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Postgrad Med J: first published as 10.1136/pgmj.43.500.428 on 1 June 1967. Downloaded from

428 Case reports

Pleural extramedullary in myelosclerosis

H. C. ANTON J. B. P. FERGUSON M.B., Ch.B., D.M.R.D., F.F.R. M.B., Ch.B. G. P. LEWIS M.D., B.Sc., M.R.C.P.(Ed.) Stobhill General Hospital, Glasgow

DESPITE the extensive literature on myelosclerosis myelofibrosis group, because it cannot be differen- and extramedullary haematopoiesis (myeloid meta- tiated pathologically once fibrosis has developed in plasia), reference to the pleura as being the site of the marrow. The case to be described belongs extramedullary haematopoiesis is not made in to the idiopathic myelofibrosis category. either the standard medical and pathology text- Extramedullary haematopoiesis accompanies books or in the radiological literature. We have many types of disease including recently encountered a case of myelosclerosis in idiopathic myelofibrosis, carcinomatosis, lym- which aspiration of what appeared on both clinical phoma, leukaemia, marble bone disease, erythro- and radiological grounds to be a pleural effusion blastosis, haemolytic anaemia, pernicious anaemia, copyright. failed to reveal the presence of fluid. Subsequent thalassaemia, Gaucher's disease, osteitis deformans, pleural biopsy carried out at the same site showed osteomalacia, osteitis fibrosa cystica, tuberculosis , at first regarded as tumour, but later shown and exposure to toxic agents such as benzene, to be a manifestation of extramedullary haema- fluorine and irradiation. In a recent report, sickle- topoiesis. Because such a lesion when it occurs at cell anaemia was found to be associated with this particular site is liable to be misinterpreted, we extramedullary haematopoiesis (Seidler & Becker, feel that a description of this case is justified. 1964). Rarely, extramedullary haematopoietic Myelosclerosis may be regarded as a form of tissue may occur in patients not suffering from http://pmj.bmj.com/ myelofibrosis with thickening of the bony diseases of the or bone marrow. Dodge & trabeculae of the marrow on histological exam- Evans (1956) describe a presacral retroperitoneal ination. The diagnosis of myelofibrosis is made fatty tumour with haematopoietic foci, for which when the presence of fibrosis on bone marrow they suggest as a suitable descriptive biopsy is associated with a leuco-erythroblastic term. It should be pointed out that extramedullary anaemia. A mild increase in bone trabeculation haematopoiesis does not necessarily occur in cause an osteosclerosis on Clatanoff & may visible X-ray myelofibrosis: Korst, Schilling (1956) on September 30, 2021 by guest. Protected examination. found it in only eleven of their twenty-three cases. Myelofibrosis may be a complicating feature of many diseases including lymphoma, metastatic Case report carcinoma, leukaemia and aplastic anaemia, under The patient, a female aged 65, was admitted to which conditions it is termed secondary myelo- hospital with a 6-month history of loss of weight fibrosis (Pitcock et al., 1962). They emphasize that and appetite, weakness and severe diarrhoea. A in secondary myelofibrosis, evidence of the under- radium menopause had been carried out 20 years lying disorder may be found on examination of previously for menorrhagia. bone-marrow sections as well as the presence of On examination there was pigmentation of ex- fibrous tissue. Furthermore, in such cases, the posed areas of skin, pallor of mucous membranes blood picture may be distinctive. Myelofibrosis and marked oedema of the legs and anterior without an associated haematological, reticulo- abdominal wall, but no ascites. The was endothelial or neoplastic disorder is classed as palpable and firm and the grossly enlarged being idiopathic. The above authors, however, and tender with some nodularity. There were consider that myelofibrosis following poly- clinical signs of a left pleural effusion. This was cythaemia vera should be included in the idiopathic confirmed by a chest X-ray which also showed a Postgrad Med J: first published as 10.1136/pgmj.43.500.428 on 1 June 1967. Downloaded from

