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Multicentric reticulohistiocytosis (lipoid dermatoarthritis)
Multicentric Reticulohistiocytosis (Lipoid Dermatoarthritis) A Multisystem
Disorder
GEORGE E. EHRLICH,
M.D., F.A.C.P.
IRVING YOUNG,
M.D.
STANLEY Z. NOSHENY,
M.D.
WARREN A. KATZ, M.D. Philadelphia,
Pennsylvania
Multicentric ,reticulohistiocytosis has been regarded as a rare disorder of the skin and synovium, simulating rheumatoid arthritis. Also known as lipoid dermatoarthritis, it has been classified among the lipid storage diseases. In the case reported, multicentric reticulohistiocytosis was documented in skin nodules, subcutaneous nodules, synovium of joint and tendon sheaths, perirenal fat and at the base of gastric ulcers. Lesions of the conjunctivas, retina and orbit were presumed to be on the same basis. Evidence is p,rovided to permit classification of multicentric reticulohistiocytosis as a systemic disease. The clinical course was characterized from the beginning by
dermatomyositis
as well as polyarthritis.
From its early days as a dermatologic and pathologic curiosity, multicentric reticulohistiocytosis has won a place as a distinct syndrome. In a searching review of thirty-three cases reported in the literature, Barrow and Holubar in 1969 [l] described the gradual development of nodules in the skin, mucosa, subcutaneous tissue, synovium and selected other tissues resulting in destructive arthritis and skin disfigurement. They emphasized a characteristic microscopic picture of multinucleated giant cells and histiocytes with ground-glass appearance of the cytoplasm secondary to lipid inclusions. With rare exceptions, the patients described had symptoms localized selectively to skin, mucosa and synovium. We present the following case history to suggest that the syndrome may not be quite that localized; to our knowledge, this case report is the first to detail gastric involvement in addition to cutaneous and joint and tendon sheath synovial reticulohistiocytic granuloma. Conjunctival, orbital and retinal infiltrates were diagnosed clinically, but not confirmed by biopsy. In addition, the patient presented features clinically indistinguishable from rheumatoid arthritis and dermatomyositis. CASE REPORT A forty-two
From the Arthritis Center, Albert Einstein Medical Center-Moss Rehabilitation Hospital, and The Department of Pathology,
Albert Einstein Medical C’enter; and the Temple University School of Medicine. Requests for reprints should be addressed to Dr. George E. Ehrlich, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia, Pennsylvania 19141. Manuscript received June 26, 1971.
830
year old white
man with
child-like
disturbance
of affect
was
admitted from the emergency room on. May 26, 1967, because of sudden onset of muscular weakness, joint pain, stiffness and rash. There had been no known antecedent history; he had worked as a platform loader until two weeks before admission. He had served in the Armed Forces during the second World War. The weakness began in the left hand and left shoulder, associated with a violaceous maculopapular eruption on his arms and heliotrope discoloration about the eyes. The left hand and forearm, right elbow and right knee became both painful and swollen. The urine turned dark, and fever developed. On initial examination, marked muscular wasting, particularly of the proximal muscles, was evident. The shoulders, elbows, wrists, fingers, knees and ankles were swollen, warm and tender, with marked limitation of motion. A lymph node measuring approximately 2 cm in diameter was
The
American
Journal
of
Medicine
MbLTICENTRIC
TABLE
I
Laboratory
RETlCULOHlSTlOCYTOSlS-EHRLICH
ET
AL.
Data Hosprtalizations
5/25/67-l/11/68
~_____~
Hemoglobin (gm %) Hematocrit (%) White blood cell count (thousands/cu mm) Differential Platelets (per cu mm) Erythrocyte sedimentation (Westergren, mm/hr) Coombs’ tests Direct Indirect
10/12/6912/24/69
8/3/68-11; 21/‘68
__~~ ~~ ~~
3/23/70-5/12/70
3/8,/71-4/8/71
8.2, 5.4, 11.0 25, 20, 36
8.7 29
10.5 35
9.1-10.2 32-35
7.4 27
6-11 Shift to left 277,000
14.6 Shift to left 318,000
8-15 Shift to left
11.3-18.3 Shift to left 386,000
7.5-13.8 Shift to left 359,000
80
60
.
rate
Reticulocytes (per cu mm) Blood volume Total (lz51 albumin) (ml) Red blood cells (ml) Plasma (ml) Blood chemistry Glucose, fasting (65-105 mg %) 2 hr postprandial (<140 mg %) Blood urea nitrogen (8-20 mg %) Creatinine (0.7-1.5 mg %) Uric acid (2-6 mg %) Calcium (9-11 mg %) Phosphorus (3-4 mg %) Alkaline phosphatase (2-6 units %) Electrolytes Albumin (gm %) Globulin (gm %) Alpha, (2-7%) Alphas (6-11%) Beta (l-14%) Gamma (13-20X) lmmunoglobulin G (850-1,550 mg %) lmmunoglobulin M (50-110 mg %) lmmunoglobulin A (150-400 mg %) Bilirubin (0.2/1.0 mg %) Prothrombin (70-100%) Enzymes Lactic dehydrogenase (ZOO-600 units/ml) Serum glutamic oxaloacetic transaminase (8-40 units/ml) Serum glutamic pyruvic transamrnase (5-40 units/ml) Creatine phosphokinase (O-l.5 IU/L) Aldolase (S-L units) Acid phosphatase (0.1-1.1 units %) Immunology Serologic test for syphilis Latex fixation test (Rh.F.) Lupus erythematosus preparation Antistreptolysin 0 titer Thyroid antibodies Haptoglobin (below 200 mg %) Serum CH 50 (20-45 p/ml) C3 complement component (120-180 mg %) Antinuclear antibodies
..
68-122 Negative Negative 0.8
Negative Negative 0.6
6,100/5,100 1,900/2,400 4,200/2,700
.. ...
75 85 23-18 0.7 4.8 8.5-7.6 3.6-4.9 12.7, 36.2, 4.4 Normal 3.2 3.1 7.4 16.7 13.5 23.7
25
.. . . 4.7
1.4
...
. ... ,.. .
0.8
100 85 . ...
9.0 3.3
...
Negative Negative
. *. . .
... .. .
4,800/5,100 1,800/2,400 3,000/2,700 68 84 25
102 90 28 1.1
.. ...
23, 46, 9 1.3 7.4 9.2 3.2 4.7-2.7 Normal 3.2 2.5 4.3 10.0 12.9 17.1
60 82 18 0.7 6.3
.
1,700, 1,080 90-190 220 1.6/3.1, 0.7/1.8 100
900 0.1/0.4 100
100
0.03/0.1 100
5.0 ‘.. Normal 3.3 2.9 5.0,4.0 10.6, 13.8 13.1, 14.6 20, 18.7 2,000 120 112 0.08/0.2 90
810, 400, 940
330
420
810-350
400
23, 121, 25
13
8
18-30
10
30 1.0, 0
0
5 0.2
21 2.3-O 6.5
5 5
...
.. ... Negative Negative Negative
_---__
Normal 3.4 3.5 4.9 12.1 12.1 19.1 1,700 90
. . ... ... ... . ...
Normal 3.6 2.4
.. ... . . . . ... .. .
. ... ...
. . .
.. ..
Negatlve Negative Negative 12 ...
Negative Negative Negative
Negative Negative Negative
Negative Negative Negative
.. ... .. ... ... ...
. .. .. ... . .. . . _____.
Negative Over 200 Less than 6.8 155 Negative
.. .. . ..
...
0.5
‘“.
. .
Continued
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52,
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1972
831
MULTICENTRIC
TABLE
RETlCULOHlSTlOCYTOSlS-EHRLICH
I (Cont’d)
Laboratory
ET AL.
Data Hospitalizations 10/12/695/26/67-1/11/68
Urine Creatinine (mg/24 hr) Urobilinogen (dilution) Calcium (mg/24 hr) Phosphorus (mg/24 hr) 17-hydroxycorticoids (mg/24 hr) 12-ketosteroids (mg/24 hr) Hydroxyproline (mg/24 hr) Hydroxyproline to creatinine ratio U ronic acid (3-9 mg/24 hr) Insulin mean clearance (90-140 ml/min) Paraaminohippurate (550-750 ml/min) Creatinine clearance (90-140 ml/min) Lipid Serum turbidity (ODU) Fasting triglyceride (30-170 mg %) Fasting cholesterol (150-250 mg %) Other Schilling test (radioactive BIZ 5-70/o) Serum vitamin B12(200-900 pg/ml) Serum folic acid (above 3.0 ng/ml) Serum iron (p %) Serum iron-binding capacity (p %) D-xylose test (gm/5 hr) Is11 uptake (10-40%) T3 uptake (ll-19%) T3 thyrobinding index (0.8-1.2) T4 uptake (5-15 p %) Fibrinogen (mg %) Anti-DNA antibody (
January
30-135 1:320 29.1 104 2.6 8.4
... ... ... ... ... ... ... ... ... ... ... ...
.. .. ... ... ... ...
... ... 48.1
12/24/69
105
... ...
“’
288 79.1
... ...
... ... ...
... ... ... ...
22-2.8”’ 29 22
... ...
...
188
30,000 1,000 Poor
..*
... ... ...
