Autoimmunity and Malignancy

Symposium on Clinical Immunology I

Autoimmunity and and Malignancy Malignancy Gale A. McCarly, McCarty, M.D.* MD.*

Abnormal iInmunoregulation immunoregulation and iInmunogenetics immunogenetics are important determinants of host susceptibility to the development of neoplasia. 14, 40, 62, 64 These factors lnay may also predispose to autoimmune, musculoske4,4, 14,40,62,64 14, 17-19, 17-19, 28, 28. 30, 30. 48, 48, 71 This letal, and connective tissue disease syndromes. 14, hypothesis is supported by the increased incidences of neoplasia in pa50, 56 56 organ transplants,31, 56 ,56 autoimnlune autoimmune tients with immunodeficiencies, 50, svndromes de novo and secondary to treatand connective tissue disease syndromes ment,3, 48, 48, 62, 62, 64 64 and previous neoplasia ne~plasia status after chemotherapy. 4,4, 39 39 The diverse ways in which these clinical disease states might share common pathogeneses have been the subject of several comprehensive and incisive 2&-31, 36, ,16, 56, 56, 62 (i2 reviews. 28-31, The difficulty in defining time of onset of discrete symptomatology due to the tumor, from that due to the underlying or predisposing conditions, prevents an accurate attempt to sumlnarize summarize the literature as regards exact incidences of tumors in connective tissue diseases and the converse. Many cases of malignancy associated with connective tissue disease such as systemic lupus erythematosus (SLE) have been recognized for two decades and are the subject of several excellent papers. 55,, 12,33,36,41,50,51,54,74 12,33,36,41,50,51,54,74 Both solid and hematologic tumors have been noted in most series, with a pre15, 30, ,50, 70 dilection for an association with lymphoproliferative disorders. 6-8, 15,30,50,70 The bases for the associations usually involve the demonstration that patients with the specific connective tissue disease have higher occurrence rates for these malignancies than expected for similar demographic popu15 ,, 28, lations. 15 28, 30, 30, 32, 32, 36 36 Goldenberg has presented an excellent overview of the studies documenting the increase in lymphoid neoplasia with autoimmune diseases. As early as 1955, the progression of patients with autoimmune hemolytic anemia to lymphomas or chronic lymphocytic leukemia was 30 Cammarata et al. reported malignant lymphoma in three patients noted. 30 with SLE and one with rheumatoid arthritis and concluded that their coexistence was not coincidental. 11 The eventuation to reticulum cell sarcoma and occasionally Waldenstrom's macroimmunoglobulinemia in patients

*Assistant

Professor of Medicine, l\fcdicine, and Director, Autoantibody Laboratory, Division of RheuP.rofessor matology, Immunology hnlnunology and Allergy, Georgetown University Medical Center, Washington, D.C. D.e.

America-Vo!' 69, No. No, 3, May 1985 Medical Clinics of North A1nerica-Vol.

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Sj6gren's syndrome was reported by Talal and Bunim. 71 ., 72 Miller and with Sjogren's Lea both addressed the statistical validity of the association of lymphopro36,, 50 Miller estimated that a liferative disorders and autoimmune disease. 36 diffuse connective tissue disease occurred in 1.86 l. 86 per cent of patients with 0,58 per cent of patients having lymphoproliferative disease, as opposed to 0.58 50, 51 Lea, Symmons, and Prior thought that there was a statumors,50, solid tumors. tistically significant higher incidence of malignancy in patients with rheu36, 56, ,'56, 57, 70 Olenick reported that the mortality from lymmatoid arthritis. 36, phoma or leukemia was the same in patients with rheumatoid arthritis or 54 Among contro!s.54 systemic lupus erythematosus as in their age-matched controls. the tumors that Calabro noted in patients with various arthropathies were ovarian, uterine, breast, lung, and stomach, as well as lymphoreticular neoplasms and myasthenia. 5 The associations with dermatomyositis and various malignancies have been well reviewed by Callen. 9, 10 An increased incidence of cancer in patients with pulmonary fibrosis with scleroderma 60 The incidence of malignancies in polyrecognized,60 has been recently recognized. high, 13 13 Systemic vasculopathies can be associated myalgia syndromes is not high. neoplasia, 16 with a variety of neoplasia. Awareness of the nature of autoimmune, musculoskeletal, or connective tissue disease symptoms in patients with diverse neoplasia may foster earlier diagnosis. diagnosis, 3, 10,28,43,59,69 10, 28, 43, 59, 69 The presence of concurrent rheumatic disease does not seem to preclude standard therapeutic intervention. Ml. fH3, 24 well-characterized patients This review presents original research on \vell-characterized musculoskeletal or connective tissue diswith neoplasia and autoimmune, luusculoskeletal symptoms, The pathologic classifications of Caldwell are used to deease symptoms. autoimmune, musculoskeletal, or connective tissue termine whether these autoiIumune, disease syndromes represent direct or indirect effects of the neoplasia, or fH3 A summary of the associations evhave no relationship to the neoplasia. Ml ident in the study and a comparison with the literature is presented for the clinician. Since systemic manifestations of neoplasia are protean, emphasis in this review will center on the autoimmune, musculoskeletal, and connective tissue disease syndromes in patients with neoplasia. 3,3, 6-8, ,59 Although 6-
METHODS Patienl·Selection Criteria Patient'Selection Using current Diagnostic-Related Groupings (DRG)80 codes for concurrent neoplasia, autoimmune, musculoskeletal, and connective tissue disease syndromes, 121 patients were selected from the Oncology Division Registory. The records of 91 inpatients with defined neoplasia who had a complete musculoskeletal examination for subtle findings of rheuluatic rheumatic dis-

