573
study can turn around almost 100 years of ill-feeling. However, the educational institutions and the recognition of the limitations of spinal manipulation and of the need for referral to medical practitioners, indicate the need for a fresh look.
upgrading of accredited chiropractic
73 Stanford Avenue, W Orange, New Jersey 07052, USA
PHILIP BRIEN
1. Meade TW, Dwyer S, Browne W, et al. Low back pain of mechanical origin: randomised comparison of chiropractic and hospital outpatient treatment. Br Med
J 1990; 300: 1431-37. 2. Kirkaldy-Willis WH. Managing Livingstone, 1988: 289.
low back
pain,
2nd ed.
Edinburgh: Churchill
SIR,-Your editorial assumes that, in the study in question, the chiropractic clinics were less busy than the outpatient departments. There is no hint of this in the paper cited. Furthermore, the study was not funded solely by the Medical Research Council, as you suggest, but jointly by four sponsors, one of whom (the ECU) is a
chiropractic professional organisation. Cashley Chiropractic Clinic, Market House, Kilworth Village, Co Cork, Ireland
from peripheral blood or lymph node were separated by 8% sodium dodecylsulphate/polyacrylamide gel electrophoresis, transferred onto nitrocellulose filter membranes, and reacted with C219 monoclonal antibody. P-glycoprotein was identified by autoradiography after incubation with 125I-protein A. Four of six pre-treatment samples, and four of five relapse stage samples expressed P-glycoprotein. In total, nine of eleven samples were positive for P-glycoprotein. One patient, in whom we could not detect P-glycoprotein in either the pre-treatment stage or the relapse stage, was alive after 37 months, and another P-glycoprotein-negative patient has now been treated with combination chemotherapy and has shown a good response. In ATL patients, trisomy 3 and trisomy 7 are the most commonly detected karyotypic abnormalitiesTrisomy 7 in particular was characteristic of acute ATL. The mdr-1 gene was located in chromosome.7,8 It is likely that this karyotypic abnormality is related to the development of multidrug resistance of ATL cells. We have demonstrated that the P-glycoprotein was frequently overexpressed in patients with ATL. This findings may explain the clinical resistance of ATL. Agents that protect the function of Pglycoprotein such as calcium-channel blockers may be useful to reduce resistance to antileukaemic agents in ATL. S. KATO
MARK A. P. CASHLEY
Overexpression of P-glycoprotein in adult T-cell leukaemia SIR,-Adult T-cell leukaemia (ATL) is characterised clinically by resistance to combination chemotherapy, including anthracyclines and vinca alkaloids, and by its poor prognosis. Median survival of patients with lymphoma-type ATL or leukaemic-type ATL is1 much shorter than that of patients with non-Hodgkin lymphoma. One mechanism for the development of resistance to anticancer agents is an overexpression of P-glycoprotein encoded by the mdr-11 gene, which has been well characterised in multidrug-resistant cell lines.2,3 P-glycoprotein is expressed in epithelia of normal intestine, kidney, and liver but not in normal lymphoid tissue. P-glycoprotein may have a physiological role in transport and excretion of different compounds in various tissues.45 Multidrug-resistant cells can maintain a lowered intracellular drug concentration by increasing the drug efflux associated with overexpression of P-glycoprotein. In
haematological malignant disease, including acute myelogenous leukaemia, acute lymphoblastic leukaemia, and non-Hodgkin lymphoma, P-glycoprotein expression has been demonstrated infrequently.6 To clarify whether the mdr-1 gene is implicated in the drug resistance of ATL, we investigated the expression of P-glycoprotein by western blotting with C219 monoclonal antibody in ATL cells from nine patients. Six samples were from patients in the pretreatment stage and five in the relapse stage; two patients were studied in both stages. Membrane proteins (100 I1g) of ATL cells
Western blot analysis of P-glycoprotein in patients with ATL.
Arrow=position of P-glycoprotem (molecular weight 170 kD); lane 1 = mdr cell line, K562/ADR500 (positive control); lanes 2-4=pretreatment stage; lanes 5-7 = relapse stage.
