FATAL RESPIRATORY FAILURE FOLLOWING CHEMOTHERAPY OF ADVANCED TERATOMA— A PULMONARY TUMOUR LYSIS...
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1505 Perhaps the pattern of ulcer disease has changed so that periodicity is no longer evident today, as it was at the beginning of the century, or perhaps social, geographical, or racial factors influence peptic ulcer more than seasons and climates do-either way, experience in Finland suggests that seasonal variation in the incidence of peptic ulcer is a myth. Department of Surgery, University Hospital, SF 33520 Tampere 52, Finland JÉRÖME NEGRE 1. Moynihan B. Duodenal ulcer. Philadelphia: WB Saunders, 1910. 2. Paulson M. Peptic ulcer. In: Gastroenterologic medicine. Philadelphia: Lea and Febiger, 1969: 711-57. 3. Fordtran JS. The pathogenesis of peptic ulcer. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal diseases. Philadelphia: WB Saunders, 1973: 628-41. 4. Safrany L, Schott B, Portocarrero G, Krause S, Neuhaus B. Zur frage der Frühjahrs-und Herbstdisposition des gastroduodenalen ulcus. Dtsch Med Wschr 1982; 107: 685-87. 5. Bradley RL, Bradley EJ. Seasonal incidence of perforated ulcer. Am J Surg 1966; 111: 656-58. FATAL RESPIRATORY FAILURE FOLLOWING CHEMOTHERAPY OF ADVANCED TERATOMA— A PULMONARY TUMOUR LYSIS SYNDROME? SIR,-A 21-year-old man with a 2-month history of left-sided chest pain, mild haemoptysis, shortness of breath on exercise, and weight loss had a small shadow in the right lower zone on chest X-ray and was referred for medical follow-up. 1 month later the haemoptysis and shortness of breath were much worse, the chest pain persisted, and scattered coarse crepitations were present bilaterally in the chest. A second chest X-ray revealed several round opacities consistent with metastatic tumour deposits. Conventional laboratory tests were normal and sputum cultures were negative. However, a pregnancy test was positive, suggesting metastatic teratoma, and very high serum 0-hCG levels confirmed this. He now had gross haemoptysis and shortness of breath at rest and a fall in haemoglobin from 13 - 9 to 9 - 0 g/dl in 6 days necessitated three units of packed cells. Repeat liver function tests revealed hepatocellular involvement. He was started on chemotherapy with etoposide 120 mg/mz and cisplatin 20 mg/m2 intravenously, repeated on the second day with the addition of intravenous bleomycin 30 mg. 36 h after the first dose of chemotherapy he became very much more dyspnoeic with central cyanosis and increased widespread crepitations. A chest X-ray showed increased diffuse shadowing. Arterial blood gases were consistent with a gross alveolar-capillary mismatch. There was no evidence of diffuse intravascular coagulation. Central venous pressure was 0 cm water. An electrocardiogram showed a sinus tachycardia. Despite intravenous frusemide and hydrocortisone he continued to deteriorate, and was transferred to intensive care and put on positive pressure 100% oxygen. The arterial p02 rose at first but then fell. The serum urea rose to 16 - 2 mmol/l but other biochemical indices remained normal and liver function did not deteriorate further. 8 days after the start of chemotherapy oxygenation could not be maintained and profound bradycardia was followed by fatal cardiac arrest. Necropsy revealed multiple metastases in the liver and lung, the largest mass being in the retroperitoneum. No macroscopic lesion was seen in the testes, but histological examination revealed a small scar interpreted as a regressed primary teratoma. Both lungs were exceptionally heavy (combined weight 3340 g), and the parenchyma between the tumour nodules was intensely congested. The tumour was a trophoblastic malignant teratoma. The tumour deposits within the lung were necrotic with only a thin rim of viable tumour cells. Between these deposits, many lung alveoli were lined by well- formed hyaline membranes, and contained large numbers of red blood cells. The alveolar septa showed early fibrosis with inflammatory cell infiltrates and many small and medium sized vessels contained fibrin thrombi. The overall appearances were of diffuse alveolar damage. Diffuse alveolar damage is the outcome of many injurious agents or processes, including infection, inhalants, drugs, shock, and radiation.’ Clinically, the syndrome manifests as increasing hypoxaemia and decreasing lung compliance; the histological features in this case were characteristic. Bleomycin can cause interstitial pneumonitis and pulmonary fibrosis. However, serious pulmonary toxicity has not been reported for’total doses below 150 mg and cytotoxic lung damage is chronic.3 Our patient had received only 30 mg bleomycin and deteriorated 12 h after the dose, so bleomycin is not likely to have contributed significantly to pulmonary damage by direct toxicity. We suggest that the diffuse alveolar damage in this case was due to massive lysis of pulmonary tumour. Necrotic tissue is a powerful stimulator of neutrophil aggregation and activation, and locally released enzymes, vasoactive peptides, and oxygen radicals could account for the diffuse alveolar damage. The patient had been exposed to 100% positive pressure oxygen, which may have contributed to the histological appearances. Nevertheless, the clinical findings and investigations at the time of acute deterioration suggest that the bulk of the damage was already present. The tumour lysis syndrome is a well recognised occasional complication of cytotoxic chemotherapy, the raised circulating phosphate, potassium, and urate resulting from the release of intracellular contents from lysed tumour cells4-ie, a systemic biochemical disturbance rather than damage to a single organ system, as here. Three cases of fatal respiratory failure after chemotherapy of malignant disease with pulmonary involvement have been reported. The pulmonary tumour burden was high, and the patients died 24-48 h after treatment began. 5-7 In one case 5 there was biochemical evidence of the tumour lysis syndrome but no details of histological findings. In another no pathological details are given. In the third there was pathological evidence of diffuse alveolar damage, and the suggested cause was diffuse intravascular coagulation. Our patient had no evidence of the biochemical tumour lysis syndrome; nor was there diffuse intravascular coagulation. We suggest that in this case a locally mediated toxic effect due to massive tumour destruction was the cause-if so, earlier cases may well have been missed. In our patient the pulmonary metastases were expanding rapidly and such patients may be at risk of diffuse alveolar damage if their tumours are very sensitive to chemotherapy. Ventilation-perfusion scanning or pre-treatment serial tests of respiratory function may prove to be of value in elucidating those characteristics of disease which render the individual susceptible to the syndrome. Once identified, such patients might benefit from lower initial doses of chemotherapy or from some other means of protecting the lungs. Once triggered, however, the chain of events is difficult to modify. Department of Radiotherapy and Oncology, Leicester Royal Infirmary, Leicester LE1 5WW J. H. FHIPPS F. J. F. MADDEN P. A. V. SHAW 1. Katzenstein AA, Askin FB. Surgical pathology of non-neoplastic lung disease. Philadelphia: Saunders, 1982: 9-39. 2. Sostman HD, Matthay RA, Putman CE. Cytotoxic induced lung disease. Am J Med 1977, 62: 609-12. 3. Collis CH. Lung damage from cytotoxic drugs. Cancer Chemother Pharmacol 1980; 4: 17-27. 4. Editorial. Tumour lysis syndrome. Lancet 1981; ii: 849. 5. Vogelzang NJ, Nelimark RA, Nath KA. Tumor lysis syndrome after induction chemotherapy of small-cell bronchogenic carcinoma. JAMA 1983; 249: 513-14. 6. Munro AJ, Duncan W, Webb JN. Extragonadal presentations of germ cell tumours. Br J Urol 1983; 55: 527-54. 7. Hewlett RI, Wilson AF. Adult respiratory distress syndrome (ARDS) following aggressive management of extensive acute lymphoblastic leukemia. Cancer 1977; 39: 2422-25 ANTIBODIES TO AIDS AND HEATED FACTOR VIII SiR,-Dr Mosseler and associates (May 11, p 1111) observe that a pasteurised factor VIII concentrate, in contrast to conventional unheated concentrates, does not induce antibodies to HTLV-III. Their results are promising, but caution is needed in interpreting the significance of this and other observations. 1 The groups of haemophiliacs considered by Mosseler and associates were not truly comparable in terms of concentrate exposure, because the median annual consumption of those who used the pasteurised concentrate (3700 IU, group A) was considerably lower than the consumption of those who used conventional concentrates (68 000 IU, group C). This difference may be important because the frequency of anti-HTLV-III
Transcript of FATAL RESPIRATORY FAILURE FOLLOWING CHEMOTHERAPY OF ADVANCED TERATOMA— A PULMONARY TUMOUR LYSIS...