601

ACTOIl\IMCNITY AND A:-ID MALIGNANCY AUTOI~IMUNITY

eases were reviewed in this study. These patients were followed for a pathologie classification of Caldmean of 2 years (range, 1 to 4 years). The pathologic determining whether the symptoms could have had well was utilized in deterlnining rr-O direct, indirect, or no relationship to the neoplasia. ~8 Syndrome Classification In this review, musculoskeletal features are defined as localized Inyalmyalgias, arthralgias, or bone pain, exclusive of inflammatory features. Synovitis or systemic inflammatory musculoskeletal features suggestive of an evolving rheumatic syndrome are considered in the category of connective tissue disease syndromes. Connective tissue disease syndromes also inelude clude systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/OM), progressive systemic sclerosis (PSS), Sjogren's syndrome, tem(PM/DM), poral arteritis, ankylosing spondylitis, carpal tunnel syndrome, rheumatoid arthritis (RA), and osteoarthritis (OA). Features of autoimmunity include syndromes characterized by production of autoantibodies and organspecific dysfunction in the absence of the usual criteria for the diagnosis of 33 a systemic connective tissue disease. 33 Autoantibody Determinations Where available, sera were tested for autoantibodies by indirect immunofluorescence on human epithelial (HEp-2) cells, and by counterimmunoelectrophoresis (CIE) against rabbit/calf thymus extracts (RTE/ CTE).42 RESULTS Nature of the Malignancies in Study Patients The types of neoplastic disorders noted in the 91 study patients are listed in order of decreasing frequency in Table 1. The three most common breast, IS or colon. llll Ten common tucarcinomas were those of the lung,23 breast,18 mors accounted for 80 of the 91 patient diagnoses; 11 other malignancies were seen in individual patients (cervix, 2; leukemia, 2; melanoma, hypernephroma, laryngeal, islet cell, mesothelial, embryonal cell, rhabdomyosarcoma cell tumors, 1 patient each). Both solid tUlnors tumors as well as helnahematologic malignancies were noted, as well as several rare tUlnors. tumors. Comparison of Malignancies in Study Group as Compared with Overall Oncologic Division Registry fi-equent malignancies occurring in the 91 study When the ten most frequent patients were compared cOlnpared with the occurrence of these same tumors in the Oncology Division Registry, a general concordance was noted (see Table 1). These data were derived to insure that the patients with concurrent musculoskeletal, autoimmune, or connective tissue disease features did not represent a skewed distribution relative to the occurrence of these maligminor differences between the occurrence of nancies. Although there are Ininor agreement with individual neoplasia in 1983 versus 1984, there is a general agreelnent tumors. Inthe distribution among the study patients for the major solid tUlnors.

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Table 1.

