Nodular Rheumatoid Disease of the Lung with Cavitation By C. D. NOONAN, FLETCHER B. TAYLOR, JR. AND EPHRAIM P. ENGLEMAN Nodular rheumatoid disease of the lung is an established clinical entity, having been recorded previously in 14 cases. The 14 cases were reviewed, with emphasis on their differentiation from nodular lung disease associated with pneumoconiosis and rheumatoid arthritis (Caplan’s syndrome). This report adds a fifteenth case to the literature with the characteristics of the second recorded instance of roentgenologically demonstrable cavitation of pulmonary nodules, an associated high F-I1 titer, and a silica-free biopsy specimen. Nodular morbo rheumatoidee del pulmon es un establite entitate clinic in tanto que ill0 ha previemente essite reportate in 14 casos. Iste 14 casos es revistate, con attention particular prestate a lor differentiation ab nodular morbo pulmonari associate con pneumoconiosis e arthritis rheumatoidee (syndrome de Caplan). Le presente communication reporta un caso additional que possede le characteristicas-jam notate in le secunde caso in le litteratura-de roentgenologicamente demonstrabile cavitation del nodulos pulmonari, un associate alte titro de F-11, e un specimen bioptic libere de silice. N UMEROUS AND VARIED pulmonary maniiestations of rheumatoid arthritis have been described often since Copeman, Ellman, and Kersley’s1 original report in 1947 and Ellman and Ball’s2 in 1948. Only 13 cases, however, of microscopically proved discrete rheumatoid nodules of the lung in patients without known occupational exposure to dust have been reported. This report of a patient with rheumatoid arthritis and cavitating rheumatoid nodules of the lung adds another case to the literature. The characteristics in this case were roentgenologic evidence of cavitation of the pulmonary nodules, an associated high F-I1 titer for the rheumatoid factor, and biopsy proof that the rheumatoid nodules were free of silica compounds. CASEREPORT A 51 year old retired businessnian was admitted to the University of California Hospital (San Francisco) on September 17, 1961, because of intermittent fever and arthralgia of 1 month‘s duration. He had been well until January 1957 at which time he was examined at the Mayo Clinic for polyarthritis. At that time synovial reaction involved the second and third metacarpophalangeal joints of the left hand, the second metacarpophalangeal joints of the right hand, and the right wrist. Systemic manifestations were absent. Both shoulder joints were slightly tender with slight limitation of motion. Urinalysis and complete blood counts were normal and the results of a serologic blood test for syphilis, negative. A serum uric acid value was 4 mg. per cent and one L.E. preparation failed to show L.E. cells, The chest roentgenogram showed evidence of left pleural reaction without other abnormalities. Roentgenograms showed that the feet, shoulders, cervical spine, and the right wrist and hand were normal except for narrowing of the fifth cervical interspace. A regimen of rest, physical therapy, and salicylates was advised. By September 1957, aspirin no longer relieved the patient’s symptoms. He was given two From the Department of Radiology, and the Rheumatic Disease Group of the Department of Medicine, University of California School of Medicine, San Francisco, Calif. 232 ARTHRITISAND RHEUMATISM,VOL.6, No. 3 (JUNE), 1963 NODULAR RHEUMATOID LUNG DISEASE 233 1-week courses of intensive prednisone therapy ( 4 0 to 60 mg. per day) for exacerbation of pain, swelling, and limitation of motion of both knees and of the left shoulder. Thz patient improved and was maintained on prednisone, 10 mg. per day, until December 1960 at which time severe low back pain developed. During the period from 1957 to 1961, the patient’s hemogram and urinalysis had been normal on two occasions. A coccidioidin skin test gave a negative result and a roentgenogram of the chest on May 5, 1958 showed that the previously described left pleural reaction had cleared completely. At the time of admission to the University of California Hospital, the patient’s complaints were of 1 month‘s duration. They consisted of myalgia, weakness, afternoon fever up to 102 F., and swelling and tenderness of the right knee and both ankles. There had been no weight loss. The patient was receiving prednisone, 10 mg. daily, and 9 Gm. of acetylsalicylic acid. No family history of rheumatoid arthritis was obtained. A review of