1476
LETTERS to the EDITOR
Lower mortality in cancer patients treated with low-molecular-weight versus standard
heparin SIR,-Studies comparing the safety and efficacy of lowmolecular-weight (LMWH) and standard heparin1 have focused on thrombosis and bleeding as endpoints, but two trials looked at mortality.2,3 Mortality rates were lower in patients randomised to LMWH. Our analysis of these deaths reveals a striking difference in cancer-related mortality. Data from the two studies were combined and analysed by multiple logistic regression, with treatment, study, and study-bytreatment interaction being included in the initial model. No evidence for study-by-treatment interaction was found so this was removed from the model; the study effect was not significant either but it was retained to allow for difference in follow-up (3 months in one study,3 6 months in the other2). Statistical significance was assessed with likelihood ratio based chi-squared tests. In Prandoni’s trial2 there were 8 deaths among 18 cancer patients on standard heparin and 1 death in 15 on LMWH. In Hull’s study3 the numbers were 13/49 for standard heparin and 6/47 for LMWH. Combined cancer deaths from the two studies were thus 21/67 (31%) for standard heparin and 7/62 (11%) for LMWH (p = 0-005); 95% confidence interval for odds ratio 1-4-9-2). Patients with cancer randomised to treatment with LMWH had a survival advantage over those treated with standard heparin. This difference cannot be attributed to thrombotic or bleeding events, which happened with the same frequency in both groups. By chance patients with more advanced tumours may have been disproportionately represented in the standard heparin group, but this seems unlikely since large numbers of cancer patients were included in the studies, which were randomised. While it is also possible that standard heparin increased cancer mortality, such an adverse effect has not been reported previously. These considerations suggest that LMWH exerts an inhibitory effect on tumour growth that is not apparent with standard heparin. Heparin suppresses the proliferation of smooth-muscle cells after endothelial injury;4 and heparin and its LMW fractions inhibit thymidine uptake and endothelial cell growthand the intimal thickening that follows endothelial injury.6 In 1983, Folkman et al7 reported that angiogenesiswas inhibited and that tumours regressed in mice treated with heparin (or heparin fragments) and cortisone. Suramin, a polysulphonated naphthylurea that inhibits the lysosomal enzyme responsible for the degradation of heparan and dermatan sulphate, has an antineoplastic effect in patients with metastatic cancers,8 and Nakamura et al9 have reported that a sulphated polysaccharide-peptidoglycan compound inhibited angiogenesis associated with Kaposi-sarcoma-like lesions in a nude mouse model.
The use of heparin and heparinoids as tumour inhibitors has lately been reviewed.1O Perhaps heparin fragments, being smaller than standard heparin, enter tumour cells more easily. The evidence of lowered cancer mortality in patients on LMWH should stimulate renewed interest in these agents as antineoplastic drugs. Division of
Hematology/Oncology,
Department of Medicine, Northwestern University Medical School and Rehabilitation Institute, Illinois 60611, USA, and Clinical Trials Unit, Division of General Internal Medicine, University of Calgary, Alberta, Canada
Chicago,
DAVID GREEN RUSSELL D. HULL ROLLIN BRANT GRAHAM F. PINEO
1. Hirsh J, Levine MN. Review: low molecular weight heparin. Blood 1992; 79: 1-17. 2. Prandoni P, Lensing AWA, Buller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-45. 3. Hull RD, Raskob GL, Pineo GF, et al. Subcutaneous low molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82. 4. Clowes AW, Karnovsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature 1977; 265: 625-26. 5. Barzu T, van Rijn J, Rosenbaum J, Tobelem G. Endothelial cell reactions with heparin. Med J Aust 1986; 144 (suppl): HS15-17. 6. Dryjski M, Mikat E, Bjornsson TD. Inhibition of intimal hyperplasia after arterial injury by heparins and heparinoid. J Vasc Surg 1988; 8: 623-33. 7. Folkman J, Langer R, Linhardt RJ, et al. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 1983; 221: 719-25. 8. Stein CA, LaRocca RV, McAfee N, Myers CE. Suramin: an anticancer drug with a unique mechanism of action. J Clin Oncol 1989; 7: 499-508. 9. Nakamura S, Sakurada S, Salahuddin SZ, et al. Inhibition of development of Kaposi’s sarcoma-related lesions by a bacterial cell wall complex. Science 1992; 255: 1437-40. 10. Regelson W. Anionic dyes, heparin and heparinoids: the rediscovery of polyanionic tumor inhibitors. J Natl Cancer Inst 1989; 81: 1929-30.
