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Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation
Subcutaneous T-cell lymphoma treated with systemic chemotherapy, autologous stem cell support, and limb amputation Claire L. Haycox, MD, PhD,^ Anthony L. Back, MD,'' Gregory J. Raugi, MD, PhD,'^ and Michael Piepkom, MD, PhD^ Seattle, Washington Subcutaneous T-cell lymphoma is an unusual variant of peripheral T-cell lymphoma in which the malignant infiltrate preferentially involves the subcutis. The disease is often initially misdiagnosed as a benign inflammatory panniculitis or a granulomatous disease. We describe subcutaneous T-cell lymphoma in a 39-year-old man who was treated with systemic chemotherapy, autologous stem cell support, and amputation of the limb primarily involved with the lymphomatous infiltrate. This is the first report of amputation being included in the treatment regimen of subcutaneous T-cell lymphoma. Because preferential involvement of the extremities often occurs in patients with subcutaneous T-cell lymphoma, surgical debulking of refractory disease by partial or complete limb amputation may be a useful therapeutic adjunct. (J Am Acad Dermatol 1997;37:832-5.)
There have been at least 27 cases of subcutaneous T-cell lymphoma reported in the literature^'-^. This unusual variant of peripheral T-cell lymphoma has been described as a diagnostic trap"* because clinically and histologically it is often initially misdiagnosed as a benign inflammatory panniculitis or a granulomatous disease. In many cases, this has resulted in a delay in diagnosis and treatment.^'^'^'^ This is unfortunate because the disease often has an aggressive course and is rapidly fatal. Of the reported cases of subcutaneous T-cell lymphoma 15 of 25 (60%) patients died from their lymphoma, despite aggressive chemotherapy, radiation therapy, or both, most of them within a period of several months to a few years.^'^ We describe a patient with subcutaneous T-cell lymphoma who was treated with systemic chemotherapy, autologous stem cell support, and amputation of the limb primarily
ORTHO This article is made possible through an educational grant I'^te'J from the Dermatological Division, Ortho Pharmaceutical \ly Corporation. From the Division of Dermatology, University of Washington, Seattle" and the Department of Oncology '' and the Division of Dermatology,'^ Veteran's Administration Medical Center, Seattle. Reprint requests: Claire L. Haycox, MD, PhD, University of Washington, Division of Dermatology, Box 356524, Seattle, WA 98195-6524. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/82008
832
involved with the lymphomatous infiltrate. This is the first report of amputation included in the treatment of subcutaneous T-cell lymphoma. Because preferential involvement of the extremities is often present, this highly morbid, but potentially lifesaving measure may warrant consideration in other patients with subcutaneous T-cell lymphoma. CASE REPORT A 39-year-old white man had a 6-month history of a painful area of erythema, edema, and induration on his right calf, resulting in a marked increase in the circumference of the leg (Fig. 1, A). The patient also complained of excessive fatigue during the past several months, intermittent low-grade fevers, and a modest weight loss. Examination revealed several other red to purple subcutaneous nodules (some with apparent vascular ectasia) ranging in size from 1 to 3 cm diameter on his anterior abdominal and chest walls (Fig. 1, B). No lymphadenopathy was present. An abdominal computed tomography scan revealed more than 30 subclinical, subcutaneous nodules on his anterior abdominal wall. A deep incisional biopsy specimen of the leg lesion and punch biopsy specimens of the other nodules displayed large areas of coagulation necrosis and multiple aggregates of histiocytes and lymphocytes extending into the subcutaneous fat. Random lymphocytes appeared atypical (Fig. 2). In some areas the cellular infiltrate percolated between adipocytes, mimicking a panniculitis. Stains for acid-fast bacilli, bacteria, and fungi were negative. Immunocytochemistry showed the predominant cell type to be a monocytehistiocyte
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 2
Haycox et al. 833
Fig. 1. A, Marked edema of right calf at time oi piLsciiLilioii. B, Li\ tlkiiLiloiis iiudiilLi with associated vascular ectasia on abdominal wall.
