Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome

The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin's disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P < 0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.     

Peripheral neuroectodermal tumor of the chest (Askin tumor) as secondary neoplasm after Hodgkin's disease: A case report

Summary The authors present the case of a 20-yearold woman who developed a peripheral neuroectodermal neoplasm of the thoracopulmonary region (Askin tumor) 7 years after achieving complete remission of stage-IV Hodgkin's disease. The previous treatment had consisted of eight courses of alternating MOPP/ ABVD combined with involved-field 20-Gy radiotherapy. The second neoplasm appeared in a nonirradiated area of the chest wall, with erosion of the ribs as shown by sonography and computed tomography. The histological pattern was in accordance with a generic diagnosis of a malignant small cell tumor; the immunostaining positivity of the neoplastic cells for the neuron-specific enolase allowed us to make the diagnosis of a tumor with a neuroectodermal origin. Partial resection of the neoplasm and four courses of chemotherapy including adriamycin, cisplatin, and ifosfamide induced a complete remission, confirmed by surgical restaging. She is alive and well 10 months after the completion of therapy. The clinical, radiological, and microscopic features of this tumor occurring as a secondary neoplasm after Hodgkin's disease are described.     

Elevated plasma lysozyme in Hodgkin's disease. An indicator of increased macrophage activity?

Plasma lysozyme levels were studied in 42 patients with Hodgkin's disease and were found significantly increased. Plasma lysozyme varied with the stage of the disease and with symptoms, but did not correlate with the histological subtype or with blood neutrophil and monocyte counts. Serial measurements in four patients on MOPP treatment showed a rapid decrease following treatment. The increased plasma lysozyme in Hodgkin's disease stems most likely from the macrophage system, either because the macrophages are hyperactive and/or because the malignant cell in Hodgkin's disease is of macrophage origin.     

Free-from-failure survival in Hodgkin's disease. Long-term analysis of 148 cases treated with a MOPP-modified protocol

The incidence of relapses and second malignant neoplasms was investigated in a group of 148 patients with bad-risk stage II, or stage III and IV Hodgkin's disease treated with a MOPP-modified protocol between 1973 and 1979. Sixty-eight patients received chemotherapy alone, 80 a combined modality treatment including radiotherapy. One hundred and twelve patients achieved complete remission with induction therapy. Thirty-six patients relapsed 3-120 months (median 27 months) after the induction program with a 10-year cumulative risk of relapse of 33.6%. Seven out of 112 complete responders developed a second malignancy 65-145 months from the start of therapy; one more neoplasm has been recorded in a patient with active Hodgkin's disease. Survival after diagnosis of second malignant neoplasm did not exceed 12 months. The cumulative risk of developing a second malignancy was 6.2% at 10 years. The free-from-failure survival was 49.2% at 10 years, being 64.7% for patients achieving complete remission and 92.4% for long-term complete responders. Although an increased number of second malignant neoplasms may occur in patients treated for Hodgkin's disease, the high risk of early relapse, together with the limited effectiveness of salvage therapy, suggests that intensive induction programs should be carried out in patients with advanced or poor-prognosis Hodgkin's disease in order to achieve long-lasting complete remission.     

Calcium status following neck radiation therapy in Hodgkin's disease

Substantial evidence links the development of primary hyperparathyroidism with a medical history of neck radiation therapy for benign disease. This report concerns 220 patients with Hodgkin's disease seen at The University of Texas M. D. Anderson Hospital, Houston, treated with neck irradiation. Serum calcium levels had been analyzed two to 22 years after radiotherapy. Hyperparathyroidism was confirmed at surgery in one patient with hypercalcemia 15 years after radiotherapy. However, the maximum follow-up was 22 years and in a reported series the mean interval between irradiation and the development of hyperparathyroidism has ranged from 29 to 47 years. We conclude that patients who have received neck radiation therapy for malignant disease are not at an increased risk for the development of hyperparathyroidism in the first two decades following treatment but should continue to be screened for this development in subsequent decades.     