1505
Perhaps the pattern of ulcer disease has changed so that
periodicity is no longer evident today, as it was at the beginning ofthe century, or perhaps social, geographical, or racial factorsinfluence peptic ulcer more than seasons and climates do-eitherway, experience in Finland suggests that seasonal variation in theincidence of peptic ulcer is a myth.Department of Surgery,University Hospital,SF 33520 Tampere 52, Finland JÉRÖME NEGRE
1. Moynihan B. Duodenal ulcer. Philadelphia: WB Saunders, 1910.2. Paulson M. Peptic ulcer. In: Gastroenterologic medicine. Philadelphia: Lea and
Febiger, 1969: 711-57.3. Fordtran JS. The pathogenesis of peptic ulcer. In: Sleisenger MH, Fordtran JS, eds.
Gastrointestinal diseases. Philadelphia: WB Saunders, 1973: 628-41.4. Safrany L, Schott B, Portocarrero G, Krause S, Neuhaus B. Zur frage der
Frühjahrs-und Herbstdisposition des gastroduodenalen ulcus. Dtsch Med Wschr1982; 107: 685-87.
5. Bradley RL, Bradley EJ. Seasonal incidence of perforated ulcer. Am J Surg 1966; 111:656-58.
FATAL RESPIRATORY FAILURE FOLLOWINGCHEMOTHERAPY OF ADVANCED TERATOMA—A PULMONARY TUMOUR LYSIS SYNDROME?
SIR,-A 21-year-old man with a 2-month history of left-sided chestpain, mild haemoptysis, shortness of breath on exercise, and weightloss had a small shadow in the right lower zone on chest X-ray andwas referred for medical follow-up. 1 month later the haemoptysisand shortness of breath were much worse, the chest pain persisted,and scattered coarse crepitations were present bilaterally in thechest. A second chest X-ray revealed several round opacitiesconsistent with metastatic tumour deposits. Conventional
laboratory tests were normal and sputum cultures were negative.However, a pregnancy test was positive, suggesting metastaticteratoma, and very high serum 0-hCG levels confirmed this. Henow had gross haemoptysis and shortness of breath at rest and a fallin haemoglobin from 13 - 9 to 9 - 0 g/dl in 6 days necessitated threeunits of packed cells. Repeat liver function tests revealed
hepatocellular involvement. He was started on chemotherapy withetoposide 120 mg/mz and cisplatin 20 mg/m2 intravenously,repeated on the second day with the addition of intravenousbleomycin 30 mg.36 h after the first dose of chemotherapy he became very much
more dyspnoeic with central cyanosis and increased widespreadcrepitations. A chest X-ray showed increased diffuse shadowing.Arterial blood gases were consistent with a gross alveolar-capillarymismatch. There was no evidence of diffuse intravascular
coagulation. Central venous pressure was 0 cm water. An
electrocardiogram showed a sinus tachycardia. Despite intravenousfrusemide and hydrocortisone he continued to deteriorate, and wastransferred to intensive care and put on positive pressure 100%oxygen. The arterial p02 rose at first but then fell. The serum urearose to 16 - 2 mmol/l but other biochemical indices remained normaland liver function did not deteriorate further. 8 days after the start ofchemotherapy oxygenation could not be maintained and profoundbradycardia was followed by fatal cardiac arrest.Necropsy revealed multiple metastases in the liver and lung, the
largest mass being in the retroperitoneum. No macroscopic lesionwas seen in the testes, but histological examination revealed a smallscar interpreted as a regressed primary teratoma. Both lungs wereexceptionally heavy (combined weight 3340 g), and the parenchymabetween the tumour nodules was intensely congested. The tumourwas a trophoblastic malignant teratoma. The tumour depositswithin the lung were necrotic with only a thin rim of viable tumourcells. Between these deposits, many lung alveoli were lined by well-formed hyaline membranes, and contained large numbers of redblood cells. The alveolar septa showed early fibrosis with
inflammatory cell infiltrates and many small and medium sizedvessels contained fibrin thrombi. The overall appearances were ofdiffuse alveolar damage.
Diffuse alveolar damage is the outcome of many injurious agentsor processes, including infection, inhalants, drugs, shock, andradiation.’ Clinically, the syndrome manifests as increasinghypoxaemia and decreasing lung compliance; the histologicalfeatures in this case were characteristic.