Treatment of small cell carcinoma of the
lung SiR,—The companion articles by Dr Carney and Dr Hansen on biology and treatment, respectively, of small cell carcinoma of lung (SCCL) (April 4, p 843 and p 846) omit mention of the importance of the blood coagulation mechanism in this disease. the the
Two
prospective,
randomised trials of warfarin1.2 and
one
prospective, randomised trial of unfractionated low dose heparin3 have shown a statistically significant increase in tumour response rates and survival in SCCL. In a pilot study, Calvo and associates4,5 found that intermittent infusion of urokinase-type plasminogen activator (U-PA) together with combination chemotherapy resulted in 100% overall and 85% complete response rates in patients with limited extent SCCL, and 87% overall and 76% complete response rates in patients with disseminated SCCL.
1477
and projected median survival values were than those in historical controls. Thrombin is considerably higher generated at the tumour cell/connective tissue interface in situ in SCCL tissue, where it converts fibrinogen to fibrin.6 Progression of SCCL, one of the few tumour types that manifest tumour-cellassociated thrombin generation,’,’ may be promoted by thrombin either because of its growth factor activity or because of its ability to generate stromal fibrin.6 Further testing of this treatment approach may be worthy of consideration for several reasons. Although some progress has been made with combination chemotherapy and radiation therapy, most patients with SCCL still die of their disease. Anticoagulant therapy is a possibility because depriving a tumour cell of a substance (eg, thrombin or fibrin) required for its growth may be just as lethal to the cell as a cytotoxic drug and would be less toxic to the patient. There is plenty of opportunity for innovation because reduction of thrombin generation by warfarin is only partial, and unfractionated heparin remains mainly within the vasculature and probably does a poor job at anticoagulating the extracellular space. It is tempting to consider newer agents for clinical trials in SCCL such as low-molecular-weight heparin, hirudin, and antistasin because of their potency, specificity, and potential ability to gain access to sites of tumour- cell-initiated thrombin fonnation. Furthermore, U-PA may be beneficial because of its ability to remove stromal fibrinogen or fibrin by activation of fibrinolysis or because it is an inhibitor of cell growth in some models.9 This notion of experimental therapy for SCCL is also appealing because it is fairly cost effective and simple in comparison with some alternative approaches under consideration.
These response
rates
Department of Veterans Affairs, Medical and Regional Office Center, White River Junction, Vermont 05009, USA
LEO R. ZACHARSKI
1. Zacharski LR, Henderson WG, Rickles FR, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: final report of the VA Cooperative Study 75. Cancer 1984; 53: 2046-52. 2. Chahinian AP, Propert KJ, Ware JH, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the cancer and leukaemia group. Br J Clin Oncol 1989; 7: 993-1002. 3. Lebeau B, Chastang CL, Brechot JM. Subcutaneous heparin treatment increases complete response rate and overall survival in small cell lung cancer (SCLC). Lung Cancer 1991; 7 (suppl): 129. 4. Calvo FA, Santos M, Hidalgo OF. Urokinase-combination chemotherapy in small cell lung cancer: a phase II study. Proc ASCO 1991; 9: 237. 5. Calvo FA, Hidalgo OF, Gonzalez F, et al. Urokinase combination chemotherapy in small cell carcinoma of the lung: a phase II study. Cancer (in press). 6. Wojtukiewicz MZ, Zacharski LR, Memoli VA, et al. Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer 1990; 65: 481-85. 7. Zacharski LR, Memoli VA, Costantini V, Wojtukiewicz MZ, Ornstein DL. Clotting factors in tumour tissue: implications for cancer therapy. Blood Coag Fibrinol 1990; 1: 71-78. 8. Zacharski LR, Howell AL, Memoli VA. The coagulation biology of cancer. Fibrinolysis 1992; 6 (suppl 1): 39-42. 9. Howell AL, Hunt JB, Henkin J, Zacharski LR. Anti-proliferative effect of urokinase on myeloid leukemia cells (HL-60). Blood 1991; (suppl 1): 76a.