J. NISHIMURA Third
Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan
K. MUTA Y. YUFU H. NAWATA
Department of Clinical Chemistry and Laboratory Medicine, School of Medicine, Fukuoka University, Fukuoka
H. IDEGUCHI
Shimamoto Y, Ono K, Sano M, et al. Differences in prognostic factors between leukemia and lymphoma type of adult T-cell leukemia. Cancer 1989; 63: 289-94. 2. Kartner N, Evenden-Porelle D, Bradley G, Ling V. Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 1985; 316: 820-23. 3. Roninson IB, Chin JE, Choi K, et al. Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells Proc Natl Acad Sci USA 1986; 83: 4538-42. 4. Weistein RS, Coon JS, Dominquez JM, et al. Correlation between ABO blood type and Golgi P-glycoprotein expression in epithelia. Lancet 1990; 336: 54-55. 5. Sugawara I, Kataoka I, Morishita Y, et al. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 1988; 48: 1926-29. 6. Ma DDF, Scurr RD, Davey RA et al. Detection of a multidrug resistant phenotype in acute non-lymphoblastic leukaemia. Lancet 1987; ii: 135-37. 7. Ushima Y. Fukuhara S, Hattori T, Uchiyama T, Takatsuki K, Uchino H. Chromosome studies in adult T-cell leukemia in Japan: significance of trisomy 7. Blood 1981; 58: 1.
420-25. 8. Foto A, Lebo R, Shimizu N, et al. Localization of MDR associated DNA sequences human chromosome 7. Somatic Cell Mol Genet 1986; 12: 415-20.
to
Endogenous steroids and pathogenesis of hepatic encephalopathy SIR,-It is now generally accepted that the affinities and densities of &Ugr;-aminobutyric acid (GABA)/benzodiazepine receptors (GBZRs) are unchanged in hepatic encephalopathy. To explain the GBZR stimulation seen in this condition, therefore, an endogenous activator of GBZRs is a plausible hypothesis.1 Plasma concentrations of GABA in patients with acute hepatic encephalopathy correlate well with clinical severity, but not when measured in controls or in patients with chronic liver diseased It is argued that GABA is poor at crossing the blood-brain barrier, but in a rabbit model of hepatic encephalopathy,3 an increase in GABA binding in the brain was observed. This increase may be due to positive allosteric modulatory effects of a BZ-like substance rather than to changes in the permeability properties of the blood-brain barrier. Indeed substances with BZ-like properties have been detected in patients’ CSF.4,5Although on high-performance liquid chromatography these substances had characteristics similar to diazepam, their origin may merely be dietary.4,s Another class of ligands for this receptor seems a better candidate. Progesterone, deoxycorticosterone, and their 5a-reduced metabolites (eg, 5oc-pregnan-3a-o 1-20-one) have profound positive allosteric modulatory effects on the GBZR .6 Some are active at nanomolar levels. It is possible that, through altered steroid
574
metabolism in the liver and/or pharmacokinetic changes in these patients, there is an increase in these metabolites which, due to their hydrophobicity, easily cross the blood-brain barrier to affect the GBZR. The second possibility is that these steroids are synthesised in excess in brain tissue in situ. There is evidence that the peripheraltype BZR density is increased in hepatic encephalopathy? This receptor’s precise function is as yet undefined; it is known not to gate a GBZR/chloride ionophore, but affects metabolism.8 When stimulated with BZ ligands these receptors initiate an increase in steroid biosynthesis.9 Thus, this source of steroid could be important in the pathophysiology of hepatic encephalopathy. I thank Dr Mark Hendrickse (Royal Hallamshire Prof E. A. Barnard for their comments. MRC Molecular MRC Centre,
Hospital, Sheffield) and
Neurobiology Unit,
Cambridge CB2 2QH,
UK
S. H. ZAMAN