... ...
13
... ... .. ..
7.6 190
3/23/70-5/12/70
3/8/71-4/8/71
... ... ... ... ...
... ...
...
26 “’ 0.06
... 3.75
10.7, 9.68
... ... ...
... ...
0.055 74 127
120 122
**.
... 200 **. 4.9-7.2 42-38 322-238
170 1.4
3.5
... ... ... ... ... ... ... ... ... ... ... ... ...
... ... ... ... ...
... ... 0.77-0.71 4.0-6.0
0.71 7.6 ... ... 93,200 5,800 Friable 1:40
0*
.**
79,300 21,220 Poor
...
-
13, 1972.
palpated in the left axilla. Oral temperature was 37.B”C. During the eight months that the patient remained in the hospital on his first admission, striking, sharply outlined brown hyperpigmented lesions developed on the upper and lower eyelids, together with mild diffuse lichenification with hyperpigmentation and healing punctate excoriations on the extensor surfaces of the forearms. A 70 degree flexion contracture of the right elbow developed and a 45 degree contracture of the left elbow. All motions at the wrists were severely compromised. Dorsal subluxation of the ulnas developed at the distal radioulnar joints. Effusions formed in both knees and bulged into the popliteal spaces. The deep tendon reflexes remained brisk and equal, despite diffuse weakness involving all his #extremities. The right supraspinatus, triceps and opponens pollicis muscles became atrophic, as did the left calf muscles. Lid lag developed bilaterally, and the eyes became prominent despite pseudoptosis. Initial laboratory data included erythrocyte sedimentation rate of 122 mm/hour (Westergren), and anemia
832
8/3/6&11/21/68
fluid and leukocytosis. Abnormaliti’es in the synovial were of the inflammatory variety, containing no crystals and with no growth on culture. Electromyogram revealed a myopathic pattern. Laboratory data are detailed in Tabl,e I. Biopsies of lymph nodes, skin and muscle were considered nonspecific at the time. Roentgenograms of the cervical spine disclosed only mild degenerative changes. Irregularity of the greater tuberosity of the right humerus suggested previous rotator cuff injury. All other roentgenograms were unremarkable. Rheumatoid arthritis and dermatomyositis were entertained as diagnoses, and a rapid increase in weakness, leading to early respiratory embarrassment, led to the institution of corticosteroid therapy. On doses of 60 mg prednisone daily, the skin eruptions faded and the joints became less painful, but edema of the legs developed. The dosage of prednisone was transiently increased to 80 mg daily. At this time bilateral hilar lymph node enlargement became apparent on roentgenograms, but sub-
The American
Journal
of Medicine
MlJLTlCENTRlC
sequently revealed
seemed erythroid
tc. recede. hyperplasia.
The patient was again followed in the clinic; the dose of prednisone was increased to 30 mg daily because of increasing symptoms. He was readmitted on March 5, 1969, when, in addition to contractures of the elbows, contractures of the shoulders and knees developed. The colonic stoma had prolapsed, and the abdomen was painful. For the first time, clubbing of the fingers and toes was apparent. Lymph nodes were enlarged in the posterior
52.
June
1972
ET
AL
Hone marrow examination Glomerular filtration rate
and renal plasma flow were both markedly impaired. Kidney biopsy revealed minimal thickening of glomerular basement membranes and Howman’s capsule. The changes were not considered sufficient to warrant a diagnosis of “collagen disease” or membranous glomerulonephritis. Nonspecific myocardial abnormality was detected on e!ectrocardlogram. Three weeks after the beginning of corticosteroid therapy the patient vomited bright red blood. In the course of a negative work-up for a possible coexistent malignant lesion, the x-ray series of the gastrointestinal tract had been unremarkable; now, ulcers were demonstrable in the antrum, requiring vagotomy and hemigastrectomy. “stress ulcers” were found in the resected Multiple specimen. A total of 35 units of blood had to be transfused during the next three months. Alternate day corticosteroid therapy was substituted for the previous daily dosage, and testosterone, 100 mg daily, was added to the regimen, being changed after two months to 100 mg every other day. Transient mild jaundice was noted, and the patient sustained a brief episode of mild congestive heart failure. In October, an electrocardiogram suggested a small subendocardial infarction. Several infections of the urinary tract and skin were treated successfully with keflin, ampicillin, and finally with chloramphenicol. In late October an abdominal fistula developed. The fistulous tract communicated with the perigastric area, the rectosigmoid colon and the abdominal wall. Roentgenograms demonstrated small pleural effusions that resorbed spontaneously and a questionable lytic lesion of the right fifth rib that was not subsequently confirmed. Prednisone dosage was tapered, so that by the time of discharge on January 11, 1968, ,the patient was receiving only 10 mg on a daily basis. He was followed as an outpatient; prednisone dosage remained at 5 mg twice daily, and methandrostenolone was added. In July 1968 severe migratory polyarthritis developed, with an increase in proximal muscle weakness, nausea, vomiting, hematemesis and recurrent fever, for which the patient was admitted on August 3, 1968. He now appeared cachectic. The temperature was 38°C. An erythematous eruption involved the neck, ears, elbows and both the dorsal and palmar aspects of the hands. Prednisone dosage was increased to 60 mg daily, with subsidence of most symptoms in four days. By the time of discharge on November 21, 1968, the dose of prednisone had been reduced to 25 mg daily, and mild arthralgias of the large joints had recurred. During hospitalization, 2 units of blood had been administered. Sigmoidoscopy revealed a fistula of the sigmoid, 7 to 8 cm from the anal margin. Consequently, a transverse colostomy and drainage of a subhepatic abscess were performed on August 23; on November 4 the colostomy was revised because of prolapse of the colonic mucosa.
Volume
RETlCULOHlSTlOCYTOSlS--EtiRLiCH
Figure
dorsun cervical
1. Nodules of various of the ‘land and fingers. and
right
axillary
areas.
sizes
ara
vrsible
The patient’s
on the
condition
improved. and he was discharged on March 19, 1969, to be followed as an outpatient; he was taking 30 mg of prednisone daily. On April 23, 1969, small slightly raised red lesions were first noticed on his fingers and the dorsa of his wrists. Roentgenograms of the hands now disclosed generalized demineralization and some atrophy of the soft tissues, but no calcific deposits, In June, joint pains Increased and frontal headaches developed. The skin nodules of the hands were now violaceous and tender, and seemed to have become larger (Figure 1).
Figure 2. A purplish grey nodule medial asoect of the right elbow.
is clearly
visible
on the
833
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The patient was readmitted on October 12, 1969. At this time there was no proximal muscle weakness, and the range of motion of the joints had improved, the flexion contractures having all but disappeared. Nevertheless, there were effusions into the knee and elbow joints, with local tenderness and knobby deformities. Abduction and elevation of the arms was somewhat difficult. Numerous soft purplish grey nodules studded the dorsa of his fingers and hands, and were cilso palpable at the right elbow (Figure 2). There were 37 nodules in all at these locations. Similar lesions, but flatter, were seen on the forehead up to the hairline. A large patch of nodules was apparent near the midline in the lumbar area, underlying the strap of the colostomy girdle. Biopsies of the nodule on the left second finger and of the synovium of the right knee were carried out. These demonstrated a fairly dense background lattice of connective tissue fibers within the interstices of which large ovoid, round and polyhedral multinucleated giant cells appeared singly and in clusters. These featured abundant cytoplasm generally of eosinophilic ground-glass character. Some nuclei were single, others multiple. They were small and regular. The cells satisfied the criteria for the diagnosis of reticulohistiocytic granuloma (Figure 3). Skull roentgenograms and brain scan were normal. An electroencephalogram was somewhat abnormal owing to a slight excess of intermittent theta waves and slowing of background activity. The symptoms of dizziness, sweating and vomiting which occurred from twelve to fifteen minutes after he ate a meal were interpreted as the dumping syndrome. After evincing some improvement, the patient was discharged on December 24, 1969, to be followed in the clinic.
Figure 3. Specimen of synovial tissue. A, low power view showing marked thickening due principally to infiltration by reticulohistiocytic giant cells. 8, high power view showing typical polygonal multinucleated giant cells of reticulohistiocytic granuloma in synovium. Original magnification x 142 (A), x 390 (6); both reduced by 45 per cent.
Figure 4. Xanthelasmas are visible on the upper lids. Proptosis and pseudoptosis are present, and the discoloration cf dcrmatomyositis remains around the eyes.
834
Because of increasing weakness, he was readmitted on March 23, 1970. Electromyography again demonstrated a myopathic pattern in all muscle groups. Roentgenograms revealed continued periarticular demineralization of the wrists, fingers and knees. Intermediate strength purified protein derivative gave a negative test but second strength purified protein derivative was strongly positive. Because the patient continued to take prednisone, albeit in reduced dose at 15 mg a day, a course of isoniazid was started on the strength of this test. With the reduction of prednisone to 10 mg daily the patient experienced increasing joint pain, with weakness, fever and nausea. New crops of nodules appeared on the skin. Increased prednisone dosage again lessened his symptoms, but the nodules remained unchanged. On May 3, 1970, a course of azathioprine was begun in doses of 200 mg daily, reduced to 150 mg a day for maintenance after one week. Within two weeks definite symptomatic improvement began, including regression of existing nodules without development of new ones. The patient was discharged on May 12, 1970, taking prednisone in doses of 20 mg daily. Three months later azathioprine therapy was discontinued because of a renewed bout of vomiting, although there was no evidence that it was related to the therapy. The patient was readmitted on August 8, 1970, for extraperitoneal Closure of the transverse colostomy, and discharged on September 2, 1970. During the interval before his next admission he took 30 mg of prednisone daily. Xanthelasmas developed on the eyelids (Figure 4) and a large orange-grey nodule appeared on the left lower lid. He gradually grew weaker, and so was readmitted on March 8, 1971.