Management of cancer pain SIR,-Professor Hanks and Dr Justins comment only once on the value of radiotherapy in the management of cancer pain, although they review extensively drug therapy (and briefly surgery) for pain relief. Patients with severe cancer pain often have spinal lesions that destroy bone and compress the spinal cord, or harbour tumour metastases that compress and infiltrate paravertebral nerve roots. At least half of patients with osseous metastases achieve complete pain relief after radiation treatment,’ and urgent radiotherapy prevents the development of paraparesis in about 60% of patients presenting with pain and early symptoms of cord compression.2 Additionally, radiotherapy has a direct effect against tumour growth, expansion, and infiltration3-the pain-causing processes. Reviewers often fail to mention the important and versatile role of radiotherapy in management of cancer pain. Despite Hanks and Justins’ brief mention of radiotherapy, doctors with little knowledge of radiotherapy may be excused if they conclude that analgesics and perhaps surgery in selected cases is the whole story about cancer
pain management. Regrettably, even good textbooks of oncology do include radiotherapy under the headings "pain" or "pain control" in their indexes.4,5Nonetheless, many patients suffering painful neoplastic lesions should receive radiotherapy as well as analgesic drugs.
not
Norwegian Radium Hospital, Oslo, Norway
KNUT LOTE
Tong D, Gillick L, Hendrickson R. The palliation of symptomatic osseous metastases. Cancer 1982; 50: 893-99. 2. Rodriguez M, Dinapoli RP. Spinal cord compression with special reference to metastatic epidural tumors. Mayo Clin Proc 1980; 5: 442-48. 3. Withers RH: Biological basis of radiation therapy for cancer. Lancet 1992; 339: 156-59. 4. DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 2nd ed. Philadelphia: JB Lippincott, 1985. 5. American Cancer Society: textbook of clinical oncology. Atlanta: American Cancer Society, 1991. 1.
Aggressive endometriosis in bone SIR,-Extraabdominal endometriosis is rare, although it has been reported in the pleura and lung, inguinal region, thigh, and sciatic nerve, but is limited to the soft tissue. We describe an unusual case of endometriosis in the femur. A 45-year-old woman, para 0, was admitted to her local hospital with a tumour in the right thigh. For 6 years she had had right footdrop due to sciatic nerve palsy, without any trauma. Five months before admission she had abdominal hysterectomy because of uterine myomatosus. 300 ml sanguinous fluid was obtained from the tumour. 2 years later she presented again with a large, painful swelling (8 x 15 cm) on the lateral right thigh. The tumour was partly removed. Histological evaluation showed old blood and endometriosis with no signs of malignant disease. Computed tomography (CT) revealed a soft-tissue tumour in the pelvis connected through the foramen obturatorium to the gluteus region. Selective angiography showed extensive vascularisation of the suspected region seen on CT scan. She was referred to us because a soft tissue sarcoma was suspected clinically. At operation a large cyst filled with old blood was removed from the right hip. Cytological and histological examination showed endometriosis with no sign of malignant disease. She was given gonadotropin-releasing hormone (GNRH) agonist (gosereline 3-6 mg per month by subcutaneous injection for six months). Eight months later she was admitted for thrombosis in the left leg, which was successfully treated. The lesion on the right leg had increased, extending from the crista iliaca downwards to halfway down the thigh. CT showed progression of bone destruction as well as atrophy of the right musculus gluteus. Magnetic resonance imaging (MRI) revealed a very large tumour with cystic components in the pelvis expanding in the right upper leg and gluteus region. Laboratory findings were normal, apart from slight anaemia (haemoglobin [Hb] 7-1 mmol/1) and greatly raised serum CA-125 (1990 IU/ml). At a second operation, a sharply outpunched defect (4x3 cm) was found in the right trochanter major, expanding into the bone marrow of the femur. The lesion was almost completely removed. Well developed endometrial glands and stroma were seen histologically. Substantial stratification or signs of atypia were not found. The stroma showed dense cellularity and was composed of cells with large round nuclei and little cytoplasm. These stromal cells closely surrounded the endometrial epithelium. In the stroma haemosiderin was present. Immunohistochemical analysis demonstrated CA-125 in the epithelial cells, as is reported in endometriosis. DNA-flow cytometry showed a diploid DNA pattern. Bilateral salpingooophorectomy was done. Histopathological evaluation showed a normal left ovary with follicular cysts and a normal right ovary with a corpus luteum. She was admitted four months later with anaemia (Hb 2-7 mmol/1) due to bleeding in the tumour. MRI, CT, and ultrasound showed tumour progression. Serum CA-125 was 10 232 IU/ml. She was given a blood transfusion and tamoxifen (20 mg twice daily). With this regimen she improved but died, two months later, possibly because of lung embolus. In our patient CT showed that the tumour originated from the sciatic nerve, which accounts for the right footdrop since this is a known complication of endometriosis of the sciatic nerved Such an aggressive form of endometriosis expanding in bone has as far as we
