Tropical Doctor, October I977
MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
Midline lethal granuloma and Wegener's granulomatosis in Nigerians: a report of three cases E. O. Adekeye, FDSRCS, FMCDS, FWACS Consultant, Maxillo-Facial Unit, Ahmadu Bello University Hospital, Kaduna, Nigeria
c. V. Abengowe
FRCP (Glas.), FWACP,
DCH (Lond.) Senior Lecturer, Department of Medicine, ABU Hospital, Kaduna
TROPICAL DOCTOR,
1977,7,169-174
In 1931, Klinger reported two cases in which the patients had destructive sinusitis, nephritis, and uraemia; at autopsy, splenic granulomata, arteritis, and glomerular lesions were seen. However, Wegener (1936, 1939) was the first to describe in detail three patients with a condition starting as rhinitis, followed by a disseminated disease, and ending in renal failure (Wegener's granulomatosis). Later, more cases, closely resembling the above condition, were published, either as examples of the midline lethal granuloma or the unusual forms of periarteritis nodosa (Williams 1949; McCart 1950; Weinberg 1946; Stratton et al. 1953; Howells and Friedmann 1950). Godman and Churg (1954)differentiated Wegener's granulomatosis from the usual forms of periarteritis nodosa. They stated three main pathological criteria for the diagnosis of the disseminated disease: namely, necrotizing respiratory tract granulomas, generalized focal necrotizing vasculitis and necrotizing glomerulitis. Mills (1967) said that midline lethal granuloma and Wegener's granulomatosis were one and the same disease, adding, that where the disease is primarily localized to the midline ofthe palate and the nose, it is called midline lethal granuloma while the disseminated disease is termed Wegener's granulomatosis. The disease is rare in Europe .and North America, but even rarer in Africa, Between 1960 and 1977 we could find only three references to the condition in Africa (Barnard et al. 1965; Cooper et al. 1970; Vaillant et al. 1967). The purpose of this paper is to report on two cases of midline lethal granuloma and one case of Wegener's granulomatosis seen within a period of two years at
I 169
the Ahmadu Bello University Teaching Hospital, Kaduna, Nigeria. The cases illustrate certain differences in the clinical features of the condition, the problems of chemotherapy, and the generally accepted poor prognosis. Furthermore, they serve as additions to the literature of the few cases reported from Africa. CASE REPORTS
Case I - O.A., a 38-year-old Nigerian man, gave a history of stuffiness and blockage of both nostrils, intermittent purulent nasal discharge, and pain in the maxilla and nose for two months. One month after the symptoms had started, a tender and gradually enlarged swelling of the nose appeared. On examination, he was a tall, fit-looking man with a grossly swollen nose (Fig. I). An ulcerative, necrotic, and granulomatous lesion, covered with crusty exudate, was seen on the nasal septum and the right lateral nasal wall. Gentle removal of the crust
Fig. I. Fullface photograph showing grossly swollen nose.
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I MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
showed an underlying necrotic bone; the right submandibular lymph node was enlarged. The general examination was normal: the chest was clear to percussion and auscultation, the abdomen was soft, and the liver and spleen were not enlarged. Radiographic examination showed mucosal thickening and opacity of the right maxillary antrum with a fluid level. The chest radiograph and the intravenous pyelogram were normal. Bacteriological cultures of swabs taken from the palatal and nasal lesions produced normal commensals. The following investigations were normal: haemoglobin, WBC and differential, blood proteins, alkaline phosphatase, creatinine, electrolytes, urea, urinalysis, VDRL, and Mantoux. The erythrocyte sedimentation rate was 37 mrn/hr (Westergren). As the disease progressed, it destroyed the hard palate which became perforated (Fig. 2). Under general anaesthesia, the right nasal cavity was inspected and it was found to contain much friable, granular tissue. A biopsy was taken from the nonnecrotic portion of the palatal ulcer. The specimen, which measured 14 x 5 x 4 mm, consisted of granulomatous soft tissue with the surface covered partly by epithelium but the major part was ulcerated. Microscopically, the sections showed extensive ulceration and submucosal fibrinoid necrosis associated with a pleomorphic lymphocytic and histiocytic granulomatous infiltrate which overran minor salivary glands (Fig. 3). There were numerous mitotic figures in the infiltrate and cytological atypia was extreme in places. Giant cells were not seen but eosinophils were prominent. There was no distinct evidence of
Fig. 2. The large perforating palatal ulcer. Note the extensive destruction and much necrosis of palatal tissues.