systems was noncontributory. In particular, the patient had had no symptoms referable to the pulmonary or gastrointestinal systems. The patient was of husky build, 5 feet 10 inches in height, and weighed 150 pounds. His blood pressure measured 120/60 mm. Hg. He suffered moderate distress upon movement of shoulders, elbows, metacarpophalangeal joints, knees, and ankles. No evidence of subcutaneous nodules or of uveoparotid disease was seen. The thyroid was not enlarged and lymph nodes were not palpable. The heart and lungs were normal on examination. No liver or spleen enlargement was noted. Localized bone tenderness or limitation of motion of the back was not present. Erythema and swelling over the right knee and both ankle joints, and slight limitation of motion due to pain were present. Joints were not deformed. Laboratory data included the following: Urinalysis was normal. Packed cell volume (P.C.V.) was 37 mm. with a sedimentation rate (Wintrobe) of 36 mm. per hour. The white blood cell count was 11,200 with 86 per cent neutrophils. On October 3, 1961 the chest roentgenogram showed evidence of multiple, well circumscribed parenchymal nodules located in the lung periphery and subpleural area (fig. 1 ) . At least two foci suggested definite central necrosis on the initial chest examination. No abnormal hilar adenopathy or pleural reaction was noted. The initial roentgenographic impression was that of multiple metastatic parenchymal nodules, some of which were thought to show cavitation. A skeletal survey on October 4, 1961 showed an over-all demineralization in the medullary cavities of the long bones (i.e., femora, humeri) with spotty demineralization in the cervical spine. Follow-up roentgenograms of the chest on November 20, 1961 and January 15, 1962 showed progression of the lung lesions, indicated by enlargement of the initial solid lesions, more foci apparent, and the excavating lesions more discernible (i.e., air fluid level) as if “exploding” (fig. 2 ) . The patient was followed for 3 months prior to thoracotomy and the radiologist’s impression was, “multiple parenchymal infiltrates, well circumscribed, some of which show definite cavitation. . . . Rheumatoid nodules should be strongly considered in the differential diagnosis.” The initial roentgenographic findings in the chest led to efforts over a 3-month period to exclude metastatic carcinoma. During this time the patient was admitted on September 17, 1961 and again on January 15, 1962. The studies included examination of aspirated sternal bone marrow, a biopsy of iliac crest bone marrow, and determinations of serum calcium, phosphorus, and alkaline acid phosphatase, all of which were normal. The results of skin tests for coccidioidomycosis, histoplasmosis, and tuberculosis were negative. Examination of three preparations for L.E. cells showed none. The total chemical serum protein was 5.4 with a reversed A/G ratio ( 2 . U 3 . 3 ) and the cephalin flocculation test gave a 3 plus result after 48 hours. The serum glutamic oxalacetic transaminase (SGOT) determination was 44 units. Electrophoresis revealed a low albumin peak ( 2 8 per cent total area; normal is 41 to 63 per cent), a high alpha-2 peak (20.5 per cent total area; normal is 7.1 to 16 per cent), and a slightly elevated gamma peak (25.5 per cent total area; normal is 234 NOONAN, TAYLOR AND ENGLEMAN Fig. 1.-Initial chest examination. Frontal and lateral views. Fig. B.--(Left) Frontal view of excavated lung lesion on January 15, 1962. (Right) Lateral view. Note air fluid level (arrow) and subpleural solid lesion. 11 to 24 per cent). The F-I1 hemoagglutination test showed a positive reaction to ii dilution of 1:1,764,000(tanned sheep cells with human Fraction 11). A diagnostic thoracotomy was done on January 23, 1962 and two nodules measuring approximately 2.5 x 1.5 x 0.5 cm. were removed from the anterior segment of the left upper lobe. On sectioning, the lumen of each nodule was filled with a yellowish-green thick pasty material mixed with anthracotic pigment. On microscopic examination, each nodule consisted of a central necrotic area of eosinophilic debris and fibrillar basophilic material, necrotic cells, and inflammatory cells (predominantly neutrophils) The necrotic area was rimmed by epithelioid or fibroblastic cells which showed peripheral palisading in (some) areas. This zone of palisaded cells was in turn rimmed by a zone of connective tissue, the interstices of which were filled with plasma cells, lymphocytes, and monocytes (fig. 3 ) . No giant cells were noted. There was no evidence of vasculitis and no organism could be . NODULAR RHEUMATOID LUNG DISEASE 235 Fig. 3.