Layrargues G. Benzodiazepine receptors and hepatic encephalopathy. Hepatology 1990; 11: 499-501. 2. Levy LJ, Losowosky MS. Plasma gamma aminobutyric acid concentrations provide evidence of different mechanisms in the pathogenesis of hepatic encephalopathy in acute and chronic liver disease. Hepatogastroentrology 1989; 36: 494. 3. Bassett ML, Mullen KD, Scholz B, Fenstermacher JD, Jones EA. Increased brain uptake of gamma aminobutyric acid in a rabbit model of hepatic encephalopathy. Gastroenterology 1990; 98: 747-57. 4. Olasmaa M, Guidotti A, Rothstein JD, Paul SM, Costa E. Naturally occurring benzodiazepines in CSF of patients with hepatic encephalopathy. Soc Neurosci 1989; 15: 199 8 (abstr). 5. Mullen KD, Szauter KM, Kaminsky K, Tolentino PD, McCullough AJ. Detection and characterization of endogenous benzodiazepine activity in both animal models and humans with hepatic encephalopathy. In: Butterworth RF, Pomier Layargues G, eds. Hepatic encephalopathy: pathophysiology and treatment. Clifton NJ: Humana, 1989: 287-94. 6. Gee KW. Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionophore. Mol Neurobiol 1988; 313: 291-317. 7. Lavoie J, Pomier Layrargues G, Butterworth RF. Increased densities of peripheraltype benzodiazepine receptors in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 1989; 10: 619 (abstr). 8. Anholt RHH, Pederson PL, DeSouza EB, Snyder SH. The peripheral-type benzodiazepine receptor: localization to the mitochondrial outer membrane. J Biol Chem 1986; 261: 576-83. 9. Mukin AG, Papadopalos V, Costa E, Krueger KE. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis. Proc Natl Acad Sci USA 1989; 86: 1. Butterworth RF, Pomier
Multiple cutaneous angiomas over patient’s knee.
differentiated carcinoma with features consistent with renal cell carcinoma, almost certainly the source of her raised erythropoietin
concentrations. Her disease
judged
advanced for
&agr;2-interferon or precluded the use of a progestagen. She was managed supportively with venesection and increased doses of diuretic and captopril. 3 months later, she had increasing numbers of painless, slightly raised, blanching angiomas over the trunk, thighs, and upper arms. The lesions were was
cytotoxic therapy,
9813-16.
Multiple cutaneous haemangiomas in patient with disseminated renal cell carcinoma and polycythaemia SIR,-Cutaneous haemangiomas can be congenital, but are seen commonly related to hyperoestrogenism. We describe a case of de novo eruptive haemangiomatosis associated with progressive malignant disease. A 72-year-old woman presented with a 6-month history of anorexia, weight loss, and lethargy and 3 months of increasing effort dyspnoea, orthopnoea, headaches, and dizziness. A 5-cm diameter cyst had been discovered on renal ultrasonography 2 years earlier. Her medical history included hypertension, angina, and symptommost
less cholelithiasis. She had never smoked and was teetotal. She was taking frusemide 80 mg twice daily, captopril 6-25 mg daily, isosorbide dinitrate 20 mg four times daily, and theophylline 300 mg twice daily. She was obese and plethoric with an aortic systolic ejection murmur, cardiac failure with bilateral basal pulmonary crackles, and dependent oedema, and there was irregular, firm, non-tender hepatomegaly with a mid-clavicular span of 15 cm. Her haemoglobin was 19-8 g/dl with a packed cell volume of 62-3%, and red cell indices and white cell and platelet counts were normal. Electrolytes, renal function, and liver function were also normal (apart from bilirubin 25 Nmol/1). Bone-marrow biopsy revealed moderate erythrocytosis and absent iron. Red cell volume (63 ml/kg) and total blood volume (106 ml/kg) were strikingly increased, as was serum erythropoietin (160 mU/ml, reference range 8-2-21-4). She had moderate cardiomegaly and pulmonary oedema. Echocardiography showed mild aortic stenosis and left ventricular hypertrophy. She had a 9-cm diameter mass in the upper pole of the left kidney with multiple hepatic metastases. Fine-needle aspiration biopsy of the renal and hepatic lesions confirmed poorly ,