Tropical Doctor, October 1977
Fig. 3. Photomicrograph showing destruction and focal necrosis of palatal mucous glands overrun by a pleomorphic, lympho-histiocytic infiltrate. (HE original magnification x 128.)
destructive vasculitis in the substantial vessels but some vessels had thickened walls. Others showed necrosis without inflammatory infiltration and some were engorged and thrombosed. On balance, these histological features were consistent with those of the midline lethal granuloma. The renal biopsy was normal histologically. Treatment was started with prednisolone, cyclophosphamide and procaine penicillin. About two weeks after the commencement of treatment, the patient's condition slowly deteriorated; there was weight loss, the nose continued to increase in size and the palatal perforation enlarged gradually. About two months after admission, the patient voluntarily discharged himself from the hospital and has never been seen since. Case 2 - F.]., a ze-year-old Nigerian man, gave a history of pain in the right ear and headache for five years. He also complained of a recent epistaxis, a dry cough, fever, and sore throat. On examination, he was a pale, moderately ill man with a temperature of 39°C, a regular pulse of 120 per minute, and a respiratory rate of 20 per minute. The liver was enlarged by about 5 cm below the costal margin but it was soft and non-tender. The lungs were clear to percussion and auscultation. Two punched-out ulcers, measuring about 10 mm and 15 mm in diameter respectively, were seen on the soft palate. The surfaces of the ulcers were irregular and had a friable necrotic appearance. Radiographic examination showed multiple rounded densities in both lungs (Fig. 4) but the radiograph of the paranasal sinuses and the intravenous pyelogram were normal.
Tropical Doctor, October J()77
MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
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The infiltrate consisted of pleomorphic lymphocytic and histiocytic cells with some atypical features including a number of mitotic figures (Fig. 5). The profile of a small vessel appeared in the ulcer bed the walls of which were overrun by inflammatory cells. Giant cells were not present in the sections and eosinophilic leucocytes were not prominent within the granuloma. However, the oedematous, fibroblastic subepithelial connective tissue at the margin of the ulcer was studded with eosinophils and neutrophils. The tissue enclosed dilated lymphatics, numerous capillaries, and endothelial sprouts. The small vessels were cuffed by lymphocytes. The granulomatous infiltration had spread to involve adjacent mucous glands which showed lobular
Fig. 4. Chest radiograph showing multiple rounded densities in both lungs.
Blood examination showed a haemoglobin of 13' 4 g/ the total WBe count was 5,600 per mrn" with a normal differential, and the platelet count was 214 x 103 per mm", The following investigations were normal: renal and liver function tests, serum electrolytes, blood urea and the serum proteins. Bacteriological cultures of swabs taken from the soft palate and the sputum produced normal commensals; the blood culture was unremarkable. The Mantoux and the VDRL tests were negative. The erythrocyte sedimentation rate was 56 mm/hr (Westergren). A biopsy of the non-necrotic part of the lesion in the soft palate was taken under local anaesthesia. The lesion was soft and it measured 13 X 10 X 6 mm. The epithelial surface was rough and lobulated and it showed an area of ulceration. Microscopically, sections showed the margin of part of the floor of an extensive ulcer associated with inflammatory changes in the submucosa involving the full thickness of the excision. The floor of the ulcer was formed by a granulomatous infiltration with foci offibrinoid necrosis covered by a pyogenic membrane. 100 ml;
Fig. 5. Photomicrograph showing diffuse lymphohistiocytic infiltration with zones of necrosis. No giant cells are present. (H.E. original magnification x 80.)
Fig. 6. Photomicrograph showing cross-section of medium-sized palatal vessel presenting destructive vasculitis. H.E. original magnification x 80.)
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infarction and loss of secretory acini. Between the lobules of the glands and within haemorrhagic and oedematous tissue lay a prominent vessel, almost wholly destroyed by a pleomorphic infiltration without giant cells (Fig. 6). However, in the samples, necrosis was not marked but destructive vasculitis of a substantial vessel was prominent (Fig. 6). The appearance of granulomatous infiltration was consistent with that found in the Stewart-type of "nonhealing" or midline lethal granuloma. The renal biopsy appeared normal histologically. Treatment was started with crystalline penicillin, prednisolone, and cyclophosphamide. The patient's condition rapidly deteriorated with marked weight loss and excruciating bone pain. The ulcers of the soft palate increased in size and coalesced to form a necrotic, rapidly destructive and granulomatous lesion (Fig. 7) which spread to the pharynx. There was intermittent pyrexia until the patient's relatives removed him from the hospital, against our wish, to try native medicine. Case J Y.A., a 29-year-old Nigerian man, gave a history of sore throat, general muscle ache, fever,
Fig. j. The large confluent ulcer of the soft palate showing extensive destruction, much necrosis and granuloma formation.