Case reports 429 marked sclerosis of bone (Fig. 1). Subsequently the pleural reaction developed. Although the first im- left pleural reaction diminished on X-ray follow- pression of one of us was that the bone sclerosis up, but did not disappear, and later a right-sided was probably due to osteoplastic metastases, films of the spine and were later reported as show- ing myelosclerosis. A pleural tap of the left base attempted 1 week after admission failed to i:·:·: reveal the presence of fluid. Because of this, pleural ··i··::..·:··:··:·: iiiiii::i'::'·:"::;:ibi.lig.i.sllll' .S.I.F.L Icllliliiiii::i:i biopsy was carried out. iii::::: The pathology report described a cellular li".iti:··: 'tumour' with giant cells, small cells with dark '''';:': I":i·I' nuclei, and a few and '::'::::' (Fig. 2). Subsequently a retrospective diagnosis of .e.slslg.a.::. .:::: myeloid metaplasia was made. As it seemed likely that the 'tumour' was secondary, numerous in- : .,.· were I:%::.81B._- vestigations carried out to locate a primary ···i:;i:ii·:··i·ii:.·:· ::· source, including IVP and barium but no ·:· :·· studies, ··· ·'· evidence of a primary focus was found. A sternal :r·:·· .:::;·:: puncture was reported as follows: 'Sections show dense bone, no marrow, a few fat and ··· spaces young fibrous tissue replacement. This is highly ·.?·:i; of ·'· ·::·::··:·:··:··::r::" suggestive myelofibrosis.' This diagnosis was ..: :. ::::i::ii::i;:iiiii8li:· confirmed by a trephine of :'··:· ··:· ·· ·· :· ·. :.:::'.:l.:::i:: ··.· :i: biopsy (Fig. 3). P::·::·:::··:···: '' ': :' ··i:··:I':'· :· ·· '·' ·'-':"- ·····i··I:lii·iil,i·:i: ·ii :: ::: 'ii:iiBCiii;di·.i; Throughout most of her illness the haemoglobin :::'''' ranged from 8-2 to 9-5 g/100 ml but terminally FIG. 1. Moderate pleural reaction at left lower zone. fell to 7-5 g/100 ml. The PCV averaged 29% and

Patchy osteosclerosis. the MCHC varied from 29% to 33%. Reticulo- copyright. cytes, at first 2%, reached 5% in the late stages of

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FIG. 3. Sternal marrow. Normal marrow FIG. 2...*Original pleural biopsy. High Marked replaced by ~~~~ power. loose young fibrous tissue with capillary spaces con- anisocytosis and poikilocytosis of cells with hyper- taining primitive red cells. Increased trabeculation of chromatic nuclei also varying in size and shape. bone gives a mosaic appearance. Postgrad Med J: first published as 10.1136/pgmj.43.500.428 on 1 June 1967. Downloaded from

430 Case reports

her illness. White cell counts ranged from 8400 to with difficulty and revealed a slightly granular sur- 15,800/mm3. The white cells showed immature face. On section there was 'pouting' of vessels and forms, mostly but with a few blast narrowing of the cortices. There was pale marrow cells. Terminally the proportion of primitive cells in the vertebrae but the sternal marrow was rose considerably. Films showed the red cells to be replaced by fibrous tissue. Other systems showed well haemoglobinated but there was moderate no abnormality. anisocytosis and poikilocytosis. Nucleated red cells Histologically, the marrow was replaced by loose were present. were increased up to fibrous tissue permeated by capillaries with small 820,000/mm3 and were unusually varied in size foci of and some bizarre mega- and shape, some being described as massive. karyocytes, i.e. the typical findings of myelofibrosis. Other haematological tests showing abnormality There was also an increased trabeculation of bone. included a serum vitamin B12 level of 25 pg/ml The spleen showed extramedullary haemato- and a serum iron of 6 tug/100 ml (TIBC 300 poiesis in the red pulp, fibrosis, bizarre giant cells g/g/100 ml). probably , a moderate degree of During the course of her illness, the patient ex- haemorrhage and slight subcapsular iron deposi- hibited proteinuria of moderate degree. On the tion. Liver sections showed that the nodules were first admission the serum urea was 55 mg/100 ml formed of young fibrous tissue with small foci of but with deterioration in her condition gradually primitive haematopoiesis and megakaryocytes. The rose so that terminally it was 156. There was mild normal liver architecture was not destroyed outside hyperchloraemia and hyperkalaemia. The total the nodules but groups of granulopoietic and serum proteins showed a persistent moderate re- erythropoietic cells were identified in and around duction; the albumin-globulin ratio was normal. dilated sinusoids. Similar histological appearances Liver function tests were at all times normal apart to that of the liver nodules were present in the from a raised alkaline phosphatase (35 KA lymph nodes and in the pleural nodules. The U/100 ml). kidneys showed features of chronic pyelonephritis,