too
and the cardiac failure
surrounded by a pale rim or "halo" (figure). Serum cortisol and oestradiol concentrations were normal. Her angiomatosis lessened spontaneously but persisted until her death 4 months later. Permission for necropsy was refused. Our patient’s eruptive haemangiomatosis was unheralded by either a change in medication (apart from the addition of bendrofluazide) or any apparent intercurrent illness or specific complication of her malignant disease. She was not on oestrogen therapy. There were no clinical or biochemical features of hepatic failure or hypercortisolism. The eruption was probably related to the metastatic renal cell carcinoma and possibly to the secondary polycythaemia. The latter may have had an effect causing expansion of the intravascular volume, increased blood viscosity, and local tissue hypoxia. Eruptive haemangiomatosis has been described in malignant disease, in 1 case each of Hodgkin’s lymphoma, chronic lymphatic leukaemia, melanoma, and multiple myeloma.1 However, in these patients the lesions were larger and more raised than in our patient, resembled granuloma pyogenicum, and proved to be capillary haemangiomas on biopsy. The lesions in these previous cases were not surrounded by a pale rim. This last feature was impressive clinically in our case and was thought possibly to represent a local vascular "steal" event. Angiogenesis is a central feature in tumour growth. Diffusible tumour angiogenic factors have been identified in malignant disease.2 The skin eruption in our patient and those reported previously may represent systemic effects of such factors synthesised in the tumour. The appearance of new, otherwise unexplained, haemangiomas should prompt evaluation for underlying malignant disease. Department of Medicine, Royal Perth Hospital, University of Western Australia, Perth 6000, Australia
D. GRAHAM S. B. DIMMITT
1. Pembroke AC, Grice K, Levantine AV, Warins AP. Eruptive angiomata in
disease. Clin Exp Dermatol 1978; 3: 147-56 2. Folkman J, Merler E, Abemathy C, Williams G. Isolation of responsible for angiogenesis. J Exp Med 1970; 133: 275-88.
malignant
a tumour
factor
study can turn around almost 100 years of ill-feeling. However, the educational institutions and the recognition of the limitations of spinal manipulation and of the need for referral to medical practitioners, indicate the need for a fresh look.
upgrading of accredited chiropractic
73 Stanford Avenue, W Orange, New Jersey 07052, USA
PHILIP BRIEN
1. Meade TW, Dwyer S, Browne W, et al. Low back pain of mechanical origin: randomised comparison of chiropractic and hospital outpatient treatment. Br Med
J 1990; 300: 1431-37. 2. Kirkaldy-Willis WH. Managing Livingstone, 1988: 289.
low back
pain,
2nd ed.
Edinburgh: Churchill
SIR,-Your editorial assumes that, in the study in question, the chiropractic clinics were less busy than the outpatient departments. There is no hint of this in the paper cited. Furthermore, the study was not funded solely by the Medical Research Council, as you suggest, but jointly by four sponsors, one of whom (the ECU) is a
chiropractic professional organisation. Cashley Chiropractic Clinic, Market House, Kilworth Village, Co Cork, Ireland
from peripheral blood or lymph node were separated by 8% sodium dodecylsulphate/polyacrylamide gel electrophoresis, transferred onto nitrocellulose filter membranes, and reacted with C219 monoclonal antibody. P-glycoprotein was identified by autoradiography after incubation with 125I-protein A. Four of six pre-treatment samples, and four of five relapse stage samples expressed P-glycoprotein. In total, nine of eleven samples were positive for P-glycoprotein. One patient, in whom we could not detect P-glycoprotein in either the pre-treatment stage or the relapse stage, was alive after 37 months, and another P-glycoprotein-negative