Tropical Doctor, October 1977
nasal blockage, and occasionalepistaxis for I I months. Until this time, he had been well, apart from a few attacks of malaria. General examination showed an emaciated man in moderate distress. The respiratory rate was 19 per minute, the oral temperature was 38'5°C, and the blood-pressure was 112/64 mmHg. The skin was normal and the chest was clear to percussion and auscultation. The abdomen was soft; the spleen, liver, and kidneys were not enlarged. A small ulcer, discharging purulent, bloody exudate was seen on the lateral surface of the right nasal cavity (Fig. 8) and a perforating ulcer of the midline of the hard palate was noted. Haemoglobin on admission was 12'4 g/IOO ml, the white cell count was 15'8 x 103 per mm" with eosinophils 7': 0' neutrophils 88°;" and lymphocytes 12%. The erythrocyte sedimentation rate was 40 mmjhr (Westergren). Bacteriological culture of a swab taken from the nose produced Streptococcus pyogenes and Candida albicans while Neisseria catarrhalis and normal flora were present in the sputum. The following investigations were normal: urinalysis, blood, sputum and urine cultures; bone-marrow smear; Mantoux test; blood urea, electrolytes, and proteins; liver and renal functions tests; rheumatoid factor, and VDRL tests. Radiological examination showed mucosal thickening and opacity of the right maxillary antrum without a fluid level. The chest radiograph and the intravenous pyelogram were normal. A biopsy was taken from the non-necrotic part of the palatal ulcer. The specimen, which was soft and
Fig. x. Full face photograph showing the small ulcer on the lateral surface of the right nasal cavity.
Tropical Doctor, October I977
MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
granulomatous, measured 20 x 6 X 5 mm. Microscopic examination showed fibrinoid necrosis and inflammatory cell infiltration of the arterioles and venules. Giant cells were not seen but eosinophils were prominent. The histological features were consistent with the acute phase of midline lethal granuloma. The renal biopsy appeared histologically normal. Two weeks after admission, treatment was started with weekly intravenous injections of 50 mg methotrexate over a five-minute interval. Subjective relief of symptoms was noted within five days of the first injection, and within five weeks, his weight increased, the nasal and palatal lesions were healing, and the brownish nasal discharge became minimal. Six weeks after admission, the patient absconded from the ward and has never been seen since. DISCUSSION
Wegener's granulomatosis is a rare disease characterized by necrotizing granulomas of the upper and lower respiratory tract or both, followed by a late stage of disseminated necrotizing vasculitis. Godman and Churg (1954) suggested that the midline lethal granuloma and Wegener's granulomatosis could be regarded as localized and widespread forms respectively of the same underlying disease and the view was later supported by other authors (Mills 1967, Friedmann 1955, and Toma 1968). However, Walton (1959) argued against the above suggestion on the basis of clinicopathological evidence. Friedmann (1964), while retaining his earlier view (Friedmann 1955) of essential similarity of the pathological features of the two conditions, pointed out certain distinct and significant differences in the histology. It would appear, however, that such distinctive histological criteria were unpredictive of the onset of Wegener's granulomatosis as shown in a series often confirmed cases (Byrd et al. 1969). According to Patchefsky and Israel (1973), the onset of the disease is most often slow and insidious as shown in Cases I and 3 but not uncommonly an explosive onset, illustrated by Case 2, occurs. In the three cases reported in this paper, the upper respiratory tract was affected. This concurs with the views of Friedmann (1955) that the predominant sites of occurrence of the lesion were the paranasal and nasal cavities. Furthermore, Wegener's original descriptive term ofthe disease as "rhinogenic" granuloma was based on this feature (Wegener 1936). The predominance of the nasal site is supported by Mills's review of 86 cases of malignant granuloma in which 67 cases began in the nose while 19 cases arose in the paranasal sinuses (Mills 1958). The involvement of oral tissues in Wegener's granulomatosis is not un-
I 173
common: out of 56 cases reviewed by Walton, 21 had oropharyngeal lesions (Walton 1958). Other sites of presentation are the lungs, the larynx, the skin, the orbit, and the ears. Over the last two decades, the treatment of Wegener's granulomatosis has depended mainly on large doses of corticosteroids (Evans and Halley 1963) which at best prolonged the lethal illness several more months until death (Aita 1973). There were reports of successful remissions with the use of antimetabolites and alkylating agents in the generalized and limited forms of the disease (Hollander and Manning 1967; Evans and Halley 1963; Novack and Pearson 1971; Raitt 1971). However, lack of response to alkylating agents has also been reported (Greenspan 1965). Two of our three cases responded poorly to cyclophosphamide combined with prednisolone. In the third case, subjective relief of symptoms was noticed following methotrexate therapy until the patient absconded from the ward. This type of self discharge is not uncommon in the hospitals in Nigeria and other developing countries and often contributes to failures in cases requiring long-term therapy. The poor prognosis of midline lethal granuloma and Wegener's granulomatosis is generally known. According to Walton (1958), only six out of 15 cases of midline lethal granuloma survived for eight to 15 years while the remainder died. In the disseminated disease, the prognosis is worse; Walton (1958) recorded 18 deaths from 20 cases of Wegener's granulomatosis within a year of diagnosis. ACKNOWLEDGEMENT
We are grateful to the Royal College of Surgeons of England for the histological reports and photomicrographs. We are also grateful to the Ministry of Information, Kaduna State, Nigeria, and to Mr Ramoni Okeniyi for photographic and secretarial help respectively. REFERENCES
Aita, J. A. (1973). Nebraska med.J., 58 335. Barnard, P. J., et al, (1965). Gent. Afr. J. Med., 11, 125. Byrd, L. J., et al. (1969). Arthr. and Rheum., 12,247. Cooper, K., et al. (1970).J. Obstet, Gynaec. Brit. Gwlth, 77, 1028. Evans, D. W., and Halley, J. B. W. (1963).J. din. Path, 16, 215. Friedmann, 1. (1955).J. Laryng., 69, 331. Friedmann, 1. (1964). Proc. roy. Soc. Med., 57, 289. Godman, G. c., and Churg, J. (1954). Arch. Path., 58, 533. Greenspan, E. M. (1965). J. Amer. med. Ass., 193,74. Hollander, D., and Manning, R. T. (1967). Ann. intern. Med., 67, 393. Howells, G. H., and Friedmann, 1. (1950). J. din. Path., 3, 220. Klinger, H. (1931). Frankfurt. Z. Path., 42, 455. McCart, H. (1950). Ganad. med. Ass. J., 63, 357. Mills, C. P. (1958).J. Laryng., 72, 849.
