Annals ofthe Rheumatic Diseases, 1983, 42, 196-200

Case report

Arthritis due to synovial involvement byextramedullary haematopoiesis in myelofibrosis withmyeloid metaplasiaMARK H. HEINICKE, MOHAMMAD H. ZARRABI, ANDPETER D. GOREVIC

From the Division ofRheumatology and Haematology, State University ofNew York at Stony Brook, andVeterans Administration Medical Center, Northport, New York

SUMMARY A 60-year-old man presented with polyarthralgias, a psoriasiform rash, and severeelbow pain. Peripheral blood smear and bone marrow biopsy established a diagnosis of myelo-fibrosis with myeloid metaplasia. Biopsy of the skin lesions revealed a nonspecific dematitis. Theclinical presentation was inconsistent with psoriatic arthritis, and there was no evidence forassociated gout or collagen-vascular disease. Histological examination of tissue taken at the time ofsynovectomy indicated elbow arthritis to be due to myeloid metaplasia involving the synovialmembrane.

Rheumatic complications of malignancy includedirect synovial invasion by metastases of solidtumours or by leukaemic infiltrates, a variety ofparaneoplastic syndromes, secondary gout, hyper-trophic osteoarthropathy, and cancer polyarthritis.'To add yet another entity we report arthritis in apatient with myelofibrosis (agnogenic myeloid meta-plasia) due to synovial infiltration by myelopoieticelements.

Case report

A 60-year-old white male presented in September1975 with profound malaise of recent onset. He gavea 5-year history of intermittent arthralgias involvinghis elbows, shoulders, and neck; pain in the rightelbow had become constant and increasingly severeover the past several months. Physical examinationdisclosed hepatomegaly and a psoriasiform rash onthe shins, knees, and elbows. There were no nailbedabnormalities. The synovial membrane of the rightelbow was thickened, and a 400 flexion contracturewas present. Roentgenograms showed mild scleroticchanges in the right elbow (Fig. 1) and calcification ofthe medial collateral ligament of the right knee.

Haematocrit (HCT) was 33%, white blood cell(WBC) count 12-1 x 109/l, (3% bands, 63% seg-mented polymorphs, 6% eosinophils, 1 % basophil,

Accepted for publication 2 February 1982.Correspondence to P. D. Gorevic, MD, Department of Medicine,Division of Allergy, Health Sciences Center, State University ofNew York, Stony Brook, New York 11794, USA.

27% lymphocytes) and platelets 415 x 109/l.Peripheral smear showed tear drop poikilocytosis,fragmented red blood cells (RBC), occasionalnucleated RBC, increased numbers of immatureleucocytes (PMN), and giant platelets. A bone mar-row aspirate yielded a dry tap; bone marrow biopsyshowed 20-25 % fibrosis with increased numbers oflarge megakaryocytes in clusters. Leucocyte alkalinephosphatase activity was normal. Skin biopsies of 2psoriasiform skin lesions showed diffuse, mild,dermal lymphocytic and histiocytic infiltrates, withnormal epidermis and cutaneous adnexa.

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Arthritis due to synovial involvement by extramedullary haematopoiesis 197

Over the next year the patient continued to com-plain of migratory arthralgias, usually lasting severaldays, involving his shoulders, wrists, knees, and ank-les, as well as nearly constant pain of the right elbow.Small warm effusions of the right elbow and left kneeresponded to intra-articular steroid injections, and heobtained modest benefit from 2600 mg of aspirindaily. The erythrocyte sedimentation rate rangedover 60-70 mm/h (Westegren).

In January 1978 he was readmitted to hospitalcomplaining of malaise, anorexia, upper extremityweakness, and severe pain, tenderness, and swellingof the right elbow. There was marked muscle wastingof both shoulder girdles, more prominent on the rightside, and massive splenomegaly. Serum aldolase was3 5 times normal, 24-hour urinary creatine 1 5 timesnormal, and for the first time his serum alkalinephosphatase was elevated. Serum protein electro-phoresis, uric acid level, rheumatoid factor, anti-nuclear antibody, immunoglobulin levels, andcomplement studies were normal, as was an electro-myogram (EMG). A biopsy of the right deltoid mus-

cle showed focal, acute, inflammatory infiltrateslocalised largely to the perimysium, with some exten-sion between muscle fibres. There was no evidence ofpolymyositis or vasculitis, and no abnormalities werefound on histochemical and immunofluorescencestudies. An elective splenectomy was performed. Thespleen weighed 3000 g and contained large amountsof myelopoietic tissue. After splenectomy theplatelet count rose to 1490 x 109/l and WBC to 174x 109/l (15% bands, 55% segmented polymorphs,18% metamyelocytes and myelocytes, 3%eosinophils, 2% basophils, 7% lymphocytes).Chlorambucil and prophylactic allopurinol werestarted. Over the next few months the serum aldolasegradually returned towards normal levels.