The American
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MliLTlCENT9lC
The oniy new findlng at this time was marked diminution of grasp owing to limited flexion at the proximal interphalangeal and metacarpophalangeal joints. Decreased dorsiflexion of the feet and diminished motion of the interphalangeal joints of the toes were also present. Proximal muscular wasting with weakness and interosseous wasting were detected. Deep tendon reflexes continued to be hyperactive, and a mild sensory polyneuropathy was present. Because of continued marked anemia. bone marrow was taken both by aspiration and by trephine biopsy of the iliac crest. Minimal osteoporosis and essentially unremarkable marrow were found. Granulopoiesis, cellularity and megakaryock*es were normal, erythropoiesis normoblastic and the myeloid-erythroid ratio was 1O:l. On scan, the thyroid gland was normal in size, shape, position and distribution of radioiodine, without indication of a nodule within the gland. Aspirated knee fluid contained 40 mg per cent triglycerides on the left, 20 mg per cent on the right, with cholesterol less than 20 mg per cent in both knees. No beta lipoproteins were found. The major component was alpha lipoproteins. Pulmonary function studies revealed vital capacity at the lower limit of normal (82 per cent) with a slight decrease in inspiratory capacity (59 per cent). The residual volume was greatly increased to almost twice the value of
RETlCULOHISTIOCYTOSIS--EHRL.iCH
ET
AL.
predicted norrr,al (3.180/1,620. 196 per cent). Total lung capacity remained within normal limits (6,590/6.150, 107 per cent). The ratio of reserve volume to total capacity was increased (48 per cent versus a normal of 26 per cent). All parameters for expiratory airflow showed a slight decrease, The single breath carbon rnonoxide diffusing capacity was wlthin normal limits (26.7 ml/minute/ mm Hg). Resting arterial blood gases showed normal oxyger! tension (pot,) (oxygen tension 88, oxygen saturation 96.8, carbon dioxide tension 31, pH 7.46). A decrease in carbon dioxide tension (pCO,), with respiratory alkalosis, was probably due to transient hyperventilation. Signs of minimal airway obstruction were noted. Chest roentgenograms once again documented transient enlargement of hliar lymph nodes. Electroencephalogram was now within normal limits. Ophthalmologic examination revealed correctable myopia; exophthalmus, probably due to retrobulbar infiltrate; blue scleras; heliotrope lids; and conjunctival infiltrate. Microrefractive cholesterol-like bodies were seen in the retina. Posterior subcapsular cataracts, considered a result of corticosteroid therapy, were also encountered. The patient refused biopsy of any of the eye lesions. However, when the extensor tendon sheaths at the wrists became enlarged, he permitted surgical removal of
Figure 5.
A, specimen of tenosynoviaf tissue, low power view. 8, high power view showing infiltration by reticulohistiocytic giant cells. C, specimen of skin nodule, low power view showing dense infiltrate of multinucleated giant cells in connective tissue lattice. Cells have ground-glass cytoplasm. D, high power view of C. Original magnification x ;42 (A and C), x 471 (8 and D); A, R and C reduced by 47 per cent, D reduced by 22 per cent.
Volume
52,
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1972
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these, as well as several painful nodules on the finger. Once again, all these tissues bore the characteristic features of reticulohistiocytic granuloma (Figure 5). Reexamination of previously removed tissues now disclosed similar lesions in the stomach (Figure 6), at the base of the ulcers and in perirenal fat (Figure 7). At the time of discharge on April 8, 1971, the patient was taking 20 mg of prednisone daily. His affect was more child-like than ever; psychologic testing established an intelligence quotient of 83 (Wechsler Adult Intelligence Scale), and projective testing suggested a fearful, timid, rigid and immature personality pattern, but without signs of or-
ganic brain disease.
COMMENTS
Figure
6.
Low
power
view
showing
shallow
ulcer
in
mucosa of resected stomach. B, high power view showing focal aggregates of reticulohistiocytic giant cells in gastric submucosa at base of shallow ulcer. Original magnification x 60 (A), x 450 (5); both reduced by 48 per cent. See legend on facing page
Specimen of perirenal fat. High power view Figure 7. showing reticulohistiocytic giant cells in perirenal fat. Original magnification x 534; reduced by 47 per cent.
836
A recent review of multicentric reticulohistiocytosis uncovered thirty-three patients reported to have this condition [l]. A definition of the syndrome has emerged only gradually. Initially, because of the prominent skin lesions, reticulohistiocytic granuloma concerned chiefly dermatologists and pathologists. Although the syndrome is defined by its anatomic features, it has been expanded by the frequent concurrence of various clinical manifestations. For some of these, anatomic correlation with the lesions of reticulohistiocytic granuloma is as yet lacking. When reticulohistiocytic granuloma involves multiple sites, the term multicentric reticulohistiocytosis [2] is preferable. Viewed as a systemic disease of unknown cause but related to lipid storage diseases, multicentric reticulohistiocytosis produces nodules of skin, synovium, bone and mucosa. The term lipoid dermatoarthritis [3] has been employed to emphasize the areas of clinical predilection but is probably unduly restrictive. Most peripheral joints are involved, often with mutilating arthritis [4], as well as the cervical spine [5]. Swelling of the tendon sheaths at the wrists resembles ganglia or, more characteristically, rheumatoid arthritis. As the illness would undoubtedly be diagnosed as rheumatoid arthritis in the absence of biopsy, one must perforce question whether multicentric reticulohistiocytosis as a cause of the symptoms and signs may not be more common. Arthritis, skin nodules, weight loss, pleuritis, weakness, fever and paresthesias are the symptoms most frequently encountered in multicentric reticulohistiocytosis [l]. The disease usually develops insidiously and becomes self-limited after a number of years. The severity of arthritis may range from disconcerting to mutilatimg, and the skin lesions may be pruritic or painful. Weakness and loss of weight are prominent symptoms, as is intermittent fever. Certain features of the joint disease have been cited as permitting ready differentiation from rheumatoid arthritis. These include frequent distal interphalangeal joint involvement, a remittent course and ultimate development of secondary degenerative changes. As proved rheumatoid arthritis may be characterized by
The American
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MULTICENTRIC
these same features, they w II not serve as reliable bases for differentiai diagnosis. Skin nodules may be present almost anywhere, most prominently on the face and hands. They may be difficult to distinguish ,:linically fcom rheumatoid nodules when they occur peripherally. Mucosal nodules are most common in the nose and mouth. Flat yellowish lesions of the lids coexist in more than a third of the reported cases, including ours. In the few instances in which biopsies were performed, the histologic characteristics have been those of true xanthelasmas rather than reticulohistiocytic granuloma [l]. Myositis and myotonia were reported in a case of multicentric reticulohistiocytosis by Anderson and coworkers [6]. Although the electromyogram was suggestive, and biopsy showed diffuse nonspecific interstitial chronic myositis. serial enzyme studies were within normal limits. Two other patients have previously been described in whom muscle weakness or pain was suggested [2,7]. In our patient, a clinical diagnosis of rheumatoid arthritis complicated by dermatomyositis was maintained for more than two years. However, with the development of multiple peripheral skin nodules, biopsy disclosed the histologic features of reticulohistiocytic granuloma. Biopsy of the synovium of the knee also demonstrated the characteristic lesion. A review of the variety of tissues previously obtained at surgery was then carried out. These included skin, subcutaneous fat, skeletal muscle, axillary lymph nodes, renal parenchyma and perirenal fat, stomach and colostomy stoma. With this review it became apparent that there was unobtrusive but definite involvement of most of these tissues by infiltrates of the characteristic cells of reticulohistiocytic granuloma. In the biopsy specimens of the skin, subcutaneous fat and skeletal muscle, the cells clustered in the areolar tissue conspicuously adjacent to blood vessels. The kidney biopsy specimen showed no typical ceils within the renal parenchyma, but the specimen of perirenal fat exhibited numerous typical aggregates. Both of these biopsy specimens antedated the institution of corticosteroid therapy and represented tissues sampled within one month of onset of the acute illness. The stomach was removed ,three weeks after the introduction of massive corticosteroid therapy. The multiple shallow ulcers found in the antrum were originally attributed to corticosteroids or stress. They consisted of denuded mucosa with a base of inflamed granulation tissue, and exhibited none of the fibrinoid change usually associated with peptic ulceration. In the submucosal areolar tissue below the base of the ulcer, definite aggregates of typical giant cells of reticulohistiocytic granuloma were recognizable. The loose tissue at the site of the revision of the colostomy showed occasional giant cells, particularly in relation to residual suture. Their morphology, how-
Volume
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1972