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Mills, C. P. (1967). Hasp. Med., 2, 183. Novack, S. N., and Pearson, C. M. (1971). New Engl. J. Med., 284, 938. Patchefsky, A. S., and Israel, H. L. (1973). Ann. din. lab. Sci., 3, 249. Raitt, J. W. (1971). Ann. intern. Med., 74, 344. Stratton, H. J. M., et al. (1953). Brit. med.J., 1, 127. Toma, G. A. (1968). J. Laryng., 82, 129.
Tropical Doctor, October I977
Vaillant, C., et al. (1966). Bull. Soc. med. Afr. noire Langue franc., 11, 302. Walton, E. W. (1958). Brit. med.J., 2, 265. Walton, E. W. (1959). J. Laryng., 73,242. Wegener, F. (1937). Verh. dtsch. path. Ges., 29,202. Wegener, F. (1939). Beitr, Path. Anat., 102,36. Weinberg, T. (1946). Amer. J. din. Path., 16,784. Williams, H. L. (1949). Ann. Owl. (St. Louis), 58, 1013.
Book Reviews Pharmacology and Therapeutics By 1. A. T. Mtulia. (Nairobi: African Medical and Research Foundation, Nairobi, Kenya (Rural Health Series 5), I97 6, pp. 240 .) This book is designed to help medical assistants in Tanzania during their training and work, but it will also be useful to a wider range of health workers and to those in other countries. The author draws on material from senior teachers, on several well-known texts, and on his own clinical and teaching experience in East Africa. The information is presented in a logical way, system by system and according to groups of drugs. There are two main sections, the first contains details about approximately 200 of the most important and common drugs, and the second section about 100 less important medicines. There are brief notes about the action of the drugs, the conditions for which they should be used, presentations, dosages, contraindications and side effects. A useful introductory chapter contains definitions and concludes with information on the important matter of the cost of medicines. At the back of the book is a practical table about dosages for different age groups. Here the author sometimes reverts to calling drugs by their trade rather than their generic names. No two physicians would agree about the selection of all drugs and the range included in this book gives some scope for personal preferences. The inclusion of six antihistamines and six topical antibiotics seems excessive. Ethacrynic acid and spironolactone are probably unnecessary in such a booklet, and it is unfortunate that "Lomotil" is included but there is no mention of a glucose-electrolyte combination for oral rehydration in diarrhoea. The transposition of material from page 121 to page 184 could cause errors. These small points do not detract seriously from the fact that this is a very valuable and balanced book which can be recommended for primary health workers. I suspect that few medical assistants will
have such a range of medications available to them, but this informative book will help them to use W.A.M.C. whatever drugs they have effectively. Health aspects of human settlements. A review based on the Technical Discussions held during the Twenty-ninth World Health Assembly, 1976 Edited by A. E. Martin. (Geneva: World Health Organization, Public Health Papers No. 66, I977, PP·57·) Whether dealing with a remote mountain village in the tropics, a nomadic community in the desert, or rapidly expanding cities anywhere, the questions of human settlements and the health of the people living in them are interrelated. In an effort to define health within the broader context of human settlements of all types and to determine how the health sector could best contribute to improving the quality of life within these settlements, the Twenty-ninth World Health Assembly, held in Geneva in May 1976, organized technical discussions on the subject. The need to ensure that health, in its broadest sense, is accepted as an integral part of the planning and development of human settlements. This involves health policies that can encompass more than the narrowly curative approach and identifies techniques, manpower, and organizational patterns that will make the health sector a genuine partner in national policy and decisionmaking in regard to human settlements. Beyond defining the priority health needs in human settlements such as adequate state of nutrition, water supply and waste disposal services, and a system of health care available to all, the discussions provided a forum for the exchange of ideas and practical experience in dealing with the health and social problems in various countries. The material in this book provides a useful starting point for anyone concerned with human settlements.
MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
Midline lethal granuloma and Wegener's granulomatosis in Nigerians: a report of three cases E. O. Adekeye, FDSRCS, FMCDS, FWACS Consultant, Maxillo-Facial Unit, Ahmadu Bello University Hospital, Kaduna, Nigeria
c. V. Abengowe
FRCP (Glas.), FWACP,
DCH (Lond.) Senior Lecturer, Department of Medicine, ABU Hospital, Kaduna
TROPICAL DOCTOR,
1977,7,169-174
In 1931, Klinger reported two cases in which the patients had destructive sinusitis, nephritis, and uraemia; at autopsy, splenic granulomata, arteritis, and glomerular lesions were seen. However, Wegener (1936, 1939) was the first to describe in detail three patients with a condition starting as rhinitis, followed by a disseminated disease, and ending in renal failure (Wegener's granulomatosis). Later, more cases, closely resembling the above condition, were published, either as examples of the midline lethal granuloma or the unusual forms of periarteritis nodosa (Williams 1949; McCart 1950; Weinberg 1946; Stratton et al. 1953; Howells and Friedmann 1950). Godman and Churg (1954)differentiated Wegener's granulomatosis from the usual forms of periarteritis nodosa. They stated three main pathological criteria for the diagnosis of the disseminated disease: namely, necrotizing respiratory tract granulomas, generalized focal necrotizing vasculitis and necrotizing glomerulitis. Mills (1967) said that midline lethal granuloma and Wegener's granulomatosis were one and the same disease, adding, that where the disease is primarily localized to the midline ofthe palate and the nose, it is called midline lethal granuloma while the disseminated disease is termed Wegener's granulomatosis. The disease is rare in Europe .and North America, but even rarer in Africa, Between 1960 and 1977 we could find only three references to the condition in Africa (Barnard et al. 1965; Cooper et al. 1970; Vaillant et al. 1967). The purpose of this paper is to report on two cases of midline lethal granuloma and one case of Wegener's granulomatosis seen within a period of two years at
I 169
the Ahmadu Bello University Teaching Hospital, Kaduna, Nigeria. The cases illustrate certain differences in the clinical features of the condition, the problems of chemotherapy, and the generally accepted poor prognosis. Furthermore, they serve as additions to the literature of the few cases reported from Africa. CASE REPORTS
Case I - O.A., a 38-year-old Nigerian man, gave a history of stuffiness and blockage of both nostrils, intermittent purulent nasal discharge, and pain in the maxilla and nose for two months. One month after the symptoms had started, a tender and gradually enlarged swelling of the nose appeared. On examination, he was a tall, fit-looking man with a grossly swollen nose (Fig. I). An ulcerative, necrotic, and granulomatous lesion, covered with crusty exudate, was seen on the nasal septum and the right lateral nasal wall. Gentle removal of the crust
Fig. I. Fullface photograph showing grossly swollen nose.
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showed an underlying necrotic bone; the right submandibular lymph node was enlarged. The general examination was normal: the chest was clear to percussion and auscultation, the abdomen was soft, and the liver and spleen were not enlarged. Radiographic examination showed mucosal thickening and opacity of the right maxillary antrum with a fluid level. The chest radiograph and the intravenous pyelogram were normal. Bacteriological cultures of swabs taken from the palatal and nasal lesions produced normal commensals. The following investigations were normal: haemoglobin, WBC and differential, blood proteins, alkaline phosphatase, creatinine, electrolytes, urea, urinalysis, VDRL, and Mantoux. The erythrocyte sedimentation rate was 37 mrn/hr (Westergren). As the disease progressed, it destroyed the hard palate which became perforated (Fig. 2). Under general anaesthesia, the right nasal cavity was inspected and it was found to contain much friable, granular tissue. A biopsy was taken from the nonnecrotic portion of the palatal ulcer. The specimen, which measured 14 x 5 x 4 mm, consisted of granulomatous soft tissue with the surface covered partly by epithelium but the major part was ulcerated. Microscopically, the sections showed extensive ulceration and submucosal fibrinoid necrosis associated with a pleomorphic lymphocytic and histiocytic granulomatous infiltrate which overran minor salivary glands (Fig. 3). There were numerous mitotic figures in the infiltrate and cytological atypia was extreme in places. Giant cells were not seen but eosinophils were prominent. There was no distinct evidence of
Fig. 2. The large perforating palatal ulcer. Note the extensive destruction and much necrosis of palatal tissues.