Oedema and anaemia persisted in spite of diffuse membranous glomerulo-nephritis and copyright. therapy with diuretics, vitamin B12, blood trans- moderate arterio and arteriolar sclerosis. Foci of fusion and oral and parenteral iron. In the summer myeloid metaplasia were present in the interstitial of 1965 her poor general state was complicated by tissue. the development of haematemesis. At the time of her final admission in August 1965, ascites was Discussion manifest. She subsequently underwent gradual deterioration and died 18 months after her first The clinical presentation and course of this patient's illness is consistent with the diagnosis of admission. http://pmj.bmj.com/ myelosclerosis with associated extramedullary haematopoiesis. The occurrence of intractable and Necropsy persistent oedema is difficult to explain on the There was clear amber fluid in both pleural basis of hypoalbuminaemia alone. The subsequent cavities. Over the visceral pleural surfaces of both demonstration at post-mortem of chronic pyelo- lower lobes and in the case of the right, especially nephritis with diffuse membranous glomerulo- the diaphragmatic surface, there were discrete flat nephritis helps to clarify this puzzling feature. It is

white nodules with serrated edges, measuring from of interest that renal disease of slight to moderate on September 30, 2021 by guest. Protected 1 to 2 cm in diameter. In places they had become degree, not characterized by calculi formation, was confluent forming large plaques. The were found in five of eight autopsies described by oedematous and congested and the showed Pitcock et al. (1962). The bone sclerosis observed slight brown atrophy. in this case could not, however, have resulted from Marked peritoneal adhesions and slight ascites renal disease because of the absence of both un- were present. The spleen (1070 g) was greatly en- calcified osteoid seams and osteoclastic erosions, larged and cut section revealed a diffusely pale features normally found in uraemic osteodystrophy infiltrated surface. The liver (2450 g) was also (Follis & Jackson, 1943; Craven, 1964). Further- greatly enlarged and on section there were large more X-ray of the lumbar vertebrae failed to nodules of white 'tumour' tissue surrounding the reveal the 'Rugger Jersey' sign of renal osteodys- porta hepatis. In the right lobe there were discrete trophy (band-like increases in the density of the white nodules surrounding the portal tracts, upper and lower parts of the vertebral bodies) des- measuring from 1 to 5 cm in diameter. Enlarged cribed by Dent (1955). glands were present along the line of the portal When first seen at the outpatient department the but there were no enlarged glands elsewhere. marked degree of cachexia exhibited by the patient The kidneys were small, the capsules were removed led to a presumptive diagnosis of neoplastic Postgrad Med J: first published as 10.1136/pgmj.43.500.428 on 1 June 1967. Downloaded from

Case reports 431 disease. This erroneous impression was later demonstrated by chest X-ray, thoracotomy was apparently confirmed by the demonstration of considered mandatory to exclude neoplastic 'neoplastic tissue' in the specimen obtained by disease (Hanford, Schneider & MacCarthy, 1960). pleural biopsy. During the post-mortem examina- Two further cases associated with congenital tion the identification of enlarged glands in the haemolytic anaemia have been described in the region of the porta hepatis and obvious intra- paper by Lowman et al. (1963). Malamos, Papa- hepatic nodules seemed again to support this vasiliou & Avramis (1962) describe a case of diagnosis. That myelofibrosis can mimic carcino- Cooley's anaemia showing on chest X-ray charac- matous metastases of osteoblastic type has been teristic thickening but with, in addition, pointed out by Wyatt & Sommers (1950). These tumour-like masses in the paravertebral gutters. authors emphasize that the metastatic lesions can Aspiration biopsy of these masses confirmed that be distinguished by the presence of tumour masses they were due to extramedullary haematopoiesis. in the liver and elsewhere. It therefore came as a Little mention has been made in the literature surprise when detailed histological studies showed to the pleura as being the site of extramedullary the tumour-like deposits affecting the glands of the haematopoietic deposits. Brannan (1927) merely porta hepatis and the liver to be solely foci of states that myeloid activity may occur at this site haematopoietic tissue with an unusual degree of but gives no further details. Knoblich (1960), using fibrotic reaction. Brannan (1927) as his authority, includes the pleura The radiological signs in this case correspond to in his comprehensive list of possible sites for extra- the description of twenty-five cases of myelo- medullary haematopoiesis. Pitcock et al. (1962) fibrosis by Leigh et al. (1959). They emphasize the describing their autopsy series found diffuse central distribution of the osteosclerosis with spar- thickening of the pleura and peritoneum in many. ing of the peripheral and state that while They make the interesting observation that extra- the bone density is often diffusely increased, in medullary haematopoietic foci may present as more severe cases discrete sclerotic foci are present. tumours, which have many of the characteristics