Thrombolytic therapy for acute myocardial infarction in unsuspected infective endocarditis

Radiation therapy is the current standard therapy for several malignant disorders, including Hodgkin's disease. Cardiac complications, pericardial disease in particular, may develop long after the treatment. However, conduction disorders have rarely been described. We report a patient with the Wolff-Parkinson-White syndrome who developed complete heart block 16 years after mediastinal radiation therapy.     

Complications malignes très tardives d’un lymphome de Hodgkin

Overall survival of patients with Hodgkin lymphoma has dramatically increased in recent years, with an increased rate of malignant complications. We report here a 54-year-old man who presented with concomitant relapse of classical Hodgkin's lymphoma and lung adenocarcinoma 20 years after initial treatment with chemotherapy and mantle radiotherapy. Pathogenic mechanisms of these malignant complications are discussed. A prolonged follow-up of patients with Hodgkin's lymphoma is required.     

A case of primary Hodgkin's disease of the stomach

A case of primary Hodgkin's disease, a lymphocyte-predominant entity, occurring in the stomach is described. The patient was a 37-year-old man who complained of general fatigue. Endoscopic biopsy revealed gastric malignant lymphoma. Subtotal gastrectomy and postoperative chemotherapy following a modifid CHOP regimen were performed. The patient has been free of recurrence during a follow-up period of 15 months. The preoperative diagnosis of gastric Hodgkin's disease is difficult. Thus far, of 100 cases of gastric Hodgkin's disease reported in Japan, only 3 were diagnosed correctly preoperatively. We also misdiagnosed our case, as B cell type malignant lymphoma, preoperatively. The final diagnosis of Hodgkin's disease of the stomach was made on the basis of histopathological and immunohistochemical examinations. Hodgkin's disease of the stomach is rare, and there are histologically similar diseases; Ki-1 lymphoma, adult T cell lymphoma, malignant hystiocytosis, and infectious monocytosis. Careful diagnosis is essential thus for Hodgkin's disease of the stomach.     

Solid tumors complicating Hodgkin's disease. A report on two patients with immunoglobulin deficiency.

Multiple epithelial malignant neoplasms developed in two patients with Hodgkin's disease subsequent to radiotherapy and intensive chemotherapy. At the time of diagnosis, each patient also demonstrated a serum immunoglobulin deficiency. The significance of the occurrence of solid tumors in patients following therapy for Hodgkin's disease and the significance of cellular and humoral immunodeficiency in Hodgkin's disease in relation to second cancer development were studied. We suggest the establishment of a registry of leukemias and solid tumors developing in patients treated for Hodgkin's disease and other malignant neoplasms, possibly with detailed recording of immunocompetence data.     

Late recurrence of Hodgkin's disease 20 years after initial diagnosis. Personal observation of two cases and a literature review

Most patients with Hodgkin's disease (especially early stage disease) are successfully treated using modern treatment modalities. Disease relapse usually occurs within the first three years after initial therapy. Late relapses of Hodgkin's disease, occurring after 10 years or even later, are rare (0.6% of cases only). Their biological behaviour is different from that of early relapses, resembling primary disease. The question whether very late relapses represent a second primary disease in patients with a genetic predisposition to Hodgkin's disease rather than a relapse of the original disease remains the subject of much discussion. We report here two cases of very late relapses of Hodgkin's disease, occurring twenty years after initial treatment. Both patients were now treated by intensified chemotherapy, escalated BEACOPP. In one case, this was followed by radiotherapy of the residual tumor (40 Gy). Both patients are in complete remission.     

Incidence and mortality of malignant lymphomas in the GDR

Based on data from the cancer register of the German Democratic Republic established in 1952 and on the official mortality statistics, incidence of and mortality from malignant lymphomas (ICD 200-203) in the GDR are analysed. Age-specific incidence and mortality of Hodgkin's disease show a peak in the age group of 25-30 years and rise steadily from 45 years on up to the highest age. Lymphosarcoma and reticulosarcoma increase slowly from infancy to old age, whereas multiple myeloma is a disease of the elderly and extremely rare before the age of 40. The apparent increase of malignant lymphoma may be due to underregistration at the beginning of the cancer register. In the past years mortality from Hodgkin's disease is slowly decreasing, thus reflecting progress in methods of treatment and results.     

