202 Journal of the Royal Society of Medicine Volume 86 April 1993 Paraneoplastic syndromes in patients with ovarian neoplasia C N Hudson MChir FRCS FRCOG1 Marigold Curling MB BS2 Penelope Potsides' D G Lowe MD MRCPath MIBiol' 'The Association of Obstetricians and Gynaecologists, NE Thames Region and 2the Department ofHistopathology, St Bartholomew's Hospital Medical College, London EClA 7BE Keywords: paraneoplastic syndromes; ovarian cancer; prevalence Summary data at presentation of 908 patients with primary The prevalence of several paraneoplastic syndromes epithelial ovarian cancer, collected prospectively in associated with ovarian cancer was determined from the North East Thames Region. a clinicopathological study of 908 patients with primary ovarian malignancy in the North East Thames Data source Region. The diversity and rarity of these manifesta- In the 1970s a data bank for ovarian cancer in the tions are great and the explanation for them is North East Metropolitan Region was set up by difficult. Circumstantial evidence suggests that in the Association of Obstetricians and Gynaecologists some cases an autoimmune phenomenon is the most of the Region in association with the Regional plausible cause. Histopathologists Group. Data was entered either by pathologist or clinician, and as soon as a case Introduction was notified, the clinical data on an agreed proforma Paraneoplastic syndromes are systemic manifestations were obtained from the surgeon concerned - he/ ofcancer that cannot readily be explained by the local she provided details of the mode of presentation, or metastatic effects of a tumour or of hormones investigation, operative staging, and treatment. indigenous to the tissue in which the tumour arises. Histological material was reviewed centrally by The syndromes fall into four broad groups, in which the two of the authors. The Regional Histopathologists patient has endocrine, neurological, haematological/ Group established a reference panel for review ofdiffi- vascular, or dermatological disease. Ovarian cancer, cult, unusual, and interesting cases. Whenever possible, itself notable for the diversity of the pathological the review panel was provided with unstained sections manifestations of the primary tumour and its meta- so that special stains could be examined. This report stases, features widely in descriptions ofparaneoplastic covers the clinical history, the clinical features at syndromes. presentation, and the histological findings in 908 Endocrine manifestations as a consequence of patients with primary ovarian cancer. oversecretion of the normal ovarian hormones by Method ovarian tumours should not, by definition, be included The proforma sent to clinicians asked for data on in the category of paraneoplastic or para-endocrine chronic medical conditions, long-standing medication, syndromes'. Certain ovarian germ cell tumours pro- previous cancer, and relevant family history. Other duce chorionic gonadotrophin and a-fetoprotein2; data were obtained from the clinical examination at there are no clinical manifestations apart from presentation and from the laboratory and radiographic formation of theca lutein cysts in the normal investigations, including features such as evidence contralateral ovary. of thrombophlebitis, venous obstruction, or poly- Some paraneoplastic syndromes are associated with cythaemia. Although this was a prospective study, so-called collagen disease, for which there may be completeness of the initial data collected varied an established or theoretical immunological basis3. between individuals and with the circumstances of Antibodies to a number of tissue antigens have presentation. An associated medical condition was been identified in patients with ovarian cancer4-6. found in just over a third of patients. Circulating immune complexes have also been demonstrated in the sera ofpatients with metastatic Results epithelial ovarian cancer7 and the nephrotic syndrome Table 1 lists the medical conditions most commonly that occurs in some patients with ovarian cancer has reported or found on examination. There was no been attributed to glomerular deposition of immune complexes8. One of the most striking demonstrations Table 1. North East Metropolitan Region ovarian cancer study ofthe autoimmune basis ofa paraneoplastic syndrome is that in certain patients with ovarian carcinoma, Cases of primary ovarian cancer 908 expression of a particular type of Purkinje cell Chronic medical disorders including: 245 antibody is associated with subacute cerebellar Hypertension 39 degeneration9"10. It has been suggested that assay of Respiratory 22 these antibodies may be a useful tumour marker",12. Thyroid 20 This paper reports the results of a study of the Cardiac 20 Gastrointestinal 14 