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ever, was not sufhciently typical to warrant Iclusion as a definite site of involvement The presence of the typicai cells at the base of the gastric ulcers permits speculation as to cause and effect. Tt-ree possible explanations may be entertained. One alternative IS that the association of cells and ulcers m,ay be coincidental and unrelated. Another explanation suggests that the accumulation of these cells IS a response to injury which rn the stomach may have been induced by either corticosteroids or stress. In support of this contention are the observations by Hanauer of classic nodules developing on the bridge of the nose at the site of continued pressure by eyeglasses [8]. Additionally, our patient provides further support for this hypothesis in the development of characteristic nodules in an area chafed by the colostomy strap. A third explanation would presume the ulcer to be secondary to the focal accumulation of reticulohistiocytic granuloma cells. The cytoplasm of the typical cells at most sites gave positive staining reaction with periodic acid-Schiff after diastase digestion. This finding is consonant with that of most other investigators and has been taken to imply a glycolipid content. Multicentric reticulohistiocytosis has been classified by some among the lipidoses [9]. The predilection of fatty tissues and the frequent association of the xanthelasmas in such cases per. haps has some further inferential value. Although a single previously reported electron microscopic examination of such ceils has been interpreted as showing lipid vacuoles within the cell [l], our own studies were unable to confirm this observation (Figure 8). From the time the lesion was detected in our patient, various laboratory, electrodiagnostic and roentgenographic studies were undertaken to discover diseases or lesions that had been reported by others to occur in conjunction with multicentric reticulohistiocytosis. No evidence of cancer, diabetes or thyroid disease could be demonstrated, but coexistent tuberculosis could not be completely excluded; a positive reaction to second strength purified protein derivative provided the sole evidence for this possibility. The transient enlargement of hilar lymph nodes paralleling the waxing and waning of the skin lesions may reflect involvement by multicentric reticulohistiocytosis. Progressively throughout the course, increasing bulging of the eyes associated with pseudoptosis was noted. During the most recent admission, xanthelasmas and nodules were detected about the eyes. Conjunctival infiltrates resembled lipid deposits, and microrefractive cholesterol-like bodies were seen in the retina. It was the opinion of the ophthalmologists that most of these lesions resulted from the same process producing the lesions of the skin, synovium and other sites. However, attempts at biopsy were rejected by the patient, so that the exact nature of the lesions remains speculative. Fistula formation, poor healing of the colostomy
a37
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See legend on facing page 838
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RETICULOHISTIOCYTOSIS-EHRLICH
ET AL
Tissue fixation was in 2 per cent gfutarafdehyde fin cacodylate buffer at pH 7.4) Figure 8. for one hour at 4°C. This was followed by postfixatron in 2 pef- cent osmium tetroxide in the same buffer for one hour in the cold. Tissue was dehydrated through graded ethanols and propylene oxide and imbedded in Epon 812. Thin sections on 200 mesh copper grids were stained with 70 per cent methanolic uranyl acetate followed by Venable’s lead citrate. Preparations were examined in a Hitachi 11A electron microscope. There appears to be a membrane surrounding the polylobate nucleus; artifact cannot be completely ruled out as the basis for this seeming separation. There are heavy deposits of chromatin at the periphery of the nucleus. The cytoplasm contains many densely staining granules, which The cells are contained in a dense meshwork of collagen. cannot be otherwise characterized. Nothing which can be characterized as lipid deposits is identifiable. Original magnification x 10,000 (A), x 25,000 (B), x 80,000 (C); all reduced by 35 per cent.
wound, frequent infections, and evidence of malabsorption and dumping syndromes may be presumed to be the result of therapy (both corticosteroid and surgery) and of protein abnormalities and anemia. Even though multicentric reticulohistiocytosis has been described as involving the heart, It would be difficult to ascribe the myocardial abnormalities detectable on electrocardiography to multicentric reticulohistiocytosis in this patient. No ready explanation for the renal and pulmonary abnormalities has as yet been discovered. It is possible to speculate that central nervous system involvement was a possible cause of his intellectual impairment; his acceptability for responsible military duties in time of war suggests that he had functioned on a more adequate level previously and that his childishness represented recent deterioration. Joint fluid was analyzed in an attempt to delineate
Volume
52. June 1972
its characteristics in this disease. These studies disclosed an essentially inflammatory type of fluid. Rheumatoid factor was detectable in a titer of 1:40 on one examination, but the fluid was not digested with hyaluronidase before testing. Lipid profile reveals very low cholesterol and triglyceride content [lo]. These extremely low values provide further basis for the speculation that the reticulohistiocytes comprising these lesions take up lipids from surrounding media. Alpha lipoprotein, which contains a higher concentration of protein than beta lipoprotein, was the major component of the joint fluid. Mutilating ar-thropathy has been described repeatedly in multicentric reticulohistiocytosis, but this patient has ;as yet been spared this development. However, he has had clinical dermatomyositis for four years, for which corticosteroid therapy has been offered. Satis-
839
MULTICENTRIC
RETICULOHISTIOCYTOSIS-EHRLICH
ET
AL.
factory therapy for this disease has yet to be established. Corticosteroids, immunosuppressive agents (in one case, azathioprine seemed helpful [8]) and supportive measures have been used with varying degrees of success. As in other diseases characterized by spontaneous remissions, the effect of any mode of therapy must be evaluated with skepticism. On the basis of studies on this patient to date, it is tempting to speculate that multicentric reticulohistiocytosis represents a generalized disease in which the response to trauma or other stimuli is the formation of reticulohistiocytes. These cells may have the property of incorporating lipids and can probably occur in most areas of the body. In the patient described, multicentric reticulohistiocytosis presented clinically as rheumatoid arthritis and dermatomyositis with demonstrated involvement of stomach, tendon sheaths, joint synovium, and deep and superficial fatty depots. The gastric ulcers were morphologically associated with infiltrates of typical reticulohistiocytic granuloma at their bases. Sites of involvement implied by clinical evidence include conjunctivas, retina, orbital tissues, muscle and hilar lymph nodes. Abnormalities of renal and pulmonary function and cerebration, and profound anemia also accompanied his disease. No associated cancer was found, and tuberculosis could not be proved, although suppressive therapy was employed because of the large and continued doses of corticosteroids re-
quired to combat the life-threatening myositis. Thyroid studies remained within normal limits. Lipid profiles consistently recorded low cholesterol determinations and normal triglycerides. Joint fluid contained no beta lipoproteins and an absolute increase in alpha lipoproteins, together with an extremely low value for lipid components.
ACKNOWLEDGMENT Dr. Nosheny part
served
by a grant
Pennsylvania ter,
a clinical
from
the
Chapter
fellowship
Arthritis
to Albert
supported
Foundation, Einstein
in
Eastern
Medical
Cen-
Philadelphia. Electron
microscopic
examination
was
carried
out
by Lewis
W. Johns, Department of Cell Biology, Division of Pediatrics. The following participated in the care and evaluation of the patient: Drs. E. U. Keates and L. Magargel (ophthalmology), E. M. Cohn (gastroenterology), A. Bank, G. Vakkur and M. McGlamery (neurology), M. Kajani (hematology), A. D. Bannett and M. S. Kauffman (surgery), J. Rosenbaum (renology) and P. Kimbel and H. Rotman (pulmonary). Dr. S. Winsten performed specialized biochemical studies and Drs. A. M. Di Piero and S. H. Cohen provided additional clinical assistance. A partial description of this case appeared as an abstract [ 111.
REFERENCES 1.
multicentric
Barrow MV, Holubar K: Multicentric reticulohistiocytosis. A review of 33 patients. Medicine 48: 287, 1969.
7.
2.
Goltz RW, Laymon CW: Multicentric reticulohistiocytosis of the skin and synovia. Arch Derm Syph 69: 717, 1954.
8.
3.
Warin RP, Evans CD, Hewitt M, Taylor AL, Price CHG, Middlemiss JH: Reticulohistiocytosis (lipoid dermato-arthritis). Brit Med J 1: 1387, 1957.
4.
Johnson HM, Tilden IL: Reticulohistiocytic lomas of the skin associated with mutilans. Arch Derm 75: 405, 1957.
5.
Martel W, Abell MR, Duff IF: Cervical spine involvement in lipoid dermato-arthritis. Radiology 77: 613, 1961. Anderson TE, Carr AJ, Chapman RS, Downie AW, MacLean GD: Myositis and myotonia in a case of
6.
840
9.
granuarthritis 10. 11.
reticuiohistiocytosis.
Brit J Derm 80:
39, 1968. Montgomery H, Pokey HF, Pugh DG: Reticulohistiocytoma (reticulohistiocytic granuloma). Arch Derm 77: 61, 1958. Hanauer L: Reticulohistiocytosis, presented at the VII European Rheumatology Congress, Brighton, June, 1971. Barrow MV, Sunderman FW, Hackett RL, Colvin WS: Identification of tissue lipids in lipoid dermatoarthritis (multicentric reticulohistiocytosis). Amer J Clin Path 47: 312, 1967. Huttl S: Synovial effusion. Acta Rheum Balneol 5: 15, 1970. Nosheny SZ, Katz WA, Young I, Ehrlich GE: A new rheumatic syndrome associated with reticulohistiocytic granuloma (abstract). Arthritis Rheum 13: 341, 1970.