LETTERS to the EDITOR
Lower mortality in cancer patients treated with low-molecular-weight versus standard
heparin SIR,-Studies comparing the safety and efficacy of lowmolecular-weight (LMWH) and standard heparin1 have focused on thrombosis and bleeding as endpoints, but two trials looked at mortality.2,3 Mortality rates were lower in patients randomised to LMWH. Our analysis of these deaths reveals a striking difference in cancer-related mortality. Data from the two studies were combined and analysed by multiple logistic regression, with treatment, study, and study-bytreatment interaction being included in the initial model. No evidence for study-by-treatment interaction was found so this was removed from the model; the study effect was not significant either but it was retained to allow for difference in follow-up (3 months in one study,3 6 months in the other2). Statistical significance was assessed with likelihood ratio based chi-squared tests. In Prandoni’s trial2 there were 8 deaths among 18 cancer patients on standard heparin and 1 death in 15 on LMWH. In Hull’s study3 the numbers were 13/49 for standard heparin and 6/47 for LMWH. Combined cancer deaths from the two studies were thus 21/67 (31%) for standard heparin and 7/62 (11%) for LMWH (p = 0-005); 95% confidence interval for odds ratio 1-4-9-2). Patients with cancer randomised to treatment with LMWH had a survival advantage over those treated with standard heparin. This difference cannot be attributed to thrombotic or bleeding events, which happened with the same frequency in both groups. By chance patients with more advanced tumours may have been disproportionately represented in the standard heparin group, but this seems unlikely since large numbers of cancer patients were included in the studies, which were randomised. While it is also possible that standard heparin increased cancer mortality, such an adverse effect has not been reported previously. These considerations suggest that LMWH exerts an inhibitory effect on tumour growth that is not apparent with standard heparin. Heparin suppresses the proliferation of smooth-muscle cells after endothelial injury;4 and heparin and its LMW fractions inhibit thymidine uptake and endothelial cell growthand the intimal thickening that follows endothelial injury.6 In 1983, Folkman et al7 reported that angiogenesiswas inhibited and that tumours regressed in mice treated with heparin (or heparin fragments) and cortisone. Suramin, a polysulphonated naphthylurea that inhibits the lysosomal enzyme responsible for the degradation of heparan and dermatan sulphate, has an antineoplastic effect in patients with metastatic cancers,8 and Nakamura et al9 have reported that a sulphated polysaccharide-peptidoglycan compound inhibited angiogenesis associated with Kaposi-sarcoma-like lesions in a nude mouse model.
The use of heparin and heparinoids as tumour inhibitors has lately been reviewed.1O Perhaps heparin fragments, being smaller than standard heparin, enter tumour cells more easily. The evidence of lowered cancer mortality in patients on LMWH should stimulate renewed interest in these agents as antineoplastic drugs. Division of
Hematology/Oncology,
Department of Medicine, Northwestern University Medical School and Rehabilitation Institute, Illinois 60611, USA, and Clinical Trials Unit, Division of General Internal Medicine, University of Calgary, Alberta, Canada
Chicago,
DAVID GREEN RUSSELL D. HULL ROLLIN BRANT GRAHAM F. PINEO
1. Hirsh J, Levine MN. Review: low molecular weight heparin. Blood 1992; 79: 1-17. 2. Prandoni P, Lensing AWA, Buller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-45. 3. Hull RD, Raskob GL, Pineo GF, et al. Subcutaneous low molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82. 4. Clowes AW, Karnovsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature 1977; 265: 625-26. 5. Barzu T, van Rijn J, Rosenbaum J, Tobelem G. Endothelial cell reactions with heparin. Med J Aust 1986; 144 (suppl): HS15-17. 6. Dryjski M, Mikat E, Bjornsson TD. Inhibition of intimal hyperplasia after arterial injury by heparins and heparinoid. J Vasc Surg 1988; 8: 623-33. 7. Folkman J, Langer R, Linhardt RJ, et al. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone. Science 1983; 221: 719-25. 8. Stein CA, LaRocca RV, McAfee N, Myers CE. Suramin: an anticancer drug with a unique mechanism of action. J Clin Oncol 1989; 7: 499-508. 9. Nakamura S, Sakurada S, Salahuddin SZ, et al. Inhibition of development of Kaposi’s sarcoma-related lesions by a bacterial cell wall complex. Science 1992; 255: 1437-40. 10. Regelson W. Anionic dyes, heparin and heparinoids: the rediscovery of polyanionic tumor inhibitors. J Natl Cancer Inst 1989; 81: 1929-30.