(Mac 387+). The lymphocytes expressed the CD4 antigen. T-cell receptor gene rearrangement studies showed a clonal proliferation of CD4+ T-cells. A diagnosis of disseminated subcutaneous T-cell lymphoma was made. A bone marrow biopsy specimen and aspirate were negative for lymphoma. The patient received three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. He had a minimal response and experienced an increase in his right calf pain. He was then treated with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) chemotherapy for two cycles followed by an autologous stem cell harvest with cyclophosphamide, etoposide, and filgrastim (granulocyte colony stimulating factor). Concomitantly he received a total of 4500 cGy of radiation therapy to the right calf. This treatment resulted in regression of most of his skin nodules and a small decrease in the right calf lesion. Because of the refractory disease in his right calf, a through-the-knee amputation of the right leg was performed. The specimen revealed persistent lymphoma with no direct extension to surgical margins. After this, the patient received two cycles of ifosfamide, carboplatin, and etoposide (ICE) salvage chemotherapy. He then underwent an autologous peripheral blood stem cell transplant. The conditioning regimen for the transplant consisted of total body irradiation (1200 cGy), cyclophosphamide, and etoposide, followed by reinfusion of his cryopreserved stem cells. He had no major complications and demonstrated neutrophil recovery by day 10 after the transplant. Sixteen months after treatment the patient is well, without evidence of recurrent disease.
DISCUSSION
The accurate diagnosis of cutaneous lymphoproliferative diseases is often challenging; subcutaneous T-cell lymphoma is no exception.^ As in our patient, a prominent granulomatous stromal response often masks the less appreciable, malignant T-cell infiltrate.^'^ This granulomatous response can mimic many other diseases. At the time of the initial biopsy, cutaneous sarcoidosis, lepromatous leprosy, tuberculosis, leishmaniasis, and sinus histiocytosis were considered in the differential diagnosis because of the prominent granulomatous infiltrates. Most of these could be ruled out by special stains, immunocytochemical markers, or by culturing the tissue for organisms. However, cutaneous sarcoidosis can be particularly challenging to exclude and a case of subcutaneous T-cell lymphoma is reported in the literature that was initially misdiagnosed as sarcoidosis.^ These authors suggested that the masking granulomatous reaction is caused by lymphokine secretion by the neoplastic T-cells.^ Histologically, subcutaneous T-cell lymphoma is also reminiscent of several inflammatory panniculidities such as erythema nodosum, WeberChristian disease, and nonspecific granulomatous lobular panniculitis. Most reported cases of subcutaneous T-cell lymphoma that were initially misinterpreted were given one of these benign diagnoses.^'^'^"^*^ Two other cases were given a
834 Haycox et al.
Fig. 2. High-power view of infiltrate showing random atypical lymphocytes. (Hematoxylin-eosin stain; original magnification (x 400.)
presumptive diagnosis of lupus profundus.^"^^ In our case, although the histologic findings of the right calf lesion were suggestive of a panniculitis, this diagnosis was not clinically consistent with the other subcutaneous nodules present on the chest and abdominal walls. In our patient no definite angiocentric pattern was found to the lymphocytic infiltrate, but this feature has occasionally been observed in other cases of subcutaneous T-cell lymphoma. ^'^ Cutaneous lymphomatoid granulomatosis can present clinically with ulcerated subcutaneous nodules.'2 Therefore, if angiocentric or angiodestructive lymphohistiocytic proliferations are observed, the diagnosis of lymphomatoid granulomatosis is usually considered as well.^'^ The prognosis of subcutaneous T-cell lymphoma is poor, resulting in death in approximately 60% of patients within several months to a few years. ^'^ Death is usually precipitated by the development of the hemophagocytic syndrome.