The
American
Journal
of
Medicine
Disorder
GEORGE E. EHRLICH,
M.D., F.A.C.P.
IRVING YOUNG,
M.D.
STANLEY Z. NOSHENY,
M.D.
WARREN A. KATZ, M.D. Philadelphia,
Pennsylvania
Multicentric ,reticulohistiocytosis has been regarded as a rare disorder of the skin and synovium, simulating rheumatoid arthritis. Also known as lipoid dermatoarthritis, it has been classified among the lipid storage diseases. In the case reported, multicentric reticulohistiocytosis was documented in skin nodules, subcutaneous nodules, synovium of joint and tendon sheaths, perirenal fat and at the base of gastric ulcers. Lesions of the conjunctivas, retina and orbit were presumed to be on the same basis. Evidence is p,rovided to permit classification of multicentric reticulohistiocytosis as a systemic disease. The clinical course was characterized from the beginning by
dermatomyositis
as well as polyarthritis.
From its early days as a dermatologic and pathologic curiosity, multicentric reticulohistiocytosis has won a place as a distinct syndrome. In a searching review of thirty-three cases reported in the literature, Barrow and Holubar in 1969 [l] described the gradual development of nodules in the skin, mucosa, subcutaneous tissue, synovium and selected other tissues resulting in destructive arthritis and skin disfigurement. They emphasized a characteristic microscopic picture of multinucleated giant cells and histiocytes with ground-glass appearance of the cytoplasm secondary to lipid inclusions. With rare exceptions, the patients described had symptoms localized selectively to skin, mucosa and synovium. We present the following case history to suggest that the syndrome may not be quite that localized; to our knowledge, this case report is the first to detail gastric involvement in addition to cutaneous and joint and tendon sheath synovial reticulohistiocytic granuloma. Conjunctival, orbital and retinal infiltrates were diagnosed clinically, but not confirmed by biopsy. In addition, the patient presented features clinically indistinguishable from rheumatoid arthritis and dermatomyositis. CASE REPORT A forty-two
From the Arthritis Center, Albert Einstein Medical Center-Moss Rehabilitation Hospital, and The Department of Pathology,
Albert Einstein Medical C’enter; and the Temple University School of Medicine. Requests for reprints should be addressed to Dr. George E. Ehrlich, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia, Pennsylvania 19141. Manuscript received June 26, 1971.
830
year old white
man with
child-like
disturbance
of affect
was
admitted from the emergency room on. May 26, 1967, because of sudden onset of muscular weakness, joint pain, stiffness and rash. There had been no known antecedent history; he had worked as a platform loader until two weeks before admission. He had served in the Armed Forces during the second World War. The weakness began in the left hand and left shoulder, associated with a violaceous maculopapular eruption on his arms and heliotrope discoloration about the eyes. The left hand and forearm, right elbow and right knee became both painful and swollen. The urine turned dark, and fever developed. On initial examination, marked muscular wasting, particularly of the proximal muscles, was evident. The shoulders, elbows, wrists, fingers, knees and ankles were swollen, warm and tender, with marked limitation of motion. A lymph node measuring approximately 2 cm in diameter was
The
American
Journal
of
Medicine
MbLTICENTRIC
TABLE
I
Laboratory
RETlCULOHlSTlOCYTOSlS-EHRLICH
ET
AL.
Data Hosprtalizations
5/25/67-l/11/68
~_____~
Hemoglobin (gm %) Hematocrit (%) White blood cell count (thousands/cu mm) Differential Platelets (per cu mm) Erythrocyte sedimentation (Westergren, mm/hr) Coombs’ tests Direct Indirect
10/12/6912/24/69
8/3/68-11; 21/‘68
__~~ ~~ ~~
3/23/70-5/12/70
3/8,/71-4/8/71
8.2, 5.4, 11.0 25, 20, 36
8.7 29
10.5 35
9.1-10.2 32-35
7.4 27
6-11 Shift to left 277,000
14.6 Shift to left 318,000
8-15 Shift to left
11.3-18.3 Shift to left 386,000
7.5-13.8 Shift to left 359,000
80
60
.
rate
Reticulocytes (per cu mm) Blood volume Total (lz51 albumin) (ml) Red blood cells (ml) Plasma (ml) Blood chemistry Glucose, fasting (65-105 mg %) 2 hr postprandial (<140 mg %) Blood urea nitrogen (8-20 mg %) Creatinine (0.7-1.5 mg %) Uric acid (2-6 mg %) Calcium (9-11 mg %) Phosphorus (3-4 mg %) Alkaline phosphatase (2-6 units %) Electrolytes Albumin (gm %) Globulin (gm %) Alpha, (2-7%) Alphas (6-11%) Beta (l-14%) Gamma (13-20X) lmmunoglobulin G (850-1,550 mg %) lmmunoglobulin M (50-110 mg %) lmmunoglobulin A (150-400 mg %) Bilirubin (0.2/1.0 mg %) Prothrombin (70-100%) Enzymes Lactic dehydrogenase (ZOO-600 units/ml) Serum glutamic oxaloacetic transaminase (8-40 units/ml) Serum glutamic pyruvic transamrnase (5-40 units/ml) Creatine phosphokinase (O-l.5 IU/L) Aldolase (S-L units) Acid phosphatase (0.1-1.1 units %) Immunology Serologic test for syphilis Latex fixation test (Rh.F.) Lupus erythematosus preparation Antistreptolysin 0 titer Thyroid antibodies Haptoglobin (below 200 mg %) Serum CH 50 (20-45 p/ml) C3 complement component (120-180 mg %) Antinuclear antibodies
..
68-122 Negative Negative 0.8
Negative Negative 0.6
6,100/5,100 1,900/2,400 4,200/2,700
.. ...
75 85 23-18 0.7 4.8 8.5-7.6 3.6-4.9 12.7, 36.2, 4.4 Normal 3.2 3.1 7.4 16.7 13.5 23.7
25
.. . . 4.7
1.4
...
. ... ,.. .
0.8
100 85 . ...
9.0 3.3
...
Negative Negative
. *. . .
... .. .
4,800/5,100 1,800/2,400 3,000/2,700 68 84 25
102 90 28 1.1
.. ...
23, 46, 9 1.3 7.4 9.2 3.2 4.7-2.7 Normal 3.2 2.5 4.3 10.0 12.9 17.1
60 82 18 0.7 6.3
.
1,700, 1,080 90-190 220 1.6/3.1, 0.7/1.8 100
900 0.1/0.4 100
100
0.03/0.1 100
5.0 ‘.. Normal 3.3 2.9 5.0,4.0 10.6, 13.8 13.1, 14.6 20, 18.7 2,000 120 112 0.08/0.2 90
810, 400, 940
330
420
810-350
400
23, 121, 25
13
8
18-30
10
30 1.0, 0
0
5 0.2
21 2.3-O 6.5
5 5
...
.. ... Negative Negative Negative
_---__
Normal 3.4 3.5 4.9 12.1 12.1 19.1 1,700 90
. . ... ... ... . ...
Normal 3.6 2.4
.. ... . . . . ... .. .
. ... ...
. . .
.. ..
Negatlve Negative Negative 12 ...
Negative Negative Negative
Negative Negative Negative
Negative Negative Negative
.. ... .. ... ... ...
. .. .. ... . .. . . _____.
Negative Over 200 Less than 6.8 155 Negative
.. .. . ..
...
0.5
‘“.
. .
Continued
Volume
52,
June
1972
831
MULTICENTRIC
TABLE
RETlCULOHlSTlOCYTOSlS-EHRLICH
I (Cont’d)
Laboratory
ET AL.
Data Hospitalizations 10/12/695/26/67-1/11/68
Urine Creatinine (mg/24 hr) Urobilinogen (dilution) Calcium (mg/24 hr) Phosphorus (mg/24 hr) 17-hydroxycorticoids (mg/24 hr) 12-ketosteroids (mg/24 hr) Hydroxyproline (mg/24 hr) Hydroxyproline to creatinine ratio U ronic acid (3-9 mg/24 hr) Insulin mean clearance (90-140 ml/min) Paraaminohippurate (550-750 ml/min) Creatinine clearance (90-140 ml/min) Lipid Serum turbidity (ODU) Fasting triglyceride (30-170 mg %) Fasting cholesterol (150-250 mg %) Other Schilling test (radioactive BIZ 5-70/o) Serum vitamin B12(200-900 pg/ml) Serum folic acid (above 3.0 ng/ml) Serum iron (p %) Serum iron-binding capacity (p %) D-xylose test (gm/5 hr) Is11 uptake (10-40%) T3 uptake (ll-19%) T3 thyrobinding index (0.8-1.2) T4 uptake (5-15 p %) Fibrinogen (mg %) Anti-DNA antibody (
January
30-135 1:320 29.1 104 2.6 8.4
... ... ... ... ... ... ... ... ... ... ... ...
.. .. ... ... ... ...
... ... 48.1
12/24/69
105
... ...
“’
288 79.1
... ...
... ... ...
... ... ... ...
22-2.8”’ 29 22
... ...
...
188
30,000 1,000 Poor
..*
... ... ...
... ...
