of these assays, it soon became apparent that their predictive value was not sufficiently specific to warrant broad application. Modification of the dye exclusion assay or the combination of the clonogenic assay with radio precursor incorporation may provide better predictability. Confirmation of these assays awaits completion of randomized clinical trials. More recently, led by the appreciation of a subset of self-renewing cells--that is, "stem cells" present in the bone marrow--Salmon and colleagues reported on the pertinent applications of the clonogenic assay in predicting in vivo patient responses to chemotherapy. Since this report, considerable advances in development, improvement, and application of the clonogenic assay have occurred. This assay has been applied to preclinical screening of new antineoplastic agents, cytogenetic analysis of human tumor specimens, and the identification of growth factors and hormones for different tumor types. Despite these major advances in applying and solving technical problems associated with the assay, major problems continue to exist, the foremost being the overall poor growth of most tumor specimens in the assay such that in vitro chemosensitivity data can be obtained only in 30% to 40% of specimens. Indeed, because only this fraction grows, it is important to demonstrate that "growth itself" in the assay is not an independent prognostic factor. Further, pharmacologic considerations will have to be completed for each drug such that in vitro studies of drug exposure and drug/drug interaction will mimic the clinical situation. Constant critical analysis of this and other assays will no doubt lead to improvements, particularly their use as tools for biologic studies. Currently, insufficient data on prospective trials evaluating in vitro assays in predicting clinical responses are available.(ABSTRACT TRUNCATED AT 400 WORDS)

Recombinant leukocyte A interferon: an active agent in advanced cutaneous T-cell lymphomas.

High-dose recombinant leukocyte A interferon (50 X 10(6) U/m2 body surface area, intramuscularly, three times weekly) was tested in a clinical trial involving patients with advanced cutaneous T-cell lymphomas to determine its effectiveness and toxicity. All 20 patients had advanced stages of disease refractory to two or more standard therapies. Objective partial remissions lasting 3 months to more than 25 months (median, 5 months) were documented in 9 patients. The major dose-limiting toxicity was a severe influenza-like syndrome with malaise, anorexia, depression, weight loss, and decreased performance status; this effect was reversible after dose reductions in all patients and did not recur with re-escalation of doses in 10 patients. This interferon preparation is highly effective in the treatment of advanced refractory cutaneous T-cell lymphomas, and new schedules to reduce toxicity and achieve complete responses, combined treatment with chemotherapy or serotherapy, and its use in earlier stages of disease should be investigated.

Immunocytochemical diagnosis of oat-cell carcinoma in pleural effusion.

Immunocytochemical studies were performed in order to accurately recognize the origin of tumor cells in a pleural effusion from a patient with a mediastinal mass. The immunoalkaline phosphatase technique was employed to examine several cell-specific surface antigens via their specific monoclonal antibodies. The tumor cells in this case did not have any demonstrable antigens of the human blood cells but did have abundance of an antigen specific for the tumor cells of oat-cell carcinoma. This diagnosis obtained by the immunochemical studies was confirmed by both cytologic and clinical findings. Immunocytochemical studies may become a mainstay for specific cytodiagnosis in the future.

Prostatic cancer presenting as metastatic adenocarcinoma of undetermined origin. Immunodiagnosis by prostatic acid phosphatase.

Adenocarcinoma of the prostate may occasionally present as distant metastatic disease. This tumor, if accurately identified, is amendable to effective treatment with hormonal manipulations. We have seen nine patients with prostatic cancer presenting as metastatic adenocarcinoma of undetermined origin: two presented with involvement in the lung and the mediastinum, five with left supraclavicular lymphadenopathy and two with known prostatic cancer with stable disease presented with supraclavicular lymphadenopathy. By employing an immunoperoxidase technique using prostatic acid phosphatase as the marker for the prostatic cells, we demonstrated the presence of the prostatic enzyme antigen in the paraffin embedded tissues from the metastatic tumor. This finding directed further investigation of the prostate gland leading to the discovery of the primary tumor in all nine patients. It may be beneficial to use this technique in all male patients with adenocarcinoma of undetermined primary site.

Cutaneous T-cell lymphoma: a review.