As well as osteosclerosis they list splenomegaly and of intramedullary bone marrow tissue in that they copyright. hepatomegaly as other radiological signs, but do contain, together with haematopoietic tissue, vari- not describe lesions in other sites due to extra- able amounts of fibrous tissue. medullary haematopoiesis. That unusual sites of More recently Lieberman, Rosvoll & Ley (1965) extramedullary haematopoiesis may be mistaken describe the clinical and autopsy findings in three for other pathological entities has been reported cases showing extramedullary myeloid tumours by many. Close, Taira & Cleveland (1958) describe out of twelve cases of myelofibrosis and myelo- a case of compression demonstrated on sclerosis with myeloid metaplasia. In one case myelography later shown to be due to extradural tumour nodules of on the pleural http://pmj.bmj.com/ myeloid metaplasia associated with myelosclerosis. surfaces, up to 1-5 cm in size, were found at post- Similar cases have been reported by Lowman, mortem, with much larger nodules in the liver and Bloor & Newcomb (1963) and Appleby et al. spleen. In their third case a scalp tumour of (1964). myeloid tissue (at first interpreted as a reticulum Intrathoracic extramedullary haematopoiesis cell ), was removed during life and later showing on chest X-ray as fairly large, well- a 7-5 cm tumour mass in the wall of the small lobulated masses intestine was excised. defined, located posteriorly in on September 30, 2021 by guest. Protected the paravertebral gutters can present a difficult It is clear that pleural involvement has been diagnostic problem. Such a picture may occur in previously noted at autopsy but we think that this seminoma metastases and reticulosis (Shanks & case is the first in which it produced a diagnostic Kerley, 1962) but a suspicion of such lesions being problem for the clinician, radiologist and path- due to tumour-simulating extramedullary haema- ologist during the life of the patient. topoiesis may be raised by the blood findings, or by radiological evidence of bone marrow disease. Summary Early reports of intrathoracic tumour-simulating An account is given of a case of myelosclerosis extramedullary haematopoiesis were based on with extramedullary haematopoiesis, involving the autopsy findings. The first diagnosis on clinico- surfaces. in a pleural Previous reports of this phenom- radiological grounds, patient with acholuric enon are quoted. Other presentations of extra- jaundice, was presented by Ask-Upmark (1945). medullary are discussed. Another case was described by Knoblich (1960) in haematopoiesis briefly which an initial diagnosis of intrathoracic neuro- fibromata was made. In two cases of congenital Acknowledgment haemolytic anaemia with paravertebral masses We wish to thank Mr!P. S. Waldie for the illustrations. Postgrad Med J: first published as 10.1136/pgmj.43.500.428 on 1 June 1967. Downloaded from