13
... ... .. ..
7.6 190
3/23/70-5/12/70
3/8/71-4/8/71
... ... ... ... ...
... ...
...
26 “’ 0.06
... 3.75
10.7, 9.68
... ... ...
... ...
0.055 74 127
120 122
**.
... 200 **. 4.9-7.2 42-38 322-238
170 1.4
3.5
... ... ... ... ... ... ... ... ... ... ... ... ...
... ... ... ... ...
... ... 0.77-0.71 4.0-6.0
0.71 7.6 ... ... 93,200 5,800 Friable 1:40
0*
.**
79,300 21,220 Poor
...
-
13, 1972.
palpated in the left axilla. Oral temperature was 37.B”C. During the eight months that the patient remained in the hospital on his first admission, striking, sharply outlined brown hyperpigmented lesions developed on the upper and lower eyelids, together with mild diffuse lichenification with hyperpigmentation and healing punctate excoriations on the extensor surfaces of the forearms. A 70 degree flexion contracture of the right elbow developed and a 45 degree contracture of the left elbow. All motions at the wrists were severely compromised. Dorsal subluxation of the ulnas developed at the distal radioulnar joints. Effusions formed in both knees and bulged into the popliteal spaces. The deep tendon reflexes remained brisk and equal, despite diffuse weakness involving all his #extremities. The right supraspinatus, triceps and opponens pollicis muscles became atrophic, as did the left calf muscles. Lid lag developed bilaterally, and the eyes became prominent despite pseudoptosis. Initial laboratory data included erythrocyte sedimentation rate of 122 mm/hour (Westergren), and anemia
832
8/3/6&11/21/68
fluid and leukocytosis. Abnormaliti’es in the synovial were of the inflammatory variety, containing no crystals and with no growth on culture. Electromyogram revealed a myopathic pattern. Laboratory data are detailed in Tabl,e I. Biopsies of lymph nodes, skin and muscle were considered nonspecific at the time. Roentgenograms of the cervical spine disclosed only mild degenerative changes. Irregularity of the greater tuberosity of the right humerus suggested previous rotator cuff injury. All other roentgenograms were unremarkable. Rheumatoid arthritis and dermatomyositis were entertained as diagnoses, and a rapid increase in weakness, leading to early respiratory embarrassment, led to the institution of corticosteroid therapy. On doses of 60 mg prednisone daily, the skin eruptions faded and the joints became less painful, but edema of the legs developed. The dosage of prednisone was transiently increased to 80 mg daily. At this time bilateral hilar lymph node enlargement became apparent on roentgenograms, but sub-
The American
Journal
of Medicine
MlJLTlCENTRlC
sequently revealed
seemed erythroid
tc. recede. hyperplasia.
The patient was again followed in the clinic; the dose of prednisone was increased to 30 mg daily because of increasing symptoms. He was readmitted on March 5, 1969, when, in addition to contractures of the elbows, contractures of the shoulders and knees developed. The colonic stoma had prolapsed, and the abdomen was painful. For the first time, clubbing of the fingers and toes was apparent. Lymph nodes were enlarged in the posterior
52.
June
1972
ET
AL
Hone marrow examination Glomerular filtration rate
and renal plasma flow were both markedly impaired. Kidney biopsy revealed minimal thickening of glomerular basement membranes and Howman’s capsule. The changes were not considered sufficient to warrant a diagnosis of “collagen disease” or membranous glomerulonephritis. Nonspecific myocardial abnormality was detected on e!ectrocardlogram. Three weeks after the beginning of corticosteroid therapy the patient vomited bright red blood. In the course of a negative work-up for a possible coexistent malignant lesion, the x-ray series of the gastrointestinal tract had been unremarkable; now, ulcers were demonstrable in the antrum, requiring vagotomy and hemigastrectomy. “stress ulcers” were found in the resected Multiple specimen. A total of 35 units of blood had to be transfused during the next three months. Alternate day corticosteroid therapy was substituted for the previous daily dosage, and testosterone, 100 mg daily, was added to the regimen, being changed after two months to 100 mg every other day. Transient mild jaundice was noted, and the patient sustained a brief episode of mild congestive heart failure. In October, an electrocardiogram suggested a small subendocardial infarction. Several infections of the urinary tract and skin were treated successfully with keflin, ampicillin, and finally with chloramphenicol. In late October an abdominal fistula developed. The fistulous tract communicated with the perigastric area, the rectosigmoid colon and the abdominal wall. Roentgenograms demonstrated small pleural effusions that resorbed spontaneously and a questionable lytic lesion of the right fifth rib that was not subsequently confirmed. Prednisone dosage was tapered, so that by the time of discharge on January 11, 1968, ,the patient was receiving only 10 mg on a daily basis. He was followed as an outpatient; prednisone dosage remained at 5 mg twice daily, and methandrostenolone was added. In July 1968 severe migratory polyarthritis developed, with an increase in proximal muscle weakness, nausea, vomiting, hematemesis and recurrent fever, for which the patient was admitted on August 3, 1968. He now appeared cachectic. The temperature was 38°C. An erythematous eruption involved the neck, ears, elbows and both the dorsal and palmar aspects of the hands. Prednisone dosage was increased to 60 mg daily, with subsidence of most symptoms in four days. By the time of discharge on November 21, 1968, the dose of prednisone had been reduced to 25 mg daily, and mild arthralgias of the large joints had recurred. During hospitalization, 2 units of blood had been administered. Sigmoidoscopy revealed a fistula of the sigmoid, 7 to 8 cm from the anal margin. Consequently, a transverse colostomy and drainage of a subhepatic abscess were performed on August 23; on November 4 the colostomy was revised because of prolapse of the colonic mucosa.
Volume
RETlCULOHlSTlOCYTOSlS--EtiRLiCH
Figure
dorsun cervical
1. Nodules of various of the ‘land and fingers. and
right
axillary
areas.
sizes
ara
vrsible
The patient’s
on the
condition
improved. and he was discharged on March 19, 1969, to be followed as an outpatient; he was taking 30 mg of prednisone daily. On April 23, 1969, small slightly raised red lesions were first noticed on his fingers and the dorsa of his wrists. Roentgenograms of the hands now disclosed generalized demineralization and some atrophy of the soft tissues, but no calcific deposits, In June, joint pains Increased and frontal headaches developed. The skin nodules of the hands were now violaceous and tender, and seemed to have become larger (Figure 1).
Figure 2. A purplish grey nodule medial asoect of the right elbow.
is clearly
visible
on the
833
MULTICENTRIC
RETlCULOHlSTlOCYTOSlS-EHRLICH
ET
AL
The patient was readmitted on October 12, 1969. At this time there was no proximal muscle weakness, and the range of motion of the joints had improved, the flexion contractures having all but disappeared. Nevertheless, there were effusions into the knee and elbow joints, with local tenderness and knobby deformities. Abduction and elevation of the arms was somewhat difficult. Numerous soft purplish grey nodules studded the dorsa of his fingers and hands, and were cilso palpable at the right elbow (Figure 2). There were 37 nodules in all at these locations. Similar lesions, but flatter, were seen on the forehead up to the hairline. A large patch of nodules was apparent near the midline in the lumbar area, underlying the strap of the colostomy girdle. Biopsies of the nodule on the left second finger and of the synovium of the right knee were carried out. These demonstrated a fairly dense background lattice of connective tissue fibers within the interstices of which large ovoid, round and polyhedral multinucleated giant cells appeared singly and in clusters. These featured abundant cytoplasm generally of eosinophilic ground-glass character. Some nuclei were single, others multiple. They were small and regular. The cells satisfied the criteria for the diagnosis of reticulohistiocytic granuloma (Figure 3). Skull roentgenograms and brain scan were normal. An electroencephalogram was somewhat abnormal owing to a slight excess of intermittent theta waves and slowing of background activity. The symptoms of dizziness, sweating and vomiting which occurred from twelve to fifteen minutes after he ate a meal were interpreted as the dumping syndrome. After evincing some improvement, the patient was discharged on December 24, 1969, to be followed in the clinic.
Figure 3. Specimen of synovial tissue. A, low power view showing marked thickening due principally to infiltration by reticulohistiocytic giant cells. 8, high power view showing typical polygonal multinucleated giant cells of reticulohistiocytic granuloma in synovium. Original magnification x 142 (A), x 390 (6); both reduced by 45 per cent.
Figure 4. Xanthelasmas are visible on the upper lids. Proptosis and pseudoptosis are present, and the discoloration cf dcrmatomyositis remains around the eyes.