Cutaneous T-cell lymphomas define a spectrum of disorders associated with T-lymphocytic proliferation with clinical manifestations occurring in the skin during the course of the disease. This review has dealt with two rather uncommon disorders, namely mycosis fungoides and Sezary syndrome which are indolent malignant lymphomas, occurring primarily in the fifth decade, and affecting males most frequently. Historically, mycosis fungoides and Sezary syndrome have been described for a relatively short time. As witnessed by Table 2, little was known concerning these disorders, other than clinical and pathologic features, until the application of immunologic, cell biologic, and cytogenetic technology which burgeoned a multitude of questions. The discovery of TCGF has allowed for both continuous growth of normal and neoplastic T cells and for the clonal expansion of some malignant clones. The establishment of these continuous cultures allowed for: (1) investigation of the mechanism of TCGF production and stimulation of T-cell growth, and (2) identification of HTLV, a retrovirus found in cell cultures from two patients with CTCL, and subsequently from patients with Japanese adult T-cell lymphoma. In addition, the HTLV has been related to a more virulent form of T-cell malignancy. The exact etiologic role of this virus in the CTCL is presently the subject of intense investigation. Through the use of immunologic methods the malignant cell of CTCL has been pheno-typically and functionally characterized as a "helper/inducer" subtype (E rosette+, anti-T-cell antisera+, T11+, T1+, T3+, 3A1-, T6-, T8-) and usually Ia-, HLADR-. Clinical manifestations of the phenotype may be clinically apparent in the serologic abnormalities present in these disorders. Utilizing these methods to investigate these disorders may provide a key to the understanding of T-cell function and cellular immunity much as myeloma provided a model for the understanding of B cells and immunity. Clinically and pathologically, these disorders behave as malignant indolent lymphomas with spread from localized cutaneous lesions to extracutaneous involvement of the blood, lymph nodes, and viscera culminating in the death of the patient from either organ dysfunction or infectious complications. At autopsy, this extracutaneous involvement is more pronounced than what was expected ante-mortem. Application of prospective staging techniques employing such special procedures as E-rosette cytology, cytogenetics, and electron microscopy in addition to usual light microscopy studies has demonstrated a greater percentage of extracutaneous involvement than otherwise expected.(ABSTRACT TRUNCATED AT 400 WORDS)

Bilateral occlusion of the central retinal artery associated with hyperglobulinemia in hairy cell leukemia.

A 49-year-old man with hairy cell leukemia experienced occlusion of both central retinal arteries in a 6-day period. Hyperglobulinemia was noted; however, immunoperoxidase studies failed to demonstrate that the hairy cells had produced the excess immunoglobulins. None of the other, more common, causes of occlusion of the central retinal artery were present. Plasmapheresis, in addition to more traditional methods of treatment, resulted in stabilization of the patient's vision. Subsequent fluorescein angiography revealed markedly diminished choroidal perfusion as well as delayed retinal perfusion. This appears to be the first account of bilateral occlusion of the central retinal artery secondary to a hyperviscosity syndrome, as well as the first description of ocular involvement by hairy cell leukemia. Speculation as to how the hyperglobulinemia related to the ocular manifestations is offered.

Therapeutic leukapheresis in hairy cell leukemia.

Therapeutic leukapheresis was performed on three patients, and plasmapheresis on two patients with far-advanced hairy cell leukemia. Two of the three patients who were treated with leukapheresis had many hairy cells in their peripheral blood, while the other had relatively few. In each patient, dramatic clinical and hematologic improvements were observed that have sustained for more than 23, 10, and 26 months, respectively. Plasmapheresis of similar intensity failed to show any appreciable therapeutic effects on two other patients with similar clinical and hematologic findings. We believe that the favorable therapeutic effects of leukapheresis are due to the removal of factors capable of inhibiting normal hematopoiesis. This factor(s) is present in the cells that were removed by leukapheresis. The exact nature of this factor(s) or the cells that produce this factor(s) remains to be identified.

Unusual manifestations of hypereosinophilia.

The hypereosinophilic syndrome is a heterogeneous group of clinical disorders comprising a spectrum of pathologic conditions. We have described a patient with chronic eosinophilia for eight years. His course of progressive organ dysfunction and tissue infiltration by eosinophils, with myelofibrosis, lytic bone lesions, hepatomegaly, and generalized adenopathy are most compatible with a chronic myeloproliferative syndrome.

Orbital metastasis from prostatic carcinoma. Identification by an immunoperoxidase technique.

A patient was seen initially with an orbital tumor causing blindness of the left eye. Although disseminated prostatic carcinoma was found, the origin of the orbital tumor was not established until prostate antigen was demonstrated in biopsy specimens by an immunoperoxidase technique. Orbital metastasis from prostatic carcinoma has been reported in 16 cases. Confirmation of the diagnosis may be difficult and, in the past, has largely been indirect as judged by clinical trial. The immunoperoxidase technique for detecting prostate antigen in tissue sections is both sensitive and specific. Application of this technique resulted in the diagnosis of this technique resulted in the diagnosis of this unusual manifestation of metastatic prostate cancer. The possibility of additional clinical applications of this immunohistochemical technique within the field of ophthalmology is raised.