A. A.

.\1CCAHTY .\1CCARTY

Common Tumors in ill Study Group as COlnpared Compared with Oncology Census COl1unon Ttl1nors

STUDY STUDY PATIENTS (80/91)*

ALL PATIENTS, PATIEl'iTS, GEORGETOWN CANCER CANCEH REGISTRY HEGISTRY (1983-1984)

1984

1983

(2:3) Lung (23) Breast (18) Colon (ll) (11) Prostate (7) lymphoma (6) Hodgkin's IYlnphon1a Non-Hodgkin's (4) Myeloma -(4) (4) (:3) Uterus (3) Gastric (2) Ovary(2)

Breast (226) Colon (89) Lung (72) Prostate (61) .\ielanoma (:39) Melanon1a (39) (:35) Cervix (35) (:3:3) Uterus (33) Bladder (28) Rectum (23) (2:3) Ovary (23)

Breast (274) Colon (121) Lung (97) Melanoma (57) Cervix (52) Prostate (51) Rectum (41) Rectun1 (:39) Uterus (39) (:38) Non-Hodgkin's (38) (:35) Ovary (35)

N=80

N=629

N=805

1983-1984

*See 'See text for types of tUlnors tumors in 11 II ren1aining remaining patients.

terestingly, there were more patients (10 of 80) in the study group with lymphoma than was reflected in the concurHodgkin's or non-Hodgkin's IYlnpholna Myeloma rent Oncology Registry for these two tumors for 1983 and 1984. Myelolna was noted in 4 of 80 study patients, but this neoplasm was not among the common neoplasia for either year in the Registry. 10 most COlnmon Occurrence of Autoimmune or Rheumatic Syndromes in Patients with Specific Tumors There were 91 study patients who had neoplasia plus an musculoskeletal, autoimmune, or connective tissue disease syndrome, as compared with 629 and 805 total patients with neoplasia on the Oncology registry in 1984 and in 1983, respectively. To deterlnine determine what percentage of patients autoimmune, or connective tiswith specific tumors had musculoskeletal, autoiInmune, sue disease syndromes, the number of patients with these syndromes were number of patients for both years with specific neodivided by the mean nUlnber terms of percentage of patients with plasia (Table 2). The rank ordering (in terlns musculoskeletal, autoimmune, or connective tissue disease symptoms) did f(Jf neoplasia occurrence in the Regisnot follow exactly the rank ordering for syndromes (27.4 per cent) had lung try. Most of the patients with these syndrolnes tumors, although lung tumors were the third most common tumor on the Registry for both years. Approximately 10.5 per cent of patients with colon carcinoma had musculoskeletal, autoimmune, or connective tissue disease syndromes, as did 12.5 per cent of men with prostate carcinoma, although musculoskeletal sYlnptoms symptoms (bone pain) were more common in the latter neoplasia group. Breast cancer was by far the most common tumor (over 200 cases in both years on the Registry); only 7.2 per cent of breast cancer patients had musculoskeletal, autoimmune, or connective tissue disease syndromes. Approximately 8 per cent of patients with uterine cancer, and 7 per cent of patients with ovarian cancers exhibited autoimmune or connective tissue disease syndromes, but not musculoskeletal syndromes. De-

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AUTOL\IMUNITY AND MALIGNANCY MALIG:\TANCY AUTOI~LMUNITY

Table 2.

Percentage of Patients with Specific Tumors TUlnors and Musculoskeletal, Autoimmune, or Connective COllnectit:e Tissue Syndromes AutoiJnrnune, NO. OF PATIENTS WITH CANCER AND SYNDROMES (191l3--4)/MEA"I NO. OF PATIENTS WITH SPECIFIC (1983-4)/MEAN

TCMOR TUMOR

CANCERS (1983-4) (1983--4)

Lung Breast Colon Prostate Uterine Ovarian

23/84 18/2,50 18/250 111105 11110.5

7/56 3/,36 3/36 2/29

PATIE"ITS PER CENT OF PATIENTS SYNDRO~IES WITH SYNDROMES 27.4% 7.2% 10.5% 12.5% 8.3% 6.9%

nominators were not available to determine the percentage of patients with specific hematologic neoplasia who had musculoskeletal, autoimmune, or connective tissue disease symptoms because these neoplasia were not among the 10 most common turrlors tumors on the Registry. Epidemiologic Features of Study Patients White women between the ages of 61 and 80 years predominated among patient groups, followed by white men in the same age range, and then black women and black men in order of decreasing frequency. One patient was an oriental woman. This frequency distribution was representative of the racial and sexual epidemiology of inpatient admissions to this private University hospital. .This This age distribution was not unexpected in light of the most frequent types of tUlTIOr tumor involvement in both the study patients and the Registry groups.