^'^'^'^'^'ii'^^ This multisystem illness is characterized by fever, wasting, generalized adenopathy, hepatosplenomegaly, pancytopenia, and coagulopathy. The most consistent histopathologic feature in hemophagocytic syndrome is the presence of mature histiocytes containing engulfed erythrocytes or other hematopoietic cells, also referred to as cytophagic histiocytosis. The hemophagocytic syndrome is not specific to subcutaneous T-cell lymphoma and has been reported in association with other lymphomas and viral infections.^'* The hemophagocytic syndrome may be a result of the production
Journal of the American Academy of Dermatology November 1997
of lymphokines by either neoplastic T-cells or those present in response to viral infections.^"^'^^ Cytophagic histiocytosis was not observed in our patient, nor has it been observed in several other cases of subcutaneous T-cell lymphoma.^'^ When present, however, it should be viewed as a poor prognostic marker, indicating the need for expedient and aggressive therapy. In most reported cases, the treatment of subcutaneous T-cell lymphoma has consisted of lowdose chemotherapeutic regimens (e.g., CHOP) either alone or in conjunction with localized radiotherapy. Dismal outcomes with these regimens prompted Romero et al.^ to use high-dose chemotherapy (ICE) with autologous stem cell support in a 23-year-old woman with subcutaneous T-cell lymphoma of the upper and lower extremities. However, the patient succumbed to her disease when it transformed into a rapidly progressive leukemia.^ In our patient, the tumor in the right calf continued to enlarge when the patient was treated with CHOP chemotherapy. Even more aggressive chemotherapy with two cycles of DHAP and concomitant localized radiation therapy did little to reduce the main tumor burden in the area of the right calf. Amputation of the right limb was considered necessary for treatment of persistent local disease. After the amputation, he also received high-dose chemotherapy with ICE and autologous stem cell support. This is the first report of amputation in a treatment protocol for subcutaneous T-cell lymphoma. In the patients reported to date, 25 of 27 (93%) had nodules involving their extremities. Surgical debulking by partial or complete limb amputation may therefore be a useful therapeutic adjunct for other patients with subcutaneous T-cell lymphoma. Although these procedures can have a high associated morbidity, we believe that limb amputation was probably a lifesaving procedure in our patient. REFERENCES 1. Romero LS, Goltz RW, Nagi C, et al. Subcutaneous Tcell lymphoma with associated hemophagocytic syndrome and terminal leukemic transformation. J Am Acad Dermatol 1996;34:904-9. 2. Prescott RJ. Subcutaneous T-cell lymphoma with florid granulomatous panniculitis. Histopathology 1992;20: 535-7. 3. Mehregan DA, Su WPD, Kurtin PJ. Subcutaneous T-cell lymphoma: a chnical, histopathologic, and immunohistochemical study of six cases. J Cutan Pathol 1994; 21:110-7.
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 2
4. Slater DN. Subcutaneous T-cell lymphoma with florid granulomatous panniculitis [letter]. Histopathology 1993;22:95. 5. Gonzalez CL, Medeiros J, Braziel RM, et al. T-cell lymphoma involving subcutaneous tissue. A clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Aurg Pathol 1991;15:17-27. 6. Pemiciaro C, Zalla MJ, White JW, et al. Subcutaneous Tcell lymphoma. Report of two additional cases and further observations. Arch Dermatol 1993;129:1171-6. 7. Slater DN. Diagnostic difficulties in 'non-mycotis' cutaneous lymphoproliferative diseases. Histopathology 1992;21:203-13. 8. Burg G, Dummer R, Wilheim M, et al. A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma. N Engl J Med 1991;325:1078-81. 9. Aronson IK, West DP, Variakojis D, et al. Panniculitis associated with cutaneous T-cell lymphoma and cytophagocytic histiocytosis. Br J Dermatol 1985; 112: 87-96. 10. Avinoach I, Halevy S, Argov S, et al. y/5 T-cell lym-
Haycox et al. 835
11. 12. 13.
14.