Bleomycin can cause interstitial pneumonitis and pulmonaryfibrosis. However, serious pulmonary toxicity has not been
reported for’total doses below 150 mg and cytotoxic lung damage ischronic.3 Our patient had received only 30 mg bleomycin anddeteriorated 12 h after the dose, so bleomycin is not likely to havecontributed significantly to pulmonary damage by direct toxicity.We suggest that the diffuse alveolar damage in this case was due to
massive lysis of pulmonary tumour. Necrotic tissue is a powerfulstimulator of neutrophil aggregation and activation, and locally
released enzymes, vasoactive peptides, and oxygen radicals couldaccount for the diffuse alveolar damage. The patient had beenexposed to 100% positive pressure oxygen, which may havecontributed to the histological appearances. Nevertheless, theclinical findings and investigations at the time of acute deteriorationsuggest that the bulk of the damage was already present.The tumour lysis syndrome is a well recognised occasional
complication of cytotoxic chemotherapy, the raised circulatingphosphate, potassium, and urate resulting from the release ofintracellular contents from lysed tumour cells4-ie, a systemicbiochemical disturbance rather than damage to a single organsystem, as here. Three cases of fatal respiratory failure after
chemotherapy of malignant disease with pulmonary involvementhave been reported. The pulmonary tumour burden was high, andthe patients died 24-48 h after treatment began. 5-7 In one case 5there was biochemical evidence of the tumour lysis syndrome but nodetails of histological findings. In another no pathological detailsare given. In the third there was pathological evidence of diffusealveolar damage, and the suggested cause was diffuse intravascularcoagulation. Our patient had no evidence of the biochemical tumourlysis syndrome; nor was there diffuse intravascular coagulation. Wesuggest that in this case a locally mediated toxic effect due to massivetumour destruction was the cause-if so, earlier cases may well havebeen missed.
In our patient the pulmonary metastases were expanding rapidlyand such patients may be at risk of diffuse alveolar damage if theirtumours are very sensitive to chemotherapy. Ventilation-perfusionscanning or pre-treatment serial tests of respiratory function mayprove to be of value in elucidating those characteristics of diseasewhich render the individual susceptible to the syndrome. Onceidentified, such patients might benefit from lower initial doses ofchemotherapy or from some other means of protecting the lungs.Once triggered, however, the chain of events is difficult to modify.
Department of Radiotherapy and Oncology,Leicester Royal Infirmary,Leicester LE1 5WW
J. H. FHIPPSF. J. F. MADDENP. A. V. SHAW
1. Katzenstein AA, Askin FB. Surgical pathology of non-neoplastic lung disease.Philadelphia: Saunders, 1982: 9-39.
2. Sostman HD, Matthay RA, Putman CE. Cytotoxic induced lung disease. Am J Med1977, 62: 609-12.
3. Collis CH. Lung damage from cytotoxic drugs. Cancer Chemother Pharmacol 1980; 4:17-27.
4. Editorial. Tumour lysis syndrome. Lancet 1981; ii: 849.5. Vogelzang NJ, Nelimark RA, Nath KA. Tumor lysis syndrome after induction
chemotherapy of small-cell bronchogenic carcinoma. JAMA 1983; 249: 513-14.6. Munro AJ, Duncan W, Webb JN. Extragonadal presentations of germ cell tumours. Br
J Urol 1983; 55: 527-54.7. Hewlett RI, Wilson AF. Adult respiratory distress syndrome (ARDS) following
aggressive management of extensive acute lymphoblastic leukemia. Cancer 1977;39: 2422-25
ANTIBODIES TO AIDS AND HEATED FACTOR VIII
SiR,-Dr Mosseler and associates (May 11, p 1111) observe that apasteurised factor VIII concentrate, in contrast to conventionalunheated concentrates, does not induce antibodies to HTLV-III.Their results are promising, but caution is needed in interpretingthe significance of this and other observations. 1The groups of haemophiliacs considered by Mosseler and
associates were not truly comparable in terms of concentrate
exposure, because the median annual consumption of those whoused the pasteurised concentrate (3700 IU, group A) was
considerably lower than the consumption of those who usedconventional concentrates (68 000 IU, group C). This differencemay be important because the frequency of anti-HTLV-III