Hodgkin's disease variant of Richter's syndrome: complete remission of the both malignancies after 14 years

Richter's syndrome is defined by the occurrence of high-grade malignant lymphoma in the course of chronic lymphocytic leukemia (CLL). The prognosis is poor with a life expectancy of a few months. We report on the case of a 68-year old male who developed Hodgkin's disease 6 years after the diagnosis of stage A CLL was made. The patient received 3 cycles of combination chemotherapy according to the ABVD regimen, followed by radiotherapy. This treatment resulted in complete apparent remission of the two diseases, which was persistent after a follow-up of 14 years. The Hodgkin's disease variant of Richter's syndrome is exceptional with about 20 reported cases to date. Recent research indicates that lymphoma cells derive from leukemia. The prognosis appears far better than that for the classical non-Hodgkin Richter's syndrome.     

Naproxen has greater antipyretic effect on Hodgkin's disease-related fever than no other tumours or infection

In 28 febrile patients with malignant lymphoma or leukaemia, the hourly temperatures were recorded following an oral dose of 125 mg naproxen (50% of normal single adult analgesic dose). 15 patients had clinical infection, and 13 had fever secondary to their malignant disease. Compared to controls, there was no significant antipyretic effect of 125 mg naproxen in infected patients, whereas this small dose in patients without infection had a significant effect. In the uninfected patients, the antipyretic effect was significantly more marked in fever related to Hodgkin's disease than to non-Hodgkin lymphoma or leukaemia. This selective antipyretic effect of a prostaglandin-synthesis inhibitor in tumour-related fever, especially in Hodgkin's disease, is unexplained but may be useful in the palliative treatment of patients with advanced disease.     

Cardiac disease late after chest radiotherapy for Hodgkin's disease: a case report.

This report presents a case of occult constrictive pericarditis and mitral valve insufficiency following chest radiotherapy. A 44-year-old man had received radiotherapy for the treatment of Hodgkin's disease 8 years ago. At age 40 years, effusive pericarditis occurred and he was treated with intrapericardial drainage. Biopsy revealed a fibrotic and thickened pericardium. He developed congestive heart failure 3 years later. The patient was found to have occult constrictive pericarditis and mitral valve insufficiency. He underwent mitral valve replacement, tricuspid annul plasty, and pericardiectomy. Although there is the benefit of cure for the Hodgkin's disease, the prognosis after treatment is affected by radiotherapy-induced heart disease. After radiotherapy of the chest and mediastinum, long-term cardiological follow-up is recommended in order to detecting patients with radiation-induced heart disease, such as the present case.     

Sarcoidosis, Hodgkin's disease, and autoimmune hemolytic anemia

Reported is the unique occurrence of sarcoidosis, Hodgkin's disease, and autoimmune hemolytic anemia in the same patient. Although the diagnosis of sarcoidosis preceded that of Hodgkin's disease by 29 years, massive splenomegaly had been present for 13 years before Hodgkin's disease was diagnosed following splenectomy. The known associations of sarcoidosis and Hodgkin's disease as well as each disease with autoimmune hemolytic anemia are reviewed.     

Unusual association of Hodgkin's disease and sarcoidosis

We report a 51-year-old patient who developed abdominal lymphadenopathy following Hodgkin's disease seven years after she was diagnosed as having sarcoidosis. The patient had been treated with steroids, methotrexate and azathioprine. After three cycles of chemotherapy for Hodgkin's disease, the patient again developed sarcoidosis in the mediastinal lymph nodes. A greater awareness of the co-existence of sarcoidosis and Hodgkin's disease could circumvent the diagnostic difficulties.     