patient has now been treated with combination chemotherapy and has shown a good response. In ATL patients, trisomy 3 and trisomy 7 are the most commonly detected karyotypic abnormalitiesTrisomy 7 in particular was characteristic of acute ATL. The mdr-1 gene was located in chromosome.7,8 It is likely that this karyotypic abnormality is related to the development of multidrug resistance of ATL cells. We have demonstrated that the P-glycoprotein was frequently overexpressed in patients with ATL. This findings may explain the clinical resistance of ATL. Agents that protect the function of Pglycoprotein such as calcium-channel blockers may be useful to reduce resistance to antileukaemic agents in ATL. S. KATO
MARK A. P. CASHLEY
Overexpression of P-glycoprotein in adult T-cell leukaemia SIR,-Adult T-cell leukaemia (ATL) is characterised clinically by resistance to combination chemotherapy, including anthracyclines and vinca alkaloids, and by its poor prognosis. Median survival of patients with lymphoma-type ATL or leukaemic-type ATL is1 much shorter than that of patients with non-Hodgkin lymphoma. One mechanism for the development of resistance to anticancer agents is an overexpression of P-glycoprotein encoded by the mdr-11 gene, which has been well characterised in multidrug-resistant cell lines.2,3 P-glycoprotein is expressed in epithelia of normal intestine, kidney, and liver but not in normal lymphoid tissue. P-glycoprotein may have a physiological role in transport and excretion of different compounds in various tissues.45 Multidrug-resistant cells can maintain a lowered intracellular drug concentration by increasing the drug efflux associated with overexpression of P-glycoprotein. In
haematological malignant disease, including acute myelogenous leukaemia, acute lymphoblastic leukaemia, and non-Hodgkin lymphoma, P-glycoprotein expression has been demonstrated infrequently.6 To clarify whether the mdr-1 gene is implicated in the drug resistance of ATL, we investigated the expression of P-glycoprotein by western blotting with C219 monoclonal antibody in ATL cells from nine patients. Six samples were from patients in the pretreatment stage and five in the relapse stage; two patients were studied in both stages. Membrane proteins (100 I1g) of ATL cells
Western blot analysis of P-glycoprotein in patients with ATL.
Arrow=position of P-glycoprotem (molecular weight 170 kD); lane 1 = mdr cell line, K562/ADR500 (positive control); lanes 2-4=pretreatment stage; lanes 5-7 = relapse stage.
J. NISHIMURA Third
Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan
K. MUTA Y. YUFU H. NAWATA
Department of Clinical Chemistry and Laboratory Medicine, School of Medicine, Fukuoka University, Fukuoka
H. IDEGUCHI
Shimamoto Y, Ono K, Sano M, et al. Differences in prognostic factors between leukemia and lymphoma type of adult T-cell leukemia. Cancer 1989; 63: 289-94. 2. Kartner N, Evenden-Porelle D, Bradley G, Ling V. Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 1985; 316: 820-23. 3. Roninson IB, Chin JE, Choi K, et al. Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells Proc Natl Acad Sci USA 1986; 83: 4538-42. 4. Weistein RS, Coon JS, Dominquez JM, et al. Correlation between ABO blood type and Golgi P-glycoprotein expression in epithelia. Lancet 1990; 336: 54-55. 5. Sugawara I, Kataoka I, Morishita Y, et al. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 1988; 48: 1926-29. 6. Ma DDF, Scurr RD, Davey RA et al. Detection of a multidrug resistant phenotype in acute non-lymphoblastic leukaemia. Lancet 1987; ii: 135-37. 7. Ushima Y. Fukuhara S, Hattori T, Uchiyama T, Takatsuki K, Uchino H. Chromosome studies in adult T-cell leukemia in Japan: significance of trisomy 7. Blood 1981; 58: 1.
420-25. 8. Foto A, Lebo R, Shimizu N, et al. Localization of MDR associated DNA sequences human chromosome 7. Somatic Cell Mol Genet 1986; 12: 415-20.