834
Because of increasing weakness, he was readmitted on March 23, 1970. Electromyography again demonstrated a myopathic pattern in all muscle groups. Roentgenograms revealed continued periarticular demineralization of the wrists, fingers and knees. Intermediate strength purified protein derivative gave a negative test but second strength purified protein derivative was strongly positive. Because the patient continued to take prednisone, albeit in reduced dose at 15 mg a day, a course of isoniazid was started on the strength of this test. With the reduction of prednisone to 10 mg daily the patient experienced increasing joint pain, with weakness, fever and nausea. New crops of nodules appeared on the skin. Increased prednisone dosage again lessened his symptoms, but the nodules remained unchanged. On May 3, 1970, a course of azathioprine was begun in doses of 200 mg daily, reduced to 150 mg a day for maintenance after one week. Within two weeks definite symptomatic improvement began, including regression of existing nodules without development of new ones. The patient was discharged on May 12, 1970, taking prednisone in doses of 20 mg daily. Three months later azathioprine therapy was discontinued because of a renewed bout of vomiting, although there was no evidence that it was related to the therapy. The patient was readmitted on August 8, 1970, for extraperitoneal Closure of the transverse colostomy, and discharged on September 2, 1970. During the interval before his next admission he took 30 mg of prednisone daily. Xanthelasmas developed on the eyelids (Figure 4) and a large orange-grey nodule appeared on the left lower lid. He gradually grew weaker, and so was readmitted on March 8, 1971.
The American
Journal
of Medicine
MliLTlCENT9lC
The oniy new findlng at this time was marked diminution of grasp owing to limited flexion at the proximal interphalangeal and metacarpophalangeal joints. Decreased dorsiflexion of the feet and diminished motion of the interphalangeal joints of the toes were also present. Proximal muscular wasting with weakness and interosseous wasting were detected. Deep tendon reflexes continued to be hyperactive, and a mild sensory polyneuropathy was present. Because of continued marked anemia. bone marrow was taken both by aspiration and by trephine biopsy of the iliac crest. Minimal osteoporosis and essentially unremarkable marrow were found. Granulopoiesis, cellularity and megakaryock*es were normal, erythropoiesis normoblastic and the myeloid-erythroid ratio was 1O:l. On scan, the thyroid gland was normal in size, shape, position and distribution of radioiodine, without indication of a nodule within the gland. Aspirated knee fluid contained 40 mg per cent triglycerides on the left, 20 mg per cent on the right, with cholesterol less than 20 mg per cent in both knees. No beta lipoproteins were found. The major component was alpha lipoproteins. Pulmonary function studies revealed vital capacity at the lower limit of normal (82 per cent) with a slight decrease in inspiratory capacity (59 per cent). The residual volume was greatly increased to almost twice the value of
RETlCULOHISTIOCYTOSIS--EHRL.iCH
ET
AL.
predicted norrr,al (3.180/1,620. 196 per cent). Total lung capacity remained within normal limits (6,590/6.150, 107 per cent). The ratio of reserve volume to total capacity was increased (48 per cent versus a normal of 26 per cent). All parameters for expiratory airflow showed a slight decrease, The single breath carbon rnonoxide diffusing capacity was wlthin normal limits (26.7 ml/minute/ mm Hg). Resting arterial blood gases showed normal oxyger! tension (pot,) (oxygen tension 88, oxygen saturation 96.8, carbon dioxide tension 31, pH 7.46). A decrease in carbon dioxide tension (pCO,), with respiratory alkalosis, was probably due to transient hyperventilation. Signs of minimal airway obstruction were noted. Chest roentgenograms once again documented transient enlargement of hliar lymph nodes. Electroencephalogram was now within normal limits. Ophthalmologic examination revealed correctable myopia; exophthalmus, probably due to retrobulbar infiltrate; blue scleras; heliotrope lids; and conjunctival infiltrate. Microrefractive cholesterol-like bodies were seen in the retina. Posterior subcapsular cataracts, considered a result of corticosteroid therapy, were also encountered. The patient refused biopsy of any of the eye lesions. However, when the extensor tendon sheaths at the wrists became enlarged, he permitted surgical removal of
Figure 5.
A, specimen of tenosynoviaf tissue, low power view. 8, high power view showing infiltration by reticulohistiocytic giant cells. C, specimen of skin nodule, low power view showing dense infiltrate of multinucleated giant cells in connective tissue lattice. Cells have ground-glass cytoplasm. D, high power view of C. Original magnification x ;42 (A and C), x 471 (8 and D); A, R and C reduced by 47 per cent, D reduced by 22 per cent.
Volume
52,
June
1972
835
MULTICENTRIC
RETICULOHISTIOCYTOSIS-EHRLICH
ET AL.
these, as well as several painful nodules on the finger. Once again, all these tissues bore the characteristic features of reticulohistiocytic granuloma (Figure 5). Reexamination of previously removed tissues now disclosed similar lesions in the stomach (Figure 6), at the base of the ulcers and in perirenal fat (Figure 7). At the time of discharge on April 8, 1971, the patient was taking 20 mg of prednisone daily. His affect was more child-like than ever; psychologic testing established an intelligence quotient of 83 (Wechsler Adult Intelligence Scale), and projective testing suggested a fearful, timid, rigid and immature personality pattern, but without signs of or-
ganic brain disease.
COMMENTS
Figure
6.
Low
power
view
showing
shallow
ulcer
in
mucosa of resected stomach. B, high power view showing focal aggregates of reticulohistiocytic giant cells in gastric submucosa at base of shallow ulcer. Original magnification x 60 (A), x 450 (5); both reduced by 48 per cent. See legend on facing page
Specimen of perirenal fat. High power view Figure 7. showing reticulohistiocytic giant cells in perirenal fat. Original magnification x 534; reduced by 47 per cent.
836
A recent review of multicentric reticulohistiocytosis uncovered thirty-three patients reported to have this condition [l]. A definition of the syndrome has emerged only gradually. Initially, because of the prominent skin lesions, reticulohistiocytic granuloma concerned chiefly dermatologists and pathologists. Although the syndrome is defined by its anatomic features, it has been expanded by the frequent concurrence of various clinical manifestations. For some of these, anatomic correlation with the lesions of reticulohistiocytic granuloma is as yet lacking. When reticulohistiocytic granuloma involves multiple sites, the term multicentric reticulohistiocytosis [2] is preferable. Viewed as a systemic disease of unknown cause but related to lipid storage diseases, multicentric reticulohistiocytosis produces nodules of skin, synovium, bone and mucosa. The term lipoid dermatoarthritis [3] has been employed to emphasize the areas of clinical predilection but is probably unduly restrictive. Most peripheral joints are involved, often with mutilating arthritis [4], as well as the cervical spine [5]. Swelling of the tendon sheaths at the wrists resembles ganglia or, more characteristically, rheumatoid arthritis. As the illness would undoubtedly be diagnosed as rheumatoid arthritis in the absence of biopsy, one must perforce question whether multicentric reticulohistiocytosis as a cause of the symptoms and signs may not be more common. Arthritis, skin nodules, weight loss, pleuritis, weakness, fever and paresthesias are the symptoms most frequently encountered in multicentric reticulohistiocytosis [l]. The disease usually develops insidiously and becomes self-limited after a number of years. The severity of arthritis may range from disconcerting to mutilatimg, and the skin lesions may be pruritic or painful. Weakness and loss of weight are prominent symptoms, as is intermittent fever. Certain features of the joint disease have been cited as permitting ready differentiation from rheumatoid arthritis. These include frequent distal interphalangeal joint involvement, a remittent course and ultimate development of secondary degenerative changes. As proved rheumatoid arthritis may be characterized by
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these same features, they w II not serve as reliable bases for differentiai diagnosis. Skin nodules may be present almost anywhere, most prominently on the face and hands. They may be difficult to distinguish ,:linically fcom rheumatoid nodules when they occur peripherally. Mucosal nodules are most common in the nose and mouth. Flat yellowish lesions of the lids coexist in more than a third of the reported cases, including ours. In the few instances in which biopsies were performed, the histologic characteristics have been those of true xanthelasmas rather than reticulohistiocytic granuloma [l]. Myositis and myotonia were reported in a case of multicentric reticulohistiocytosis by Anderson and coworkers [6]. Although the electromyogram was suggestive, and biopsy showed diffuse nonspecific interstitial chronic myositis. serial enzyme studies were within normal limits. Two other patients have previously been described in whom muscle weakness or pain was suggested [2,7]. In our patient, a clinical diagnosis of rheumatoid arthritis complicated by dermatomyositis was maintained for more than two years. However, with the development of multiple peripheral skin nodules, biopsy disclosed the histologic features of reticulohistiocytic granuloma. Biopsy of the synovium of the knee also demonstrated the characteristic lesion. A review of the variety of tissues previously obtained at surgery was then carried out. These included skin, subcutaneous fat, skeletal muscle, axillary lymph nodes, renal parenchyma and perirenal fat, stomach and colostomy stoma. With this review it became apparent that there was unobtrusive but definite involvement of most of these tissues by infiltrates of the characteristic cells of reticulohistiocytic granuloma. In the biopsy specimens of the skin, subcutaneous fat and skeletal muscle, the cells clustered in the areolar tissue conspicuously adjacent to blood vessels. The kidney biopsy specimen showed no typical ceils within the renal parenchyma, but the specimen of perirenal fat exhibited numerous typical aggregates. Both of these biopsy specimens antedated the institution of corticosteroid therapy and represented tissues sampled within one month of onset of the acute illness. The stomach was removed ,three weeks after the introduction of massive corticosteroid therapy. The multiple shallow ulcers found in the antrum were originally attributed to corticosteroids or stress. They consisted of denuded mucosa with a base of inflamed granulation tissue, and exhibited none of the fibrinoid change usually associated with peptic ulceration. In the submucosal areolar tissue below the base of the ulcer, definite aggregates of typical giant cells of reticulohistiocytic granuloma were recognizable. The loose tissue at the site of the revision of the colostomy showed occasional giant cells, particularly in relation to residual suture. Their morphology, how-