Nature of Presumed Pathogenetic Relationship between Rheumatic or Autoimmune Syndromes and Neoplasia Previous reviews by Caldwell have utilized an organized conceptual approach to the possible pathologic relationships between musculoskeletal and autoimmune and connective tissue disease manifestations and neoplasdiseases.5--8 His classification has proved most useful and will be distic diseases.6-8 cussed in this review. Theoretically, there can be three interrelationships. The syndromes syndrolTIes may result from: (1) direct metastatic or direct primary involvement with the musculoskeletal system; (2) an indirect association as in the autoimmune and paraneoplastic syndromes, or with concurrent inflammatory connective tissue disease, and (3) no relationship may be presflamlTIatory ent, and the lTIusculoskeletal, musculoskeletal, autoimmune, and connective tissue disease syndromes are independent of the the tUlTIOr. tumor. Direct Pathologic Relationship Table 3 records the nature of involvement in 30 of the 91 study patients in whom a direct pathologic relationship between the neoplasia and the syndrome was thought to exist. For 28 patients, metastatic tumor to bone accounted for their musculoskeletal pain syndromes, with 23 involvYIetastases involving the vertebral bodies or ribs ocing the long bones. Metastases

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curred in five patients and three had secondary nerve compression. In these 28 patients, no involvement of meningeal, synovial, synovial,. or periarticular structures was appreciated. There was a striking lack of hypertrophic pulmonary osteoarthropathy in this group by both clinical and radiographic criteria. With the high incidence of lung and breast tumors in the study patients, this finding was unexpected. Since no leukemias were present in this group of patients with metastatic disease, it may not be surprising that synovial structures were not involved. There were no features of the pain, radiation, or relationship to time of diagnosis or tumor type that were distinguishing. When the 23 patients with metastatic disease and bone pain were analyzed further, breast, lung, and colon neoplasia were most frequent (see Table 3). Long bones, lumbosacral spine, and ribs were most common sites of metastatic disease with these tumors. Patients with primary neoplasia involving the musculoskeletal system are also listed in Table 3. The patient who had pain in a long bone had a chloroma due to chronic granulocytic leukemia at that site. The patient with primary muscle pain had a rhabdomyosarcoma of a gluteal muscle. For the majority of patients with the musculoskeletal syndromes (bone pain or vertebral involvement), their symptoms were due to metastatic disease and not primary tumors of musculoskeletal structures. Indirect Pathologic Relationship There are distinct musculoskeletal syndromes that occur in patients with neoplastic disorders that are generally considered to have an indirect pathologic relationship to the tumor. This category, according to Caldwell and others, included connective tissue, immunologic, and paraneoplastic syndromes.~, 59 Table 4 lists the number of patients with each of these syndromes.6--8, entities in order of decreasing frequency. Myoneuropathies (often poorly localized clinically, but very painful) and lupus-like syndromes were the

Table 3.

Direct Pathologic Relationships Between Neoplasia and Musculoskeletal Syndromes (N === 30)

DIRECT ASSOCIATION

Metastatic Disease (28) Bone

Spinal Cord Meninges Synovium Periarticular structures Primary Disease (2) Bone Muscle Synovium

NUMBER OF PATIENTS

23 5 0o 0o 0o

1 1 0o

TUMOR TYPES

Breast (7), lung (6), colon (4), myeloma (2), prostate (2), gastric (1), ovarian (1) Breast (4), lung (1)

Chronic granulocytic leukemia Rhabdomyosarcoma

605 605

AUTOIMMUNITY AND MALIGNANCY MALIG"IANCY AUTOIM~1UNITY

Table 4. Indirect Pathologic Relationships Between Neoplasia and Rheumatologic, Immunologic, or Paraneoplastic Syndromes (N = 34) NUMBER OF INDIRECT ASSOCIATION

PATIENTS

TUMOR TYPES

Myoneuropathy

9

Lupus-like syndromes

8

Myopathy

3

Secondary gout Carcinomatous polyarthritis Carpal tunnel syndrome Endocrinopathies (SIADH, Cushing's) Temporal arteritis Rheumatoid arthritis Diffuse interstitial fibrosis