to
Endogenous steroids and pathogenesis of hepatic encephalopathy SIR,-It is now generally accepted that the affinities and densities of &Ugr;-aminobutyric acid (GABA)/benzodiazepine receptors (GBZRs) are unchanged in hepatic encephalopathy. To explain the GBZR stimulation seen in this condition, therefore, an endogenous activator of GBZRs is a plausible hypothesis.1 Plasma concentrations of GABA in patients with acute hepatic encephalopathy correlate well with clinical severity, but not when measured in controls or in patients with chronic liver diseased It is argued that GABA is poor at crossing the blood-brain barrier, but in a rabbit model of hepatic encephalopathy,3 an increase in GABA binding in the brain was observed. This increase may be due to positive allosteric modulatory effects of a BZ-like substance rather than to changes in the permeability properties of the blood-brain barrier. Indeed substances with BZ-like properties have been detected in patients’ CSF.4,5Although on high-performance liquid chromatography these substances had characteristics similar to diazepam, their origin may merely be dietary.4,s Another class of ligands for this receptor seems a better candidate. Progesterone, deoxycorticosterone, and their 5a-reduced metabolites (eg, 5oc-pregnan-3a-o 1-20-one) have profound positive allosteric modulatory effects on the GBZR .6 Some are active at nanomolar levels. It is possible that, through altered steroid
574
metabolism in the liver and/or pharmacokinetic changes in these patients, there is an increase in these metabolites which, due to their hydrophobicity, easily cross the blood-brain barrier to affect the GBZR. The second possibility is that these steroids are synthesised in excess in brain tissue in situ. There is evidence that the peripheraltype BZR density is increased in hepatic encephalopathy? This receptor’s precise function is as yet undefined; it is known not to gate a GBZR/chloride ionophore, but affects metabolism.8 When stimulated with BZ ligands these receptors initiate an increase in steroid biosynthesis.9 Thus, this source of steroid could be important in the pathophysiology of hepatic encephalopathy. I thank Dr Mark Hendrickse (Royal Hallamshire Prof E. A. Barnard for their comments. MRC Molecular MRC Centre,
Hospital, Sheffield) and
Neurobiology Unit,
Cambridge CB2 2QH,
UK
S. H. ZAMAN
Layrargues G. Benzodiazepine receptors and hepatic encephalopathy. Hepatology 1990; 11: 499-501. 2. Levy LJ, Losowosky MS. Plasma gamma aminobutyric acid concentrations provide evidence of different mechanisms in the pathogenesis of hepatic encephalopathy in acute and chronic liver disease. Hepatogastroentrology 1989; 36: 494. 3. Bassett ML, Mullen KD, Scholz B, Fenstermacher JD, Jones EA. Increased brain uptake of gamma aminobutyric acid in a rabbit model of hepatic encephalopathy. Gastroenterology 1990; 98: 747-57. 4. Olasmaa M, Guidotti A, Rothstein JD, Paul SM, Costa E. Naturally occurring benzodiazepines in CSF of patients with hepatic encephalopathy. Soc Neurosci 1989; 15: 199 8 (abstr). 5. Mullen KD, Szauter KM, Kaminsky K, Tolentino PD, McCullough AJ. Detection and characterization of endogenous benzodiazepine activity in both animal models and humans with hepatic encephalopathy. In: Butterworth RF, Pomier Layargues G, eds. Hepatic encephalopathy: pathophysiology and treatment. Clifton NJ: Humana, 1989: 287-94. 6. Gee KW. Steroid modulation of the GABA/benzodiazepine receptor-linked chloride ionophore. Mol Neurobiol 1988; 313: 291-317. 7. Lavoie J, Pomier Layrargues G, Butterworth RF. Increased densities of peripheraltype benzodiazepine receptors in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Hepatology 1989; 10: 619 (abstr). 8. Anholt RHH, Pederson PL, DeSouza EB, Snyder SH. The peripheral-type benzodiazepine receptor: localization to the mitochondrial outer membrane. J Biol Chem 1986; 261: 576-83. 9. Mukin AG, Papadopalos V, Costa E, Krueger KE. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis. Proc Natl Acad Sci USA 1989; 86: 1. Butterworth RF, Pomier
Multiple cutaneous angiomas over patient’s knee.
differentiated carcinoma with features consistent with renal cell carcinoma, almost certainly the source of her raised erythropoietin
concentrations. Her disease
judged
advanced for
&agr;2-interferon or precluded the use of a progestagen. She was managed supportively with venesection and increased doses of diuretic and captopril. 3 months later, she had increasing numbers of painless, slightly raised, blanching angiomas over the trunk, thighs, and upper arms. The lesions were was
cytotoxic therapy,
9813-16.