-Photomicrographs of a nodule in the lung showing typical nodular granulomatous lesions with central necrosis, palisading, and peripheral cellular infiltration. Hematoxylin and eosin stain. (Left) Original magnification ( 1OX) ; (right) (40X). demonstrated using acid-fast or PAS stains. Cultures for acid-fast bacteria and fungi were negative. The nodule was incinerated and the ash assayed for silica content, but none could be seen. The final diagnosis was granuloma of the left upper lobe of lung with central necrosis consistent with rheumatoid arthritis.394 The patient’s postoperative course was uneventful and the patient was discharged 7 days after the operation with instructions to continue 2.5 mg. of prednisone and 0.6 Gm. of aspirin, four times a day. Follow-up roentgenologic findings on January 19 and February 14, 1962 showed progressive improvement in the left pleural reaction which had been present at operation. Central cavitation developed in at least one additional focus of solid infiltrate. DISCUSSION The 14 cases of nodular rheumatoid disease of the lung reported previously,5-13J7and the one in the present report are summarized in table 1. The ages ranged from 30 to 65 years and 10 of the patients were men. Our case adds further weight to the incidence of nodular rheumatoid disease of the lung in men. The occupational history, important in excluding associated pneumoconiosis (Caplan’s syndrome),le w a s reported in only 7 of the 15 patients. One of these was a coal miner in whom the nodules were described as not absolutely typical of the lesions in Caplan’s syndrome.*l Our patient h a d worked as a clerk in Chicago since 1937, and prior to that time was in the floral business. There was no history of exposure to irritant dusts. Subcutaneous noduEes were reported i n four patients, and in three others 236 NOONAN, TAYLOR AND ENGLEMAN Table 1.-Non-Pneumoconwtic, Necrobiotic Rheumatoid Lung Nodules (Reported) Clinical Data No. Age Sex Occupation Year Author 1954 Bevans e t al.' Case 2 41 ChristieR Case 1 59 SeCretaW Subcut. nodules none F 67 Ellman et al." 65 M jeweler (retired ) Mahe+ 64 housewife ext. occipital protuberance: left olecranon, forearms, ischium. F Skogrand* 6 41 43 F 8 62 M 9 57 M over right olecranon 1958 Greshamand Kellaway'O 1959 Flatleyl? 10 62 M factory foreman: no exposure to coal. dusts or vapors Horlerand Thompson" Case 8 11 51 coalminer forearm Robertson and Brinkma+ 12 bricklayer both wrists, fingers, arms, shoulders, scapulae. SaeNrn. ears. scalp, knees. ankles. feet 1961 M 54 M Chest X-ray Initial thickened left pleura 9 mo. fibrosis LUL Oct. 1943; gross cardiac enlargement (? effusion) 19 yr.. 1934 to 1953 cortisone, 71 days cardiac enlargement: left pleural effusion 21 yr. 1932 to 1953 cortisone nodular lesions interpreted as Tbc; globular heart 7 mo., Apr. to Nov. 1960 ACTH parenchymal densities both bases, Aug. 1950 4 yr.. 1950 to 1964 ACTR Sept. 1963 cortisone prolonged therapy 10 yr., 1938 to 1948 M 7 Steroid therapy cortisone: corticotrophin 16 yr., 1936 to 1962 34 Yr., 1913 to 1947 F 1956 Duration lung nod. 15 yr. 1934 to 1949 M Case 3 Duration R.A. E e p t . 1960 21 yr. 10 yr., 1948 to 1958 6 wk. 4yr., 1948 to 1952 1952tm 1966. unchanged onset Feb. 1959 cortisone LLL infiltrate with effusion mass RML: auspect carcinoma hydrocortisone chronic lung process; acute pleural change; pulm. nodules suggest metast. 237 NODULAR RHEUMATOID LUNG DISEASE Table 1.-(Continued Laboratory Data Follow-UP Proof F-II* L.E. left lower lobe consolidation, effusion Oct. 1946.9 mo. prior to death, round dense shadow 6 em. RUL right pleuuraleffusion: calcified pleural adhesions, left base 1:6120 neg. 1966 nodular shadows both lung f i e . &usion 1:128 neg. Autopsy Biopsy several small circumscribed yellow nodules; 3 mm. LUL soft and necrotic granulomas of the lungs, not tuberculous firm white subpleural nodules 2 to 3 em.; two on left, three on right fibrinous pneumonia foci undergoing central necrhsis. spreading edge sharp encapsulated necrotic mass with fibrotic edges 7 em. RUL indistinguishable from a subcutaneous PeriaJticular nodule of rheumatoid arthritis numerous spherical lesions up to 1 to 2 cm. in periphery, and subpleural soft, cheese-like centers occasional rheumatoid lesion in the lung parenchymal