High dose alpha-2-recombinant interferon in the treatment of malignant lymphoproliferative diseases. A pilot study

In the presented clinical study, 10 patients with malignant lymphoproliferative diseases (2 with acute lymphoblastic leukemia, 3 with Hodgkin's disease, and 5 with non-Hodgkin's lymphoma), resistant to standard therapy, were administered alpha-2-recombinant interferon at a dosage of 120 x 10(6) IU as a continuous 48 h i.v. infusion. The second administration was performed after an interval of 1 month. A therapeutic response was seen in 50% of the patients, of them there were two complete remissions (in the two acute lymphoblastic leukemia patients) and 3 partial remissions (in 2 patients with Hodgkin's disease and in 1 patient with low malignant non-Hodgkin's lymphoma). In four patients with high malignant non-Hodgkin's lymphomas the treatment did not evoke any response, and in 1 patient with the same diagnosis progression was noted after the treatment. The toxic effects of the drug were in accord with literature data, and although high doses of alpha-2-recombinant interferon were administered, it was not necessary to interrupt the treatment in any of the patients. Considering the therapeutic effect of this immunomodulator used in the treatment of malignant lymphoproliferative diseases, our results are promising, nevertheless further studies will be required.     

Non-Hodgkin's lymphoma after treatment of Hodgkin's disease: association with Epstein-Barr virus

Non-Hodgkin's lymphoma occurs infrequently as a late complication of obscure cause after treatment of Hodgkin's disease. We investigated the possible role of Epstein-Barr virus in the pathogenesis of such secondary malignancies of B-cell lineage. Two patients, aged 25 and 43 years, developed high-grade non-Hodgkin's lymphomas 12 and 8 years after radiation therapy for Hodgkin's disease. Serologic profiles in these patients showed evidence of acute and past Epstein-Barr virus infections, respectively. Molecular hybridization analysis showed the presence of multiple cellular equivalents of virus genome in tumor specimens from each patient. Our findings suggest that Epstein-Barr virus may play an integral role in the pathogenesis of non-Hodgkin's lymphoma of B-cell lineage that develops after treatment of Hodgkin's disease.     

Malignant pituitary corticotroph adenomas: report of two cases and a comprehensive review of the literature

Corticotroph pituitary carcinomas are tumors, defined by the presence of distant metastases that determine their poor prognosis. The diagnosis and therapy of malignant corticotroph adenomas remains a clinical challenge. The molecular mechanisms of malignant transformation of pituitary adenomas are unclear, although they are believed to arise in an adenoma-to-carcinoma sequence. We describe two cases of malignant Cushing’s disease with metastases in liver and bone, respectively. The primary pituitary tumors were treated by a combination of radiotherapy and transsphenoidal surgery, but recurred several times in both patients. The time interval between the diagnosis of Cushing’s disease and the discovery of metastases was 32 and 17 years, respectively. In the first case the patient died within 6 months after diagnosis of metastasis, whereas the second patient is alive at a follow-up of 2 years after the discovery of the metastasis. Furthermore, we reviewed all available cases of corticotroph pituitary carcinomas reported in the literature and analyzed their clinical features and therapeutical management. In conclusion, frequent relapses of Cushing’s disease, aggressive growth of macroadenoma, Nelson’s syndrome after adrenalectomy or persistently high ACTH levels should prompt the clinician to consider the possibility of pituitary corticotroph carcinomas. A. A. van der Klaauw and T. Kienitz contributed equally to this study.     

Neoplastic meningitis with eosinophilic pleocytosis in Hodgkin's disease: a case with cerebellar dysfunction and a review of the literature

A 31-year-old man had Hodgkin's disease (stage IIA, nodular sclerosis) in apparent remission after radiotherapy. Nine months after the diagnosis of Hodgkin's disease, he developed neoplastic meningitis with eosinophilic pleocytosis and neurologic findings suggestive of peri-fourth ventricle infiltration. Morphologic and surface marker analysis of cerebrospinal fluid cells showed large numbers of T-lymphocytes and Reed-Sternberg variant cells positive for CD15, the Lex hapten expressed on myeloid cells and on a variety of malignant cells. Therapy with intrathecal methotrexate, oral dexamethasone, and cranial irradiation resulted in prompt resolution of his cerebrospinal fluid abnormalities and neurologic deficits. Ten months after the diagnosis of eosinophilic meningitis, systemic relapse of Hodgkin's disease occurred in right iliac and inguinal lymph nodes. The diagnosis, pathogenesis, and therapy of this unusual complication of Hodgkin's disease are reviewed.