15.
phoma involving the subcutaneous tissue and associated with a hemopagocytic syndrome. Am J Dermatopathol 1994; 16:426-33. Cho KH, Oh JK, Kim CW, et al. Peripheral T-cell lymphoma involving subcutaneous tissue. Br J Dermatol 1995;132:290-5. Wood ML, Harrington CI, Slater DN, et al. Cutaneous lymphomatoid granulomatosis: a rare cause of recurrent skin ulceration. Br J Dermatol 1984;110:619-25. Kaplan MA, Jacobsen JO, Ferry JA, et al. T-cell lymphoma of the vulva in a renal allograft recipient with associated hemophagocytosis. Am J Surg Pathol 1993; 17:842-9. Smith KJ, Skelton HG, Yeager J, et al. Cutaneous histopathologic, immunohistochemical, and clinical manifestations in patients with hemophagocytic syndrome. Arch Dermatol 1992;128:193-200. Jaffa ES, Costa J, Fauci AS, et al. Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med 1983;75:741-9.
There have been at least 27 cases of subcutaneous T-cell lymphoma reported in the literature^'-^. This unusual variant of peripheral T-cell lymphoma has been described as a diagnostic trap"* because clinically and histologically it is often initially misdiagnosed as a benign inflammatory panniculitis or a granulomatous disease. In many cases, this has resulted in a delay in diagnosis and treatment.^'^'^'^ This is unfortunate because the disease often has an aggressive course and is rapidly fatal. Of the reported cases of subcutaneous T-cell lymphoma 15 of 25 (60%) patients died from their lymphoma, despite aggressive chemotherapy, radiation therapy, or both, most of them within a period of several months to a few years.^'^ We describe a patient with subcutaneous T-cell lymphoma who was treated with systemic chemotherapy, autologous stem cell support, and amputation of the limb primarily
ORTHO This article is made possible through an educational grant I'^te'J from the Dermatological Division, Ortho Pharmaceutical \ly Corporation. From the Division of Dermatology, University of Washington, Seattle" and the Department of Oncology '' and the Division of Dermatology,'^ Veteran's Administration Medical Center, Seattle. Reprint requests: Claire L. Haycox, MD, PhD, University of Washington, Division of Dermatology, Box 356524, Seattle, WA 98195-6524. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/82008
832
involved with the lymphomatous infiltrate. This is the first report of amputation included in the treatment of subcutaneous T-cell lymphoma. Because preferential involvement of the extremities is often present, this highly morbid, but potentially lifesaving measure may warrant consideration in other patients with subcutaneous T-cell lymphoma. CASE REPORT A 39-year-old white man had a 6-month history of a painful area of erythema, edema, and induration on his right calf, resulting in a marked increase in the circumference of the leg (Fig. 1, A). The patient also complained of excessive fatigue during the past several months, intermittent low-grade fevers, and a modest weight loss. Examination revealed several other red to purple subcutaneous nodules (some with apparent vascular ectasia) ranging in size from 1 to 3 cm diameter on his anterior abdominal and chest walls (Fig. 1, B). No lymphadenopathy was present. An abdominal computed tomography scan revealed more than 30 subclinical, subcutaneous nodules on his anterior abdominal wall. A deep incisional biopsy specimen of the leg lesion and punch biopsy specimens of the other nodules displayed large areas of coagulation necrosis and multiple aggregates of histiocytes and lymphocytes extending into the subcutaneous fat. Random lymphocytes appeared atypical (Fig. 2). In some areas the cellular infiltrate percolated between adipocytes, mimicking a panniculitis. Stains for acid-fast bacilli, bacteria, and fungi were negative. Immunocytochemistry showed the predominant cell type to be a monocytehistiocyte
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 2
Haycox et al. 833
Fig. 1. A, Marked edema of right calf at time oi piLsciiLilioii. B, Li\ tlkiiLiloiis iiudiilLi with associated vascular ectasia on abdominal wall.