Tropical Doctor, October 1977
Fig. 3. Photomicrograph showing destruction and focal necrosis of palatal mucous glands overrun by a pleomorphic, lympho-histiocytic infiltrate. (HE original magnification x 128.)
destructive vasculitis in the substantial vessels but some vessels had thickened walls. Others showed necrosis without inflammatory infiltration and some were engorged and thrombosed. On balance, these histological features were consistent with those of the midline lethal granuloma. The renal biopsy was normal histologically. Treatment was started with prednisolone, cyclophosphamide and procaine penicillin. About two weeks after the commencement of treatment, the patient's condition slowly deteriorated; there was weight loss, the nose continued to increase in size and the palatal perforation enlarged gradually. About two months after admission, the patient voluntarily discharged himself from the hospital and has never been seen since. Case 2 - F.]., a ze-year-old Nigerian man, gave a history of pain in the right ear and headache for five years. He also complained of a recent epistaxis, a dry cough, fever, and sore throat. On examination, he was a pale, moderately ill man with a temperature of 39°C, a regular pulse of 120 per minute, and a respiratory rate of 20 per minute. The liver was enlarged by about 5 cm below the costal margin but it was soft and non-tender. The lungs were clear to percussion and auscultation. Two punched-out ulcers, measuring about 10 mm and 15 mm in diameter respectively, were seen on the soft palate. The surfaces of the ulcers were irregular and had a friable necrotic appearance. Radiographic examination showed multiple rounded densities in both lungs (Fig. 4) but the radiograph of the paranasal sinuses and the intravenous pyelogram were normal.
Tropical Doctor, October J()77
MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
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The infiltrate consisted of pleomorphic lymphocytic and histiocytic cells with some atypical features including a number of mitotic figures (Fig. 5). The profile of a small vessel appeared in the ulcer bed the walls of which were overrun by inflammatory cells. Giant cells were not present in the sections and eosinophilic leucocytes were not prominent within the granuloma. However, the oedematous, fibroblastic subepithelial connective tissue at the margin of the ulcer was studded with eosinophils and neutrophils. The tissue enclosed dilated lymphatics, numerous capillaries, and endothelial sprouts. The small vessels were cuffed by lymphocytes. The granulomatous infiltration had spread to involve adjacent mucous glands which showed lobular
Fig. 4. Chest radiograph showing multiple rounded densities in both lungs.
Blood examination showed a haemoglobin of 13' 4 g/ the total WBe count was 5,600 per mrn" with a normal differential, and the platelet count was 214 x 103 per mm", The following investigations were normal: renal and liver function tests, serum electrolytes, blood urea and the serum proteins. Bacteriological cultures of swabs taken from the soft palate and the sputum produced normal commensals; the blood culture was unremarkable. The Mantoux and the VDRL tests were negative. The erythrocyte sedimentation rate was 56 mm/hr (Westergren). A biopsy of the non-necrotic part of the lesion in the soft palate was taken under local anaesthesia. The lesion was soft and it measured 13 X 10 X 6 mm. The epithelial surface was rough and lobulated and it showed an area of ulceration. Microscopically, sections showed the margin of part of the floor of an extensive ulcer associated with inflammatory changes in the submucosa involving the full thickness of the excision. The floor of the ulcer was formed by a granulomatous infiltration with foci offibrinoid necrosis covered by a pyogenic membrane. 100 ml;
Fig. 5. Photomicrograph showing diffuse lymphohistiocytic infiltration with zones of necrosis. No giant cells are present. (H.E. original magnification x 80.)
Fig. 6. Photomicrograph showing cross-section of medium-sized palatal vessel presenting destructive vasculitis. H.E. original magnification x 80.)
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infarction and loss of secretory acini. Between the lobules of the glands and within haemorrhagic and oedematous tissue lay a prominent vessel, almost wholly destroyed by a pleomorphic infiltration without giant cells (Fig. 6). However, in the samples, necrosis was not marked but destructive vasculitis of a substantial vessel was prominent (Fig. 6). The appearance of granulomatous infiltration was consistent with that found in the Stewart-type of "nonhealing" or midline lethal granuloma. The renal biopsy appeared normal histologically. Treatment was started with crystalline penicillin, prednisolone, and cyclophosphamide. The patient's condition rapidly deteriorated with marked weight loss and excruciating bone pain. The ulcers of the soft palate increased in size and coalesced to form a necrotic, rapidly destructive and granulomatous lesion (Fig. 7) which spread to the pharynx. There was intermittent pyrexia until the patient's relatives removed him from the hospital, against our wish, to try native medicine. Case J Y.A., a 29-year-old Nigerian man, gave a history of sore throat, general muscle ache, fever,
Fig. j. The large confluent ulcer of the soft palate showing extensive destruction, much necrosis and granuloma formation.