3 3 3 2 1 1 1

Lung (5), lymphoma (2), breast (1), embryonal cell (1) Hodgkin's disease (4), lung (3), colon and myeloma (1) Colon, breast, chronic granulocytic leukemia (1 each) Lung (2), uterine (1) Lung (2), colon (1) Ovarian, myeloma, gastric (1 each) Lung, islet cell (1 each) Lung Breast Breast

predominant categories noted in the study patients. A A third category included patients with myopathy independent of neuropathic symptoms. symptoms, Secondary gout was noted in two patients receiving chemotherapy for neoplastic disorders, despite prophylactic therapy with allupurinol; a third patient experienced an acute attack of gout as a result of tissue necrosis from a radium implant for a uterine tumor. There were three patients with the carcinoma polyarthritis syndrome, an entity that will be discussed in more detaiL One patient with a lung tumor exhibited the syndrome of inapprodetail. priate secretion of antidiuretic hormone, and one had a neoplasm-related Cushing's syndrome. The remaining three patients had clinical criteria for the separate diagnoses of rheumatoid arthritis (two patients) and temporal arteritis (1), each with an onset within 3 months of the diagnosis of their tumors, One patient had the coincident onset of shortness of breath and tumors. diffuse interstitial fibrosis (DIF) with a primary breast lesion, which was surgically amenable. Lymphangitic spread was ruled out by transbronchial biopsy. biopsy, No environmental or toxin exposures that could have contributed historically, to the DIF were obtained historically. Clinical data are presented on selected patients to illustrate these indirect pathologic relationships with the variety of tumors in which they were associated.

MyoneuropathieslMyopathies. The nine patients with myoneuropathy Myoneuropathies/Myopathies. syndromes represented a wide variety of tumors: lung (adenocarcinoma, 2; large cell undifferentiated, 1; oat cell, 1; squamous, 1), lymphoma (lymphocytic, 1; nodembryonal cell carcinoma (1). The two patients with only a ular, 1), breast (1), and elnbryonal myopathic component had chronic granulocytic leukemia and colon carcinoma, respectively. The patient with chronic granulocytic leukemia had been on chronic prednisone therapy but had an elevated creatine phosphokinase (CPK), proximal phcnommyopathy, and an electromyogram (EMG) consistent with mild irritative phenomena, but not suggestive of Eaton-Lambert syndrome nor diagnostic of polymyositis. The man with colon carcinoma did not have polymyositis or dermatomyositis by clinical history or physical examination, but did have a systemic proximal myopathy