(Mac 387+). The lymphocytes expressed the CD4 antigen. T-cell receptor gene rearrangement studies showed a clonal proliferation of CD4+ T-cells. A diagnosis of disseminated subcutaneous T-cell lymphoma was made. A bone marrow biopsy specimen and aspirate were negative for lymphoma. The patient received three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. He had a minimal response and experienced an increase in his right calf pain. He was then treated with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) chemotherapy for two cycles followed by an autologous stem cell harvest with cyclophosphamide, etoposide, and filgrastim (granulocyte colony stimulating factor). Concomitantly he received a total of 4500 cGy of radiation therapy to the right calf. This treatment resulted in regression of most of his skin nodules and a small decrease in the right calf lesion. Because of the refractory disease in his right calf, a through-the-knee amputation of the right leg was performed. The specimen revealed persistent lymphoma with no direct extension to surgical margins. After this, the patient received two cycles of ifosfamide, carboplatin, and etoposide (ICE) salvage chemotherapy. He then underwent an autologous peripheral blood stem cell transplant. The conditioning regimen for the transplant consisted of total body irradiation (1200 cGy), cyclophosphamide, and etoposide, followed by reinfusion of his cryopreserved stem cells. He had no major complications and demonstrated neutrophil recovery by day 10 after the transplant. Sixteen months after treatment the patient is well, without evidence of recurrent disease.
DISCUSSION
The accurate diagnosis of cutaneous lymphoproliferative diseases is often challenging; subcutaneous T-cell lymphoma is no exception.^ As in our patient, a prominent granulomatous stromal response often masks the less appreciable, malignant T-cell infiltrate.^'^ This granulomatous response can mimic many other diseases. At the time of the initial biopsy, cutaneous sarcoidosis, lepromatous leprosy, tuberculosis, leishmaniasis, and sinus histiocytosis were considered in the differential diagnosis because of the prominent granulomatous infiltrates. Most of these could be ruled out by special stains, immunocytochemical markers, or by culturing the tissue for organisms. However, cutaneous sarcoidosis can be particularly challenging to exclude and a case of subcutaneous T-cell lymphoma is reported in the literature that was initially misdiagnosed as sarcoidosis.^ These authors suggested that the masking granulomatous reaction is caused by lymphokine secretion by the neoplastic T-cells.^ Histologically, subcutaneous T-cell lymphoma is also reminiscent of several inflammatory panniculidities such as erythema nodosum, WeberChristian disease, and nonspecific granulomatous lobular panniculitis. Most reported cases of subcutaneous T-cell lymphoma that were initially misinterpreted were given one of these benign diagnoses.^'^'^"^*^ Two other cases were given a
834 Haycox et al.
Fig. 2. High-power view of infiltrate showing random atypical lymphocytes. (Hematoxylin-eosin stain; original magnification (x 400.)
presumptive diagnosis of lupus profundus.^"^^ In our case, although the histologic findings of the right calf lesion were suggestive of a panniculitis, this diagnosis was not clinically consistent with the other subcutaneous nodules present on the chest and abdominal walls. In our patient no definite angiocentric pattern was found to the lymphocytic infiltrate, but this feature has occasionally been observed in other cases of subcutaneous T-cell lymphoma. ^'^ Cutaneous lymphomatoid granulomatosis can present clinically with ulcerated subcutaneous nodules.'2 Therefore, if angiocentric or angiodestructive lymphohistiocytic proliferations are observed, the diagnosis of lymphomatoid granulomatosis is usually considered as well.^'^ The prognosis of subcutaneous T-cell lymphoma is poor, resulting in death in approximately 60% of patients within several months to a few years. ^'^ Death is usually precipitated by the development of the hemophagocytic syndrome.^'^'^'^'^'ii'^^ This multisystem illness is characterized by fever, wasting, generalized adenopathy, hepatosplenomegaly, pancytopenia, and coagulopathy. The most consistent histopathologic feature in hemophagocytic syndrome is the presence of mature histiocytes containing engulfed erythrocytes or other hematopoietic cells, also referred to as cytophagic histiocytosis. The hemophagocytic syndrome is not specific to subcutaneous T-cell lymphoma and has been reported in association with other lymphomas and viral infections.^'* The hemophagocytic syndrome may be a result of the production