Treatment of small cell carcinoma of the
lung SiR,—The companion articles by Dr Carney and Dr Hansen on biology and treatment, respectively, of small cell carcinoma of lung (SCCL) (April 4, p 843 and p 846) omit mention of the importance of the blood coagulation mechanism in this disease. the the
Two
prospective,
randomised trials of warfarin1.2 and
one
prospective, randomised trial of unfractionated low dose heparin3 have shown a statistically significant increase in tumour response rates and survival in SCCL. In a pilot study, Calvo and associates4,5 found that intermittent infusion of urokinase-type plasminogen activator (U-PA) together with combination chemotherapy resulted in 100% overall and 85% complete response rates in patients with limited extent SCCL, and 87% overall and 76% complete response rates in patients with disseminated SCCL.
1477
and projected median survival values were than those in historical controls. Thrombin is considerably higher generated at the tumour cell/connective tissue interface in situ in SCCL tissue, where it converts fibrinogen to fibrin.6 Progression of SCCL, one of the few tumour types that manifest tumour-cellassociated thrombin generation,’,’ may be promoted by thrombin either because of its growth factor activity or because of its ability to generate stromal fibrin.6 Further testing of this treatment approach may be worthy of consideration for several reasons. Although some progress has been made with combination chemotherapy and radiation therapy, most patients with SCCL still die of their disease. Anticoagulant therapy is a possibility because depriving a tumour cell of a substance (eg, thrombin or fibrin) required for its growth may be just as lethal to the cell as a cytotoxic drug and would be less toxic to the patient. There is plenty of opportunity for innovation because reduction of thrombin generation by warfarin is only partial, and unfractionated heparin remains mainly within the vasculature and probably does a poor job at anticoagulating the extracellular space. It is tempting to consider newer agents for clinical trials in SCCL such as low-molecular-weight heparin, hirudin, and antistasin because of their potency, specificity, and potential ability to gain access to sites of tumour- cell-initiated thrombin fonnation. Furthermore, U-PA may be beneficial because of its ability to remove stromal fibrinogen or fibrin by activation of fibrinolysis or because it is an inhibitor of cell growth in some models.9 This notion of experimental therapy for SCCL is also appealing because it is fairly cost effective and simple in comparison with some alternative approaches under consideration.
These response
rates
Department of Veterans Affairs, Medical and Regional Office Center, White River Junction, Vermont 05009, USA
LEO R. ZACHARSKI
1. Zacharski LR, Henderson WG, Rickles FR, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: final report of the VA Cooperative Study 75. Cancer 1984; 53: 2046-52. 2. Chahinian AP, Propert KJ, Ware JH, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the cancer and leukaemia group. Br J Clin Oncol 1989; 7: 993-1002. 3. Lebeau B, Chastang CL, Brechot JM. Subcutaneous heparin treatment increases complete response rate and overall survival in small cell lung cancer (SCLC). Lung Cancer 1991; 7 (suppl): 129. 4. Calvo FA, Santos M, Hidalgo OF. Urokinase-combination chemotherapy in small cell lung cancer: a phase II study. Proc ASCO 1991; 9: 237. 5. Calvo FA, Hidalgo OF, Gonzalez F, et al. Urokinase combination chemotherapy in small cell carcinoma of the lung: a phase II study. Cancer (in press). 6. Wojtukiewicz MZ, Zacharski LR, Memoli VA, et al. Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer 1990; 65: 481-85. 7. Zacharski LR, Memoli VA, Costantini V, Wojtukiewicz MZ, Ornstein DL. Clotting factors in tumour tissue: implications for cancer therapy. Blood Coag Fibrinol 1990; 1: 71-78. 8. Zacharski LR, Howell AL, Memoli VA. The coagulation biology of cancer. Fibrinolysis 1992; 6 (suppl 1): 39-42. 9. Howell AL, Hunt JB, Henkin J, Zacharski LR. Anti-proliferative effect of urokinase on myeloid leukemia cells (HL-60). Blood 1991; (suppl 1): 76a.