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ever, was not sufhciently typical to warrant Iclusion as a definite site of involvement The presence of the typicai cells at the base of the gastric ulcers permits speculation as to cause and effect. Tt-ree possible explanations may be entertained. One alternative IS that the association of cells and ulcers m,ay be coincidental and unrelated. Another explanation suggests that the accumulation of these cells IS a response to injury which rn the stomach may have been induced by either corticosteroids or stress. In support of this contention are the observations by Hanauer of classic nodules developing on the bridge of the nose at the site of continued pressure by eyeglasses [8]. Additionally, our patient provides further support for this hypothesis in the development of characteristic nodules in an area chafed by the colostomy strap. A third explanation would presume the ulcer to be secondary to the focal accumulation of reticulohistiocytic granuloma cells. The cytoplasm of the typical cells at most sites gave positive staining reaction with periodic acid-Schiff after diastase digestion. This finding is consonant with that of most other investigators and has been taken to imply a glycolipid content. Multicentric reticulohistiocytosis has been classified by some among the lipidoses [9]. The predilection of fatty tissues and the frequent association of the xanthelasmas in such cases per. haps has some further inferential value. Although a single previously reported electron microscopic examination of such ceils has been interpreted as showing lipid vacuoles within the cell [l], our own studies were unable to confirm this observation (Figure 8). From the time the lesion was detected in our patient, various laboratory, electrodiagnostic and roentgenographic studies were undertaken to discover diseases or lesions that had been reported by others to occur in conjunction with multicentric reticulohistiocytosis. No evidence of cancer, diabetes or thyroid disease could be demonstrated, but coexistent tuberculosis could not be completely excluded; a positive reaction to second strength purified protein derivative provided the sole evidence for this possibility. The transient enlargement of hilar lymph nodes paralleling the waxing and waning of the skin lesions may reflect involvement by multicentric reticulohistiocytosis. Progressively throughout the course, increasing bulging of the eyes associated with pseudoptosis was noted. During the most recent admission, xanthelasmas and nodules were detected about the eyes. Conjunctival infiltrates resembled lipid deposits, and microrefractive cholesterol-like bodies were seen in the retina. It was the opinion of the ophthalmologists that most of these lesions resulted from the same process producing the lesions of the skin, synovium and other sites. However, attempts at biopsy were rejected by the patient, so that the exact nature of the lesions remains speculative. Fistula formation, poor healing of the colostomy
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Tissue fixation was in 2 per cent gfutarafdehyde fin cacodylate buffer at pH 7.4) Figure 8. for one hour at 4°C. This was followed by postfixatron in 2 pef- cent osmium tetroxide in the same buffer for one hour in the cold. Tissue was dehydrated through graded ethanols and propylene oxide and imbedded in Epon 812. Thin sections on 200 mesh copper grids were stained with 70 per cent methanolic uranyl acetate followed by Venable’s lead citrate. Preparations were examined in a Hitachi 11A electron microscope. There appears to be a membrane surrounding the polylobate nucleus; artifact cannot be completely ruled out as the basis for this seeming separation. There are heavy deposits of chromatin at the periphery of the nucleus. The cytoplasm contains many densely staining granules, which The cells are contained in a dense meshwork of collagen. cannot be otherwise characterized. Nothing which can be characterized as lipid deposits is identifiable. Original magnification x 10,000 (A), x 25,000 (B), x 80,000 (C); all reduced by 35 per cent.
wound, frequent infections, and evidence of malabsorption and dumping syndromes may be presumed to be the result of therapy (both corticosteroid and surgery) and of protein abnormalities and anemia. Even though multicentric reticulohistiocytosis has been described as involving the heart, It would be difficult to ascribe the myocardial abnormalities detectable on electrocardiography to multicentric reticulohistiocytosis in this patient. No ready explanation for the renal and pulmonary abnormalities has as yet been discovered. It is possible to speculate that central nervous system involvement was a possible cause of his intellectual impairment; his acceptability for responsible military duties in time of war suggests that he had functioned on a more adequate level previously and that his childishness represented recent deterioration. Joint fluid was analyzed in an attempt to delineate
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its characteristics in this disease. These studies disclosed an essentially inflammatory type of fluid. Rheumatoid factor was detectable in a titer of 1:40 on one examination, but the fluid was not digested with hyaluronidase before testing. Lipid profile reveals very low cholesterol and triglyceride content [lo]. These extremely low values provide further basis for the speculation that the reticulohistiocytes comprising these lesions take up lipids from surrounding media. Alpha lipoprotein, which contains a higher concentration of protein than beta lipoprotein, was the major component of the joint fluid. Mutilating ar-thropathy has been described repeatedly in multicentric reticulohistiocytosis, but this patient has ;as yet been spared this development. However, he has had clinical dermatomyositis for four years, for which corticosteroid therapy has been offered. Satis-
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factory therapy for this disease has yet to be established. Corticosteroids, immunosuppressive agents (in one case, azathioprine seemed helpful [8]) and supportive measures have been used with varying degrees of success. As in other diseases characterized by spontaneous remissions, the effect of any mode of therapy must be evaluated with skepticism. On the basis of studies on this patient to date, it is tempting to speculate that multicentric reticulohistiocytosis represents a generalized disease in which the response to trauma or other stimuli is the formation of reticulohistiocytes. These cells may have the property of incorporating lipids and can probably occur in most areas of the body. In the patient described, multicentric reticulohistiocytosis presented clinically as rheumatoid arthritis and dermatomyositis with demonstrated involvement of stomach, tendon sheaths, joint synovium, and deep and superficial fatty depots. The gastric ulcers were morphologically associated with infiltrates of typical reticulohistiocytic granuloma at their bases. Sites of involvement implied by clinical evidence include conjunctivas, retina, orbital tissues, muscle and hilar lymph nodes. Abnormalities of renal and pulmonary function and cerebration, and profound anemia also accompanied his disease. No associated cancer was found, and tuberculosis could not be proved, although suppressive therapy was employed because of the large and continued doses of corticosteroids re-
quired to combat the life-threatening myositis. Thyroid studies remained within normal limits. Lipid profiles consistently recorded low cholesterol determinations and normal triglycerides. Joint fluid contained no beta lipoproteins and an absolute increase in alpha lipoproteins, together with an extremely low value for lipid components.
ACKNOWLEDGMENT Dr. Nosheny part
served
by a grant
Pennsylvania ter,
a clinical
from
the
Chapter
fellowship
Arthritis
to Albert
supported
Foundation, Einstein
in
Eastern
Medical
Cen-
Philadelphia. Electron
microscopic
examination
was
carried
out
by Lewis
W. Johns, Department of Cell Biology, Division of Pediatrics. The following participated in the care and evaluation of the patient: Drs. E. U. Keates and L. Magargel (ophthalmology), E. M. Cohn (gastroenterology), A. Bank, G. Vakkur and M. McGlamery (neurology), M. Kajani (hematology), A. D. Bannett and M. S. Kauffman (surgery), J. Rosenbaum (renology) and P. Kimbel and H. Rotman (pulmonary). Dr. S. Winsten performed specialized biochemical studies and Drs. A. M. Di Piero and S. H. Cohen provided additional clinical assistance. A partial description of this case appeared as an abstract [ 111.
REFERENCES 1.
multicentric
Barrow MV, Holubar K: Multicentric reticulohistiocytosis. A review of 33 patients. Medicine 48: 287, 1969.
7.
2.
Goltz RW, Laymon CW: Multicentric reticulohistiocytosis of the skin and synovia. Arch Derm Syph 69: 717, 1954.
8.
3.
Warin RP, Evans CD, Hewitt M, Taylor AL, Price CHG, Middlemiss JH: Reticulohistiocytosis (lipoid dermato-arthritis). Brit Med J 1: 1387, 1957.
4.
Johnson HM, Tilden IL: Reticulohistiocytic lomas of the skin associated with mutilans. Arch Derm 75: 405, 1957.
5.
Martel W, Abell MR, Duff IF: Cervical spine involvement in lipoid dermato-arthritis. Radiology 77: 613, 1961. Anderson TE, Carr AJ, Chapman RS, Downie AW, MacLean GD: Myositis and myotonia in a case of
6.
840
9.
granuarthritis 10. 11.
reticuiohistiocytosis.
Brit J Derm 80:
39, 1968. Montgomery H, Pokey HF, Pugh DG: Reticulohistiocytoma (reticulohistiocytic granuloma). Arch Derm 77: 61, 1958. Hanauer L: Reticulohistiocytosis, presented at the VII European Rheumatology Congress, Brighton, June, 1971. Barrow MV, Sunderman FW, Hackett RL, Colvin WS: Identification of tissue lipids in lipoid dermatoarthritis (multicentric reticulohistiocytosis). Amer J Clin Path 47: 312, 1967. Huttl S: Synovial effusion. Acta Rheum Balneol 5: 15, 1970. Nosheny SZ, Katz WA, Young I, Ehrlich GE: A new rheumatic syndrome associated with reticulohistiocytic granuloma (abstract). Arthritis Rheum 13: 341, 1970.
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