Journal of the American Academy of Dermatology November 1997
of lymphokines by either neoplastic T-cells or those present in response to viral infections.^"^'^^ Cytophagic histiocytosis was not observed in our patient, nor has it been observed in several other cases of subcutaneous T-cell lymphoma.^'^ When present, however, it should be viewed as a poor prognostic marker, indicating the need for expedient and aggressive therapy. In most reported cases, the treatment of subcutaneous T-cell lymphoma has consisted of lowdose chemotherapeutic regimens (e.g., CHOP) either alone or in conjunction with localized radiotherapy. Dismal outcomes with these regimens prompted Romero et al.^ to use high-dose chemotherapy (ICE) with autologous stem cell support in a 23-year-old woman with subcutaneous T-cell lymphoma of the upper and lower extremities. However, the patient succumbed to her disease when it transformed into a rapidly progressive leukemia.^ In our patient, the tumor in the right calf continued to enlarge when the patient was treated with CHOP chemotherapy. Even more aggressive chemotherapy with two cycles of DHAP and concomitant localized radiation therapy did little to reduce the main tumor burden in the area of the right calf. Amputation of the right limb was considered necessary for treatment of persistent local disease. After the amputation, he also received high-dose chemotherapy with ICE and autologous stem cell support. This is the first report of amputation in a treatment protocol for subcutaneous T-cell lymphoma. In the patients reported to date, 25 of 27 (93%) had nodules involving their extremities. Surgical debulking by partial or complete limb amputation may therefore be a useful therapeutic adjunct for other patients with subcutaneous T-cell lymphoma. Although these procedures can have a high associated morbidity, we believe that limb amputation was probably a lifesaving procedure in our patient. REFERENCES 1. Romero LS, Goltz RW, Nagi C, et al. Subcutaneous Tcell lymphoma with associated hemophagocytic syndrome and terminal leukemic transformation. J Am Acad Dermatol 1996;34:904-9. 2. Prescott RJ. Subcutaneous T-cell lymphoma with florid granulomatous panniculitis. Histopathology 1992;20: 535-7. 3. Mehregan DA, Su WPD, Kurtin PJ. Subcutaneous T-cell lymphoma: a chnical, histopathologic, and immunohistochemical study of six cases. J Cutan Pathol 1994; 21:110-7.
Journal of the American Academy of Dermatology Volume 37, Number 5, Part 2
4. Slater DN. Subcutaneous T-cell lymphoma with florid granulomatous panniculitis [letter]. Histopathology 1993;22:95. 5. Gonzalez CL, Medeiros J, Braziel RM, et al. T-cell lymphoma involving subcutaneous tissue. A clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Aurg Pathol 1991;15:17-27. 6. Pemiciaro C, Zalla MJ, White JW, et al. Subcutaneous Tcell lymphoma. Report of two additional cases and further observations. Arch Dermatol 1993;129:1171-6. 7. Slater DN. Diagnostic difficulties in 'non-mycotis' cutaneous lymphoproliferative diseases. Histopathology 1992;21:203-13. 8. Burg G, Dummer R, Wilheim M, et al. A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma. N Engl J Med 1991;325:1078-81. 9. Aronson IK, West DP, Variakojis D, et al. Panniculitis associated with cutaneous T-cell lymphoma and cytophagocytic histiocytosis. Br J Dermatol 1985; 112: 87-96. 10. Avinoach I, Halevy S, Argov S, et al. y/5 T-cell lym-
Haycox et al. 835
11. 12. 13.
14.
15.
phoma involving the subcutaneous tissue and associated with a hemopagocytic syndrome. Am J Dermatopathol 1994; 16:426-33. Cho KH, Oh JK, Kim CW, et al. Peripheral T-cell lymphoma involving subcutaneous tissue. Br J Dermatol 1995;132:290-5. Wood ML, Harrington CI, Slater DN, et al. Cutaneous lymphomatoid granulomatosis: a rare cause of recurrent skin ulceration. Br J Dermatol 1984;110:619-25. Kaplan MA, Jacobsen JO, Ferry JA, et al. T-cell lymphoma of the vulva in a renal allograft recipient with associated hemophagocytosis. Am J Surg Pathol 1993; 17:842-9. Smith KJ, Skelton HG, Yeager J, et al. Cutaneous histopathologic, immunohistochemical, and clinical manifestations in patients with hemophagocytic syndrome. Arch Dermatol 1992;128:193-200. Jaffa ES, Costa J, Fauci AS, et al. Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med 1983;75:741-9.