Diabetes 12 Correspondence to: Professor C N Hudson, Williamson Osteoarthritis 11 Laboratory, St Bartholomew's Hospital, West Smithfield, Psychiatric 10 London EClA 7BE Journal of the Royal Society of Medicine Volume 86 April 1993 203 Table 2. Possible para-neoplastic syndromes Osteoarticular disease Ofthe collagen disorders, rheumatoid arthritis hasbeen Collagen disorders described as occurring as a paraneoplastic syndrome. Dermatomyositis In none ofthe cases recorded here for which sufficient Polyarteritis nodosa detail was made available was it possible to postulate Rheumatoid arthritis atemporal relation withtheprogress ofthe disease. Syste- Reflex sympathetic dystrophy mic sclerosis and dermatomyositis have a much stronger Other skin manifestations relationship with underlying visceral malignancy, Neurological including ovarian cancer18 and in this series the two Cerebellar degeneration patients with dermatomyositis and polyarteritis may Haematological be considered to have had a paraneoplastic condition. Polycythaemia Reflex sympathetic dystrophy (shoulder-hand syn- Pre-existing thrombosis/thrombophlebitis drome) in association with endometrioid ovarian Haemolytic anaemia cancer has been shown to antedate the clinical Para-endocrine detection of the cancer19. It is unlikely that the Hypercalcaemia presence ofpalmar fasciitis (Dupuytren's contracture), which is characteristic ofthis paraneoplastic syndrome, would have been recorded in the routine clerking of recorded history of a chronic medical condition in the gynaecological patients and so would not have been other patients, and so, by implication, no pre-existing recorded as a chronic medical disorder. Any such case symptomatic paraneoplastic syndrome. It is recognized would have been overlooked. that there was an inherent tendency to under- reporting. From these data it was possible to prepare a Dermatological conditions list of conditions that might be considered to form part During the period of study there were no dermato- ofa paraneoplastic syndrome (see Table 2). Some are so logical manifestations of paraneoplastic syndromes common that a coincidental relationship might be anti- other than dermatomyositis recorded, though shortly cipated. Ofthe other chronic medical conditions reported, before the study started a patient who presented with thyroid disease occurs with surprising frequency. The endometrioid ovarian carcinoma later developed significance of this association is unknown13. acanthosis nigricans and metastatic carcinoma, Haematological conditions a previously reported association20'21. These data that from venous complications (many The figures given for the prevalence of venous suggest apart which have been from mechanical causes involvement include venous obstruction from extrinsic of may rather than from a paraneoplastic coagulopathy) and compression due to pelvic tumour, as well as spon- rheumatoid arthritis (which is of doubtful relevance), taneous iliofemoral thrombosis, as distinction between the of individual paraneoplastic these was not possible in many cases. Ovarian prevalence syndromes in association with malignant ovarian malignancy may be silent even when it presents with disease is of the order of only one in 1000. venous gangrene14. Of the patients in this series with vascular problems, a diagnosis of thrombophlebitis migrans in one prompted a gynaecological consultation Discussion which brought to light an unsuspected ovarian Because the prevalence ofparaneoplastic syndromes is so low few gynaecologists, even those in specialist malignancy15. This was clearly a paraneoplastic will encounter them. The syn- phenomenon, but in other cases a thrombotic tendency oncological practice, dromes will tend, therefore, to be diagnosed by may have been operating as a paraneoplastic process. consultants in endocrine, neurological One other patient with a haematological disorder was dermatological, and other to whom the patient may be found; she had secondary polycythaemia with a specialties haemoglobin concentration of 16 g/dl. The tumour in referred, and in some cases will precede the diagnosis this instance was a well differentiated mucinous or even suspicion of cancer. Inappropriate secretion adenocarcinoma that had arisen between the leaves of of hormones is the subject of much continuing study. the broad ligament. It is at this site that leiomyomas Ectopic secretion of ACTH by bronchial carcinoma is well but it has also been reported have been reported to have a similar haematological recognized, that neoplasms of the ovary can cause Cushing's effect16. It may be that this is due to excessive production of erythropoietin by the kidney secondary syndrome22 and secrete polypeptide hormones such as to a pressure effect on the ureter;