Management of cancer pain SIR,-Professor Hanks and Dr Justins comment only once on the value of radiotherapy in the management of cancer pain, although they review extensively drug therapy (and briefly surgery) for pain relief. Patients with severe cancer pain often have spinal lesions that destroy bone and compress the spinal cord, or harbour tumour metastases that compress and infiltrate paravertebral nerve roots. At least half of patients with osseous metastases achieve complete pain relief after radiation treatment,’ and urgent radiotherapy prevents the development of paraparesis in about 60% of patients presenting with pain and early symptoms of cord compression.2 Additionally, radiotherapy has a direct effect against tumour growth, expansion, and infiltration3-the pain-causing processes. Reviewers often fail to mention the important and versatile role of radiotherapy in management of cancer pain. Despite Hanks and Justins’ brief mention of radiotherapy, doctors with little knowledge of radiotherapy may be excused if they conclude that analgesics and perhaps surgery in selected cases is the whole story about cancer
pain management. Regrettably, even good textbooks of oncology do include radiotherapy under the headings "pain" or "pain control" in their indexes.4,5Nonetheless, many patients suffering painful neoplastic lesions should receive radiotherapy as well as analgesic drugs.
not
Norwegian Radium Hospital, Oslo, Norway
KNUT LOTE
Tong D, Gillick L, Hendrickson R. The palliation of symptomatic osseous metastases. Cancer 1982; 50: 893-99. 2. Rodriguez M, Dinapoli RP. Spinal cord compression with special reference to metastatic epidural tumors. Mayo Clin Proc 1980; 5: 442-48. 3. Withers RH: Biological basis of radiation therapy for cancer. Lancet 1992; 339: 156-59. 4. DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 2nd ed. Philadelphia: JB Lippincott, 1985. 5. American Cancer Society: textbook of clinical oncology. Atlanta: American Cancer Society, 1991. 1.
Aggressive endometriosis in bone SIR,-Extraabdominal endometriosis is rare, although it has been reported in the pleura and lung, inguinal region, thigh, and sciatic nerve, but is limited to the soft tissue. We describe an unusual case of endometriosis in the femur. A 45-year-old woman, para 0, was admitted to her local hospital with a tumour in the right thigh. For 6 years she had had right footdrop due to sciatic nerve palsy, without any trauma. Five months before admission she had abdominal hysterectomy because of uterine myomatosus. 300 ml sanguinous fluid was obtained from the tumour. 2 years later she presented again with a large, painful swelling (8 x 15 cm) on the lateral right thigh. The tumour was partly removed. Histological evaluation showed old blood and endometriosis with no signs of malignant disease. Computed tomography (CT) revealed a soft-tissue tumour in the pelvis connected through the foramen obturatorium to the gluteus region. Selective angiography showed extensive vascularisation of the suspected region seen on CT scan. She was referred to us because a soft tissue sarcoma was suspected clinically. At operation a large cyst filled with old blood was removed from the right hip. Cytological and histological examination showed endometriosis with no sign of malignant disease. She was given gonadotropin-releasing hormone (GNRH) agonist (gosereline 3-6 mg per month by subcutaneous injection for six months). Eight months later she was admitted for thrombosis in the left leg, which was successfully treated. The lesion on the right leg had increased, extending from the crista iliaca downwards to halfway down the thigh. CT showed progression of bone destruction as well as atrophy of the right musculus gluteus. Magnetic resonance imaging (MRI) revealed a very large tumour with cystic components in the pelvis expanding in the right upper leg and gluteus region. Laboratory findings were normal, apart from slight anaemia (haemoglobin [Hb] 7-1 mmol/1) and greatly raised serum CA-125 (1990 IU/ml). At a second operation, a sharply outpunched defect (4x3 cm) was found in the right trochanter major, expanding into the bone marrow of the femur. The lesion was almost completely removed. Well developed endometrial glands and stroma were seen histologically. Substantial stratification or signs of atypia were not found. The stroma showed dense cellularity and was composed of cells with large round nuclei and little cytoplasm. These stromal cells closely surrounded the endometrial epithelium. In the stroma haemosiderin was present. Immunohistochemical analysis demonstrated CA-125 in the epithelial cells, as is reported in endometriosis. DNA-flow cytometry showed a diploid DNA pattern. Bilateral salpingooophorectomy was done. Histopathological evaluation showed a normal left ovary with follicular cysts and a normal right ovary with a corpus luteum. She was admitted four months later with anaemia (Hb 2-7 mmol/1) due to bleeding in the tumour. MRI, CT, and ultrasound showed tumour progression. Serum CA-125 was 10 232 IU/ml. She was given a blood transfusion and tamoxifen (20 mg twice daily). With this regimen she improved but died, two months later, possibly because of lung embolus. In our patient CT showed that the tumour originated from the sciatic nerve, which accounts for the right footdrop since this is a known complication of endometriosis of the sciatic nerved Such an aggressive form of endometriosis expanding in bone has as far as we