Multiple cutaneous haemangiomas in patient with disseminated renal cell carcinoma and polycythaemia SIR,-Cutaneous haemangiomas can be congenital, but are seen commonly related to hyperoestrogenism. We describe a case of de novo eruptive haemangiomatosis associated with progressive malignant disease. A 72-year-old woman presented with a 6-month history of anorexia, weight loss, and lethargy and 3 months of increasing effort dyspnoea, orthopnoea, headaches, and dizziness. A 5-cm diameter cyst had been discovered on renal ultrasonography 2 years earlier. Her medical history included hypertension, angina, and symptommost
less cholelithiasis. She had never smoked and was teetotal. She was taking frusemide 80 mg twice daily, captopril 6-25 mg daily, isosorbide dinitrate 20 mg four times daily, and theophylline 300 mg twice daily. She was obese and plethoric with an aortic systolic ejection murmur, cardiac failure with bilateral basal pulmonary crackles, and dependent oedema, and there was irregular, firm, non-tender hepatomegaly with a mid-clavicular span of 15 cm. Her haemoglobin was 19-8 g/dl with a packed cell volume of 62-3%, and red cell indices and white cell and platelet counts were normal. Electrolytes, renal function, and liver function were also normal (apart from bilirubin 25 Nmol/1). Bone-marrow biopsy revealed moderate erythrocytosis and absent iron. Red cell volume (63 ml/kg) and total blood volume (106 ml/kg) were strikingly increased, as was serum erythropoietin (160 mU/ml, reference range 8-2-21-4). She had moderate cardiomegaly and pulmonary oedema. Echocardiography showed mild aortic stenosis and left ventricular hypertrophy. She had a 9-cm diameter mass in the upper pole of the left kidney with multiple hepatic metastases. Fine-needle aspiration biopsy of the renal and hepatic lesions confirmed poorly ,
too
and the cardiac failure
surrounded by a pale rim or "halo" (figure). Serum cortisol and oestradiol concentrations were normal. Her angiomatosis lessened spontaneously but persisted until her death 4 months later. Permission for necropsy was refused. Our patient’s eruptive haemangiomatosis was unheralded by either a change in medication (apart from the addition of bendrofluazide) or any apparent intercurrent illness or specific complication of her malignant disease. She was not on oestrogen therapy. There were no clinical or biochemical features of hepatic failure or hypercortisolism. The eruption was probably related to the metastatic renal cell carcinoma and possibly to the secondary polycythaemia. The latter may have had an effect causing expansion of the intravascular volume, increased blood viscosity, and local tissue hypoxia. Eruptive haemangiomatosis has been described in malignant disease, in 1 case each of Hodgkin’s lymphoma, chronic lymphatic leukaemia, melanoma, and multiple myeloma.1 However, in these patients the lesions were larger and more raised than in our patient, resembled granuloma pyogenicum, and proved to be capillary haemangiomas on biopsy. The lesions in these previous cases were not surrounded by a pale rim. This last feature was impressive clinically in our case and was thought possibly to represent a local vascular "steal" event. Angiogenesis is a central feature in tumour growth. Diffusible tumour angiogenic factors have been identified in malignant disease.2 The skin eruption in our patient and those reported previously may represent systemic effects of such factors synthesised in the tumour. The appearance of new, otherwise unexplained, haemangiomas should prompt evaluation for underlying malignant disease. Department of Medicine, Royal Perth Hospital, University of Western Australia, Perth 6000, Australia
D. GRAHAM S. B. DIMMITT
1. Pembroke AC, Grice K, Levantine AV, Warins AP. Eruptive angiomata in
disease. Clin Exp Dermatol 1978; 3: 147-56 2. Folkman J, Merler E, Abemathy C, Williams G. Isolation of responsible for angiogenesis. J Exp Med 1970; 133: 275-88.
malignant
a tumour
factor