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and elevated elcvated CPK which was not further furthcr pursued pursucd by E~G E.vIG or biopsy studies. TemTcmporally, the onset of the thc Inyopathy myopathy was 3:3 Inonths months prior to rectal bleeding, at which time the thc colonic carcinOlna carcinoma was diagnosed. Thc . eight· eight patients with lupus-like illnesses were wcre Lupus-Like Illnesses. The very interesting intcresting in the thc variety varicty of clinical and serologic scrologic findings they exhibited. Half of these thesc patients paticnts had Hodgkin's disease or non-Hodgkin's lynlpholna. lymphoma. Two had ccllularity Hodgkin's disease. discasc. Both patients paticnts had myalgias, arthralgias, and mixed cellularity (F ANA) tests (negative for specific autopositive fluorescent antinuclear antibody (FANA) antibodics such as anti-Snl, anti-Sm, RNP, R]\;P, Ro, La by CIE, anti-DNA by fluorescence) but antibodies symptoms. One Onc of these thesc patients paticnts had presented presentcd with idioextreme constitutional symptolns. pathic thrombocytopenic purpura, and developed hypertension and mild renal insufficiency. Shc later developed frank arthropathy (minimally deforming) dcforming) and was sufficicncy. She ncgativc, but remained ANA-positive. Both diagnoses of lymphoma and anti-DNA negative, SLE were established within 3:3 months of each other, and the serologic findings antedated chenl0therapy. chemotherapy. The patient with lymphocyte-depletion lymphocytc-depletion Hodgkin's disease had arthritis, erythema nodosuln, nodosum, a malar rash, and hypocomplementemia without proteinuria or nephritis by urine sediment and functional testing. The palymphoma was anergic with renal failure and choroiditief'tt with diffuse histiocytic lympholna tieftt tis; she was a young black WOlnan woman who had a positive low titer ANA, negative for anti-Srn, RNP, Ro, La, negative ncgativc DNA, and no findings for sarcoidosis. She develanti-Sm, oped intermittent arthralgias. Three patients with large cell, squamous, and oat carcinomas of the lung had clinical features (arthralgias, myalgias) and positive cell carcinOlnas serologies 'Suggestive of lupus or Sj6gren's autoantibodies were demonstrable. The patient with oat cell carcinOlna carcinoma had autoimnlune autoimmune thyroiditis with clinical and functional hypothyroidisnl, hypothyroidism, and synllnetric symmetric seronegative, nondeforming non deforming arthritis. The patien.t patient with squan10us squamous cell ccll carcinOlna carcinoma had arthralgias, myalgias, hypothyroidisln, hypothyroidism, and lupus-like serologies without other organ involvement. The patient with large nondeforming arthritis, a negative rheumatoid cell undifferentiated carcinoma had nondefornling factor, and a pericardial effusion, which responded to steroids; he also had a posiFANA anti-Srn, Ro, or La ANA without specific autoantibodies such as anti-SIn, tive low titer F delnonstrable demonstrable by CIE. Lastly, one onc patient with colon carcinoma treated treatcd surgically myeloma (IgG type) several years later, and had autoimmune autoimmunc hemodeveloped a myelolna thrombocytopenia with only a positive low titer FANA that could lytic anemia and throlnbocytopenia not be related to the myeloma therapy. Secondary Gout. The three patients with secondary sccondary gout had no antecedantccedent family or personal history of gout, hyperuricelnia, hyperuricemia, obesity, dietary excesses, or diuretic use. It was interesting that none of the three patients had hematologic malignancies where the development of secondary gout with onset of aggressive chemotherapeutic regiInens rcgimens is sOlnetimes sometimes seen, despite adequate prophylaxis with Two patients in this category had lung tumors, one each \vith with large cell allopurinol. T\vo undifferentiated, and oat cell. The patient with oat cell carcinoma did, however, symptoms with the onset of chelnotherapy, chemotherapy, and thus tUlnor tumor burden and develop sYlnptonls necrosis are arc nlost most likely contributory, since other COlnmon common causes for gout were measuremcnts antecedent to chemotherapy. excluded by history and laboratory lneasurements massive hyperuricemia secondary to uterThe last patient in this group developed lnassive ine tumor necrosis from an intracavitary radiuln radium ilnplantation. implantation. No drugs known to precipitate hyperuricemia were in use before the event, which developed 2 weeks implantation. Clinical podagra and lnigratory migratory arthralgias were synlptoms, symptoms, after the inlplantation. which responded rcsponded to standard therapies. Arthrocentesis confirmed the presence of monosodium urate. male smoker with adenocarcinoma of the Carcinomatous Polyarthritis. A l1lale lun g had presented with a 2 nlonth month history of arthritis pain and no extra-articular lung features. The Thc presence of a seropositive aSylnlnetric asymmetric polyarthritis involving PIPs, MCPs and wrists was noted. No digital clubbing, erosions, or periostitis were seen

AUTOIMrvIUNITY MALIGNANCY AUTOIMMUNITY AND :VIALIGNANCY

607

radiographically. He was begun on non-steroidal anti-inflalnmatory anti-inflammatory medications \vith good clinical response. Approximately 4 months later, he developed an exacwith mild chronic bronchitis, and a routine chest roentgenogram showed an erbation of Inild unsuspected mass. Bronchoscopy was positive for an adenocarcinoma. A lobectomy was performed and the patient did well, but he continued to smoke. His arthritis relnained remained in control with no progression to erosions or requirement for other therapy. Rheumatoid factor remained rcmained negative, negativc, but the arthritis began to flare 3 months later. An exacerbation of bronchitis with pleuritic pain prompted a chest roentgenogram and a pneumonic pncumonic process with an effusion was present. Thoracentesis fluid showed adenocarcinoma cells and grew staphylococci. He responded to antibiotics and another anti-inflammatory agent. Conservative medical therapy was pneumonia, and plans for possible chemotherapy or radiation therpursued for the pneulnonia, apy were withheld pending radiographic clearing of the pneumonia. non erosive A second patient had been treated for a symmetric seronegative nonerosive polysynovitis of metacarpophalangeal joints, proximal interphalangal joints, and knees with nonsteroidal anti-inflammatory therapy for 6 months with good clinical response, but suddenly began to note increased stiffness, pain, and swelling. He was changed to flare therapy with initially good results, but a course marked by exacerbations and intercritical periods. During routine follow-up of therapy, a CBC microcytic hypochromic anemia, and stool guaiac was positive. Barium showed a Inicrocytic enema disclosed a lesion in the left colon. Biopsy was positive for carcinoma and a successful resection was performed. Rheumatoid