In June 1978 he was admitted to hospital followingthe development of a large haematoma in the leftflank. Repeat right deltoid muscle biopsy showedminimal round cell infiltrate in the perimysial fat. TheEMG remained normal. A technetium-99m pyro-phosphate bone scan showed increased uptake in thevertebral column and the ends of all long bones, with

Fig. 2 A Technetium-99mpyrophosphate scan showinghyperconcentration of isotope invertebral column, shoulders, ster-noclavicular joints, knees, and ank-les. B Intense uptake of isotope inthe right elbow.

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198 Heinicke, Zarrabi, Gorevic

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Fig. 3 A Circumscribed myeloidin synovial frond. A low-grade dif-fuse inflammatory infiltrate and fib-rovascular proliferation are presentin the adjacent tissue. (Haematoxy-lin and eosin, x144). B Highermagnification of nodule in Fig. 1discloses polymorphous myeloidelements. MK = megakaryocyte.PMN = polymorphonuclear leuco-cyte. EOS = eosinophile.(Haematoxylin and eosin, x460).C Greater magnification of marginof synovial frond discloses hyperp-lastic synovial lining cells (Syn) anda nonspecific chronic inflammatoryinfiltrate composed primarily ofmononuclear and plasma cells(PC). (Haematoxylin and eosin,x650). Inset shows PC with typi-cally eccentric nucleus and vas-culoar cytoplasm.

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Arthritis due to synovial involvement by extramedullary haematopoiesis 199

the most intense uptake occurring in the right elbow(Fig. 2). Roentgenographic studies showed sclerosisof the thoracic and lumbar vertebrae and distal righthumerus. The right elbow showed marked symmetri-cal narrowing of the joint space and small juxta-articular cortical lucencies. Arthrocentesis of theelbow yielded 4 ml of turbid yellow fluid. It contained44 x 109/l WBC (83% polymorphs and 17%lymphocytes), glucose 68 mg/dl (3 8 mmolIl) (serumglucose 100 mg/dl (5 6 mmol/l)), and total protein4 5 g/dl (45 g/l). No abnormal cells were seen in thecentrifuged synovial fluid sediment either by light orelectron microscopy, and no crystals were seen bypolarising microscopy. Cultures for bacteria, myco-bacteria, and fungi were negative.Synovectomy of the right elbow was performed

because of intractable pain and loss of motion.Grossly, the synovial membrane was hyperaemic andthickened. The cartilage had mild to moderatedegenerative changes.

Microscopically the synovial membrane disclosed2 types of cellular infiltration (Figs. 3A, B, C): anonspecific, chronic inflammatory reaction involvingprincipally the superficial portions of the specimen,and nodular infiltrates of myeloid cells, includingmany megakaryocytes and eosinophils, in the deeperareas.

Surgical operation gave 75 % relief of the pain butno improvement of range of movement. The subse-quent course was complicated by several moreepisodes of spontaneous soft-tissue haemorrhages. InJanuary 1979 he was switched to hydroxyurea forbetter control of thrombocytosis. There were nofurther arthralgias, and the skin lesions remainedinactive, with no development of nail pitting.A final admission to hospital in July 1981 was

precipitated by a one-week history of nausea, weak-ness, and fever to 101°C. HCT was now 49%, WBC93 *4 x 109/l (20% PMN, 9% bands, 36% blasts),platelets 9 x 109/l. Bone marrow biopsy showedmyelofibrosis and changes consistent with acutegranulocytic leukaemia. There followed rapid pro-gression of bilateral bronchopneumonia, respiratoryfailure, and death. Post-mortem examination con-firmed diffused osteosclerosis and extramedullaryhaematopoieisis involving the liver; peripheral jointswere not examined.