432 Case reports References KORST, D.R., CLATANOFF, D.V. & SCHILLING, R.F. (1956) APPLEBY, A., BATSON, G.A., LASSMAN, L.P. & SIMPSON, On myelofibrosis. Arch. intern. Med. 97, 169. C.A. (1964) Spinal cord compression by extramedullary LEIBERMAN, P.H., ROSVOLL, R.V. & LEY, A.B. (1965) Extra- haematopoiesis in myelosclerosis. J. Neurol. Neurosurg. medullary myeloid tumors in . Psychiat. 27, 313. Cancer, 18, 727. ASK-UPMARK, E. (1945) Tumour-simulating intra-thoracic LEIGH, T.F., CORLEY, C.C., Jr, HUGULEY, C.M. & ROGERS, heterotopia of bone marrow, Acta radiol. (Stockh.), 26, J.V., Jr (1959) Myelofibrosis. The general and radiologic 425. in 25 cases. Amer. J. 82, 183. BRANNAN, D. (1927) Extramedullary hematopoiesis in findings proved Roentgenol. anaemias. Bull. Johns Hopk. Hosp. 41 104. LOWMAN, R.M., BLOOR, C.M. & NEWCOMB, A.W. (1963) CLOSE, A.S., TAIRA, Y. & CLEVELAND, D.A. (1958) Spinal Thoracic extramedullary hematopoiesis. Dis. Chest. 44, cord compression due to extramedullary hematopoiesis. 154. Ann. intern. Med. 48, 421. MALAMOS, B., PAPAVASILIOU, C. & AVRAMIS, A. (1962) CRAVEN, J.D. (1964) Renal glomerular osteodystrophy. Tumor-simulating intrathoracic extramedullary hemo- Clin. Radiol. 15, 210. poiesis. Report of a case. Acta radiol. (Stockh.), 57, 227. DENT, C.E. (1955) Clinical section. Proc. roy. Soc. Med. 48, 530. PITCOCK, J.A., REINHARD, E.H., JUSTUS, B.W. & MENDEL- DODGE, O.G. & EVANS, D. (1956) Haemopoiesis in a pre- SOHN, R.S. (1962) A clinical and pathological study of 70 sacral tumor (myelolipoma). J. Path. Bact. 72, 313. cases of myelofibrosis. Ann. intern. Med. 57, 73. FOLLIS, R.H. & JACKSON, D.A. (1943) Renal osteomalacia SEIDLER, R.C. & BECKER, J.A. (1964) Intrathoracic extra- and osteitis fibrosa in adults. Bull. Johns Hopk. Hosp. 72, medullary hematopoiesis. Radiology, 83, 1057. 232. HANFORD, R.B., SCHNEIDER, G.F. & MACCARTHY, J.D. SHANKS, S.C. & KERLEY, P. (1962) A Text-book of X-ray (1960) Massive thoracic extramedullary hemopoiesis. Diagnosis by British Authors, vol. 2, 3rd edn, p. 895. New Engl. J. Med. 263, 120. Lewis, London. KNOBLICH, R. (1960) Extramedullary hematopoiesis pre- WYATT, J.P. & SOMMERS, S.C. (1950) Chronic marrow failure, senting as intrathoracic tumours. Report of a case in a myelosclerosis and extramedullary hematopoiesis. Blood, patient with thalassemia minor. Cancer, 13, 462. 5, 329. copyright. Neurofibromatosis with pancreatic duct obstruction and steatorrhoea

K. G. WORMSLEY W. F. W. E. LOGAN M.D., M.R.C.P. M.B., M.R.C.P. V. F. SORRELL G. C. COLE http://pmj.bmj.com/ M.B.(N.Z.), F.R.C.S. M.B., Ch.B. Manchester Royal Infirmary

INVOLVEMENT of the tract is a well confirmed the of severe alimentary Investigation presence on September 30, 2021 by guest. Protected recognized and documented manifestation of steatorrhoea (Table 1). Jejunal biopsy was normal neurofibromatosis, but there appears to be no but duodenal intubation with pancreatic stimula- record of steatorrhoea complicating this disorder. tion (Burton et al., 1960) showed no appreciable We have encountered two patients in whom pancreatic secretion although the biliary fraction steatorrhoea was due to obstruction of the pan- was normal. Radiological studies of the alimentary creatic duct by neoplastic processes attributable tract and gall bladder were normal. The anaemia to this disease. (Hb 9-6 g/100 ml) was due to thalassemia minor (/, chain type, Hb A2 4-1%, Hb F 1-5%). Case 1 Laparotomy revealed a nodule (7 mm diameter) F.S., male, aged 40, was admitted to hospital on the medial wall of the second part of the for investigation of severe diarrhoea of 1 years duodenum at the orifice of the pancreatic duct, duration associated with considerable weight loss. which was obstructed 1 cm from its entry into the The faeces were typically fatty. duodenum. The was small and atrophic. Examination revealed a cachectic anaemic man The bile duct opened into the duodenum 2 cm with oedema of the feet and the typical cutaneous proximally to the pancreatic duct. The obstructing stigmata of neurofibromatosis. nodule was excised. Histological examination