nodules 1 cm. in diameter two large lung nodules probably rheumatoid, not to be attributed to tuberculosis microscopic lung granuloma rheumatoid granulomae in lungs macroscopic grain-sized nodules (lung) rheumatoid granulomas in lunm macroscopic pinhead to pea-sized nodules in placea to coalesce rheumatoid granulomas in lungs; nodules grayishyellow coalesced into larger yellow infiltrates LUL nodules Typical appearance of rheumatoid disease; rheumatoid granuloma 1968 thoraeotonw; pleura thickened gray-white, 8 x 2 x 1 cm. dense white fibrous firm lesion, surrounding atelectasis and fibrosis histologic appearance of rheumatoid nodules; one rheumatoid lung nodule, several subpleural 1962 thoracotomy; inter- identical with thoue found in a rheumatoid nodule lobar effusion; small nodule right apex RLL - Pa. Pathologic report nodular areas easily palpated; one excised from superior segment of lower lobe large granuloma; central zone had undergone a little cavitation 238 NOONAN, TAYLOR AND ENGLEMAN Table 1.4Continued) Clinical Data Sex Occupation No. Age Year Author 1962 Sieniewicz et al.” Case 1 13 Case 2 14 41 M Subeut. nodules none Duration R.A. 1 yr., 1959 to 1960 Duration lung nod. Steroid therapy 1 mo. several nodular lesions at both bases (peripheral), localized pleural reactive changeonthe right nodular lesions, both uDper lobes, with right pleural effusion 1 mo. 30 F 1963 Noonanetal. 15 51 M husinessman (retired) none 5 yr., 1957 to 1962 Chest X-ray Initial Oct. 3, 1961 to present ( 3 mo.) cortisone well circnmscribed lung nodules (peripheral and subpleural). some with cavitation nodules of other visceral organs were described.8*9This distribution reflects the potential dissemination of nodules in rheumatoid arthritis. In our patient, however, no evidence of subcutaneous nodules was present. The duration of this patient’s rheumatoid arthritis was 4 years, whereas that in the reported patients varied from 1 month to 21 years. Our patient and 6 of those reported were receiving steroid medication. Although the reports of the other eight did not mention steroid therapy, additional inquiry verified that it had not been used in those patients.6.9-11J’In none of the literature is a relationship suggested between this medication and the formation of pulmonary rheumatoid nodules. Reports of chest roentgenograms were given in 10 of the 14 previously reported cases. Five of these described discrete pulmonary nodules, and in Sieniewicz’s case 1, cavitation was reported. To our knowledge, our patient was the second whose roentgenograms gave evidence of cavitation. This finding is expected ordinarily in 9 per cent of primary lung tumor cases and in 4 per cent of metastatic lung tumors.14 Thus, seen initially in a patient with rheumatoid arthritis, the possibility of malignant disease was considered. The F-11 test* was done in four previous patients with pulmonary nodules, one with a positive result at a dilution of 1:5120.12In our patient, the F-I1 test gave positive results at a dilution of 1:1,764,000. A titer this highly concentrated has been associated more frequently with rheumatoid arthritis in patients who have subcutaneous nodule formation and associated pulmonary disease (i.e., fibrosis, Caplan’s syndrome, pleural nodules) .15 The search for L.E. cells was successful in one of five previously reported patients. In our patient, ‘See footnote to table, facing page. 239 NODULAR RHEUMATOID LUNG DISEASE Table l..--(Continued) Laboratory Data Follow-up Proof F-11* L.E. Cavitation in one nodule 1 mo. later at right base; no new lesions seen atter operation pos. neg. thoracotomy 2.6 em. nodule RML, grayish pleural exudate over lower lobe with communication to another necrotic nodule behind visceral pleura post-operative: no new lesions; reduction in size to disappearance 1 year later pos. neg. thoracotomy serous effusion on right, multiple small nodules with exudate over lung surface; at wedge resection, escape of thick grayish material of toothpaste viscosity Progression in sire and foci of cavitation 1:1.'764 neg. thoracotomy nodules. left upper lobe; lumen on section yellow-green thick pasty material x10" Autopsy Biopsy Pathologic report histoloaic flndinns nonspecific but have been described as being typical of rheumatoid nodule;%gassociated nonnecrotizing vasculitis granuloma of the lung with central necrosis consistent with rheumatoid arthritis; ash assay: no silica content *The reported rheumatoid factor tarts