Discussion

Infiltration of the synovial membrane by bone mar-row elements has not so far been described as acomplication of myelofibrosis with myeloid meta-plasia. The usual course of this disorder is that of anindolent progression of bone marrow fibrosis, withmetaplastic haematopoeisis occurring primarily in

the liver, spleen, and lymph nodes. Occasionally loc-ally aggressive tumefactions of metaplastic marrowelements occur. In most cases these 'tumours ofhaematopoeisis' are of modest clinical significance.They may occasionally cause abdominal masses, sub-cutaneous nodules, or other skin lesions, pleuraleffusions, or ascites without portal hypertension.Profoundly disabling or lethal complications includespinal cord compression, portal hypertension, andgastrointestinal haemorrhage, small bowel obstruc-tion, hydronephrosis, and pulmonary infarction dueto emboli of haematopoietic tissue. Evolution toacute granulocytic or myelomonocytic leukaemia is acommon cause of death.2

Histological association of chronic synovitis withrests of ectopic marrow tissue in the specimen takenat synovectomy suggested to us that the latter mayhave contributed significantly to the chronic elbowpain in our patient. It may have been responsible forthe elbow synovitis at least as far back as his clinicalpresentation 3 years prior to synovectomy. Hyper-uricaemia has been found in 25-50% patients withmyelofibrosis, with 6-13 % developing symptomaticgouty arthritis.2 Our patient was normouricaemic andcareful study of synovial fluid and tissue by polarisingand electron microscopy failed to reveal character-istic uric acid crystals. We also considered pauci-articular psoriatic arthritis as a possible diagnosis inview of the psoriasiform skin lesions. Against thispossibility, however, was the lack of distal inter-phalangeal joint involvement, nailbed pitting, orankylosing changes on x-ray.The cause of polyarthralgias involving our

patient's shoulders, wrists, knees, and ankles remainsobscure. Myelofibrosis has been described as a com-plication of systemic lupus erythematosus in 10 cases3and in one patient with long-standing sclerodermatreated with chlorambucil.4 It has been suggested thatthe bone marrow may be a target organ for auto-antibodies produced in the course of these disorders.In our patient, however, multiple serological studiesdone to investigate other rheumatic diseases werenegative.

Similarly, although we confirmed an inflammatorymyopathy by serum enzyme and histological studies,its pathogenesis in this setting remains obscure.Infiltration of muscle by myeloid elements has beendescribed in one case report of myelofibrosis andparticularly aggressive peripheral neuropathy.5 Thisfinding, however, was not seen in biopsy materialobtained from our patient.The x-ray findings reported here differ from those

previously noted in patients with myelofibrosis.Osteosclerosis is found in about 40% of cases,6 andthere has been at least one case report of lytic lesionscaused by exuberant marrow metaplasia.7 The com-

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200 Heinicke, Zarrabi, Gorevic

bination of these findings in one patient, however,has not been recorded. Mason et al.8 described 2patients with myelofibrosis who developed fever andsevere bone pains. In one case the elbow wasinvolved. Radioscintigraphy showed increaseduptake over involved bones in both patients. One ofthem subsequently developed x-ray evidence ofperiosteitis. This was confirmed at necropsy, withareas of hypercellular marrow being noted in adjac-ent tissue.8 The existence of cortical defects in thedistal humerus in our patient raises the possibilitythat the synovial infiltration may have come aboutthrough local extension of marrow elements throughthe eroded bone. It is also possible that they arose denovo from metaplasia of pluripotential mesenchymalcells in the synovium.

In retrospect is seems that the aetiology of chronicarthritis in our patient might have been suggested bythe bone marrow biopsy and distinctive x-ray andbone scan findings. Synovial biopsy and synovectomywere required to establish the diagnosis and to treatthis unusual complication of myelofibrosis.

The authors thank Dr Leon Sokoloff for help in the interpretation ofthe pathology and preparation of the photomicrographs.

References

1 Caldwell D S. Musculoskeletal syndromes associated with malig-nancy. Semin Arthritis Rheum 1981; 10: 198-223.

2 SilversteinM N. Agnogenic Myeloid Metaplasia. Mass, PublishingSciences Group, 1975.

3 Rosen P J, Cramer A D, DuBois E L, Lukes R J. Systemic lupuserythematosus and myelofibrosis: a possible pathogenetic rela-tionship (abstr). Clin Res 1973; 21: 565.

4 Gisser S D, Chung B. Acute myelofibrosis in progressive systemicsclerosis. Am J Med 1979; 67: 151-4.

5 Mussini J M, Poisson M, Leporrier M, Mashaly R. A case ofmyelofibrosis with aberrant myelogenesis in neuromuscularbiopsy. Muscle Nerve 1979; 2: 78-9.

6 Pettigrew J D, Ward H P. Correlation of radiologic, histologic andclinical findings in agnogenic myeloid metaplasia. Radiology1969; 93: 541-8.

7 Fayemi A 0, Gerber M A, Cohen I, Davis S, Rubin A 0. Myeloidsarcoma: review of the literature and report of a case. Cancer1973; 43: 253-8.

8 Mason B A, Kressel B R, Cashdoliar M R, Bemath A M,Schecter G P. Periosteitis associated with myelofibrosis. Cancer1979; 43: 1568-71.

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