Tropical Doctor, October 1977
nasal blockage, and occasionalepistaxis for I I months. Until this time, he had been well, apart from a few attacks of malaria. General examination showed an emaciated man in moderate distress. The respiratory rate was 19 per minute, the oral temperature was 38'5°C, and the blood-pressure was 112/64 mmHg. The skin was normal and the chest was clear to percussion and auscultation. The abdomen was soft; the spleen, liver, and kidneys were not enlarged. A small ulcer, discharging purulent, bloody exudate was seen on the lateral surface of the right nasal cavity (Fig. 8) and a perforating ulcer of the midline of the hard palate was noted. Haemoglobin on admission was 12'4 g/IOO ml, the white cell count was 15'8 x 103 per mm" with eosinophils 7': 0' neutrophils 88°;" and lymphocytes 12%. The erythrocyte sedimentation rate was 40 mmjhr (Westergren). Bacteriological culture of a swab taken from the nose produced Streptococcus pyogenes and Candida albicans while Neisseria catarrhalis and normal flora were present in the sputum. The following investigations were normal: urinalysis, blood, sputum and urine cultures; bone-marrow smear; Mantoux test; blood urea, electrolytes, and proteins; liver and renal functions tests; rheumatoid factor, and VDRL tests. Radiological examination showed mucosal thickening and opacity of the right maxillary antrum without a fluid level. The chest radiograph and the intravenous pyelogram were normal. A biopsy was taken from the non-necrotic part of the palatal ulcer. The specimen, which was soft and
Fig. x. Full face photograph showing the small ulcer on the lateral surface of the right nasal cavity.
Tropical Doctor, October I977
MIDLINE LETHAL GRANULOMA AND WEGENER'S GRANULOMATOSIS
granulomatous, measured 20 x 6 X 5 mm. Microscopic examination showed fibrinoid necrosis and inflammatory cell infiltration of the arterioles and venules. Giant cells were not seen but eosinophils were prominent. The histological features were consistent with the acute phase of midline lethal granuloma. The renal biopsy appeared histologically normal. Two weeks after admission, treatment was started with weekly intravenous injections of 50 mg methotrexate over a five-minute interval. Subjective relief of symptoms was noted within five days of the first injection, and within five weeks, his weight increased, the nasal and palatal lesions were healing, and the brownish nasal discharge became minimal. Six weeks after admission, the patient absconded from the ward and has never been seen since. DISCUSSION
Wegener's granulomatosis is a rare disease characterized by necrotizing granulomas of the upper and lower respiratory tract or both, followed by a late stage of disseminated necrotizing vasculitis. Godman and Churg (1954) suggested that the midline lethal granuloma and Wegener's granulomatosis could be regarded as localized and widespread forms respectively of the same underlying disease and the view was later supported by other authors (Mills 1967, Friedmann 1955, and Toma 1968). However, Walton (1959) argued against the above suggestion on the basis of clinicopathological evidence. Friedmann (1964), while retaining his earlier view (Friedmann 1955) of essential similarity of the pathological features of the two conditions, pointed out certain distinct and significant differences in the histology. It would appear, however, that such distinctive histological criteria were unpredictive of the onset of Wegener's granulomatosis as shown in a series often confirmed cases (Byrd et al. 1969). According to Patchefsky and Israel (1973), the onset of the disease is most often slow and insidious as shown in Cases I and 3 but not uncommonly an explosive onset, illustrated by Case 2, occurs. In the three cases reported in this paper, the upper respiratory tract was affected. This concurs with the views of Friedmann (1955) that the predominant sites of occurrence of the lesion were the paranasal and nasal cavities. Furthermore, Wegener's original descriptive term ofthe disease as "rhinogenic" granuloma was based on this feature (Wegener 1936). The predominance of the nasal site is supported by Mills's review of 86 cases of malignant granuloma in which 67 cases began in the nose while 19 cases arose in the paranasal sinuses (Mills 1958). The involvement of oral tissues in Wegener's granulomatosis is not un-
I 173
common: out of 56 cases reviewed by Walton, 21 had oropharyngeal lesions (Walton 1958). Other sites of presentation are the lungs, the larynx, the skin, the orbit, and the ears. Over the last two decades, the treatment of Wegener's granulomatosis has depended mainly on large doses of corticosteroids (Evans and Halley 1963) which at best prolonged the lethal illness several more months until death (Aita 1973). There were reports of successful remissions with the use of antimetabolites and alkylating agents in the generalized and limited forms of the disease (Hollander and Manning 1967; Evans and Halley 1963; Novack and Pearson 1971; Raitt 1971). However, lack of response to alkylating agents has also been reported (Greenspan 1965). Two of our three cases responded poorly to cyclophosphamide combined with prednisolone. In the third case, subjective relief of symptoms was noticed following methotrexate therapy until the patient absconded from the ward. This type of self discharge is not uncommon in the hospitals in Nigeria and other developing countries and often contributes to failures in cases requiring long-term therapy. The poor prognosis of midline lethal granuloma and Wegener's granulomatosis is generally known. According to Walton (1958), only six out of 15 cases of midline lethal granuloma survived for eight to 15 years while the remainder died. In the disseminated disease, the prognosis is worse; Walton (1958) recorded 18 deaths from 20 cases of Wegener's granulomatosis within a year of diagnosis. ACKNOWLEDGEMENT
We are grateful to the Royal College of Surgeons of England for the histological reports and photomicrographs. We are also grateful to the Ministry of Information, Kaduna State, Nigeria, and to Mr Ramoni Okeniyi for photographic and secretarial help respectively. REFERENCES
Aita, J. A. (1973). Nebraska med.J., 58 335. Barnard, P. J., et al, (1965). Gent. Afr. J. Med., 11, 125. Byrd, L. J., et al. (1969). Arthr. and Rheum., 12,247. Cooper, K., et al. (1970).J. Obstet, Gynaec. Brit. Gwlth, 77, 1028. Evans, D. W., and Halley, J. B. W. (1963).J. din. Path, 16, 215. Friedmann, 1. (1955).J. Laryng., 69, 331. Friedmann, 1. (1964). Proc. roy. Soc. Med., 57, 289. Godman, G. c., and Churg, J. (1954). Arch. Path., 58, 533. Greenspan, E. M. (1965). J. Amer. med. Ass., 193,74. Hollander, D., and Manning, R. T. (1967). Ann. intern. Med., 67, 393. Howells, G. H., and Friedmann, 1. (1950). J. din. Path., 3, 220. Klinger, H. (1931). Frankfurt. Z. Path., 42, 455. McCart, H. (1950). Ganad. med. Ass. J., 63, 357. Mills, C. P. (1958).J. Laryng., 72, 849.