varied as to method. Flatley used the latex agglutination method; Horler and Thompson used the Rose Waaler test; and Sieniewici used the Hyland Slide latex fixation method. Our method used tanned sheep cells with human Fraction 11. no L.E. cells were found in three preparations, Of the cases reported, nine were proved at necropsy, and six, including the one reported here, were proved by biopsy. From the preceding review it will be noted that the presence of nonpneumoconiotic, nodular, necrobiotic rheumatoid lung disease must rest on a firm clinical diagnosis of rheumatoid arthritis. Evidence must be obtained by history, microscopic examination, and analysis for silica to exclude associated pneumoconiosis or chronic pulmonary disease. In terms of diagnosis, these criteria serve to distinguish nodular rheumatoid disease of the lung from Caplan's syndrome.le This syndrome is characterized by rheumatoid nodules of the lung with rheumatoid arthritis and pneumoconiosis. Moreover, the diagnosis must be differentiated from an associated malignant tumor with cavitating pulmonary lesions, and from necrotizing arteritis, tuberculosis, fungus, Wegner's granulomatosis and histiocytosis X, among others It is apparent that with roentgen evidence of lung nodules with cavitation in patients with rhmeumatoid arthritis, the presence of rheumatoid nodules must be given serious consideration. SUMMARY A patient with nodular rheumatoid lung disease characterized by cavitation of the nodules and by an associated high F-I1 titer is described. A lung biopsy confirmed the diagnosis. The relevant literature is reviewed. 240 NOONAN, TAYLOR AND ENGLEMAN ACKNOWLEDGMENT The authors are indebted to Dr. L. Emerson Ward for supplying data from the Mayo Clinic regarding the patient reported here. REFERENCES 1. Copeman, W. S. C., Ellman, P., and Kersley, G. D.: Aetiology of chronic rheumatism. Proc. Roy. SOC. Med. 40:329, 1947. 2. Ellman, P., and Ball, R. E.: “Rheumatoid disease” with joint and pulmonary manifestations. Brit. M. J. 2: 816, 1948. 3. Collins, D. H.: Subcutaneous nodule of rheumatoid arthritis. J. Path. & Bact. 45:97, 1937. 4. Bennett, G. A., Zeller, J. W., and Bauer, W.: Subcutaneous nodules of rheumatoid arthritis and rheumatic fever; pathologic study. Arch. Path. 30:70, 1940. 5. Ellman, P., Cudkowicz, L., and Elwood, J. S.: Widespread serous membrane involvement by rheumatoid nodules. J. Clin. Path. 7:239, 1954. 6. Christie, G . S.: Pulmonary lesions in rheumatoid arthritis. Australasian Ann. Med. 3:49, 1954. 7. Bevans, M., Nadell, J., Demartini, F. E., and Ragan, C.: Systemic lesions of malignant rheumatoid arthritis. Am. ]. Med. 16:197, 1954. 8. Maher, J. A,: Dural nodules in rheumatoid arthritis; report of case. A. M. A. Arch. Path. 58:354, 1954. 9. Skogrand, A,: Visceral lesions in rheumatoid arthritis. Acta rheumat. scandinav. 2:17, 1956. 10. Gresham, G. A., and Kellaway, T. D.: Rheumatoid disease in the larynx and lung. Ann. Rheumat. Dis. 17:286, 1958. 11. Horler, A. R., and Thompson, M.: Pleural and pulmonary complications of rheumatoid arthritis. Ann. Int. Med. 51:1179, 1959. 12. Flatley, F. J.: Rheumatoid pulmonary disease; report of a case. New England J. Med. 261:1105, 1959. 13. Robertson, J. L., and Brinkman, G. L.: Nodular rheumatoid lung disease. Am. J. Med. 31:483, 1961. 14. Dodd, G.D., and Boyle, J. J.: Excavating pulmonary metastases. Am. J. Roentgenol. 85:277, 1961. 15. Jacobson, A. S., Kammerer, W. H., Wolf, J., Epstein, W. V., and Heller, G.: Hemagglutination test for rheumatoid arthritis; clinical evaluation of sheep erythrocyte agglutination (S.E.A.) test and gamma globulin ( F 11) tests. Am. J. Med. 20:490, 1956. 16. Caplan, A.: Certain unusual radiological appearances in chest of coalminers suffering from rheumatoid arthritis. Thorax 8:29, 1953. 17. Sieniewicz, D. J., Martin, J. R., Moore, S., and Miller, A.: Rheumatoid nodules in the lung. J. Canadian Assoc. Radiol. 13:73, 1962. D. Noonun, M.D., Assistant Professm of Radwlogy and Assistant Radiologist, D t ? p a m of R d i o b g y , University of California School of Medicine, San Francisco, Calif. Churbs Fletcher B . Taylor, M.D., at present, Assistant Research Physician, Cardimascular Research Institute, University of califmnia School of Medicine, Son Francisco, Calif. Ephraim P . Engleman, M .D., Associate Clinicd Professor of Medicine, Rheumatic Disease Group, Department of Medkiw, University of California School of Medicine, San Francisco, Calif.