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Mills, C. P. (1967). Hasp. Med., 2, 183. Novack, S. N., and Pearson, C. M. (1971). New Engl. J. Med., 284, 938. Patchefsky, A. S., and Israel, H. L. (1973). Ann. din. lab. Sci., 3, 249. Raitt, J. W. (1971). Ann. intern. Med., 74, 344. Stratton, H. J. M., et al. (1953). Brit. med.J., 1, 127. Toma, G. A. (1968). J. Laryng., 82, 129.
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Vaillant, C., et al. (1966). Bull. Soc. med. Afr. noire Langue franc., 11, 302. Walton, E. W. (1958). Brit. med.J., 2, 265. Walton, E. W. (1959). J. Laryng., 73,242. Wegener, F. (1937). Verh. dtsch. path. Ges., 29,202. Wegener, F. (1939). Beitr, Path. Anat., 102,36. Weinberg, T. (1946). Amer. J. din. Path., 16,784. Williams, H. L. (1949). Ann. Owl. (St. Louis), 58, 1013.
Book Reviews Pharmacology and Therapeutics By 1. A. T. Mtulia. (Nairobi: African Medical and Research Foundation, Nairobi, Kenya (Rural Health Series 5), I97 6, pp. 240 .) This book is designed to help medical assistants in Tanzania during their training and work, but it will also be useful to a wider range of health workers and to those in other countries. The author draws on material from senior teachers, on several well-known texts, and on his own clinical and teaching experience in East Africa. The information is presented in a logical way, system by system and according to groups of drugs. There are two main sections, the first contains details about approximately 200 of the most important and common drugs, and the second section about 100 less important medicines. There are brief notes about the action of the drugs, the conditions for which they should be used, presentations, dosages, contraindications and side effects. A useful introductory chapter contains definitions and concludes with information on the important matter of the cost of medicines. At the back of the book is a practical table about dosages for different age groups. Here the author sometimes reverts to calling drugs by their trade rather than their generic names. No two physicians would agree about the selection of all drugs and the range included in this book gives some scope for personal preferences. The inclusion of six antihistamines and six topical antibiotics seems excessive. Ethacrynic acid and spironolactone are probably unnecessary in such a booklet, and it is unfortunate that "Lomotil" is included but there is no mention of a glucose-electrolyte combination for oral rehydration in diarrhoea. The transposition of material from page 121 to page 184 could cause errors. These small points do not detract seriously from the fact that this is a very valuable and balanced book which can be recommended for primary health workers. I suspect that few medical assistants will
have such a range of medications available to them, but this informative book will help them to use W.A.M.C. whatever drugs they have effectively. Health aspects of human settlements. A review based on the Technical Discussions held during the Twenty-ninth World Health Assembly, 1976 Edited by A. E. Martin. (Geneva: World Health Organization, Public Health Papers No. 66, I977, PP·57·) Whether dealing with a remote mountain village in the tropics, a nomadic community in the desert, or rapidly expanding cities anywhere, the questions of human settlements and the health of the people living in them are interrelated. In an effort to define health within the broader context of human settlements of all types and to determine how the health sector could best contribute to improving the quality of life within these settlements, the Twenty-ninth World Health Assembly, held in Geneva in May 1976, organized technical discussions on the subject. The need to ensure that health, in its broadest sense, is accepted as an integral part of the planning and development of human settlements. This involves health policies that can encompass more than the narrowly curative approach and identifies techniques, manpower, and organizational patterns that will make the health sector a genuine partner in national policy and decisionmaking in regard to human settlements. Beyond defining the priority health needs in human settlements such as adequate state of nutrition, water supply and waste disposal services, and a system of health care available to all, the discussions provided a forum for the exchange of ideas and practical experience in dealing with the health and social problems in various countries. The material in this book provides a useful starting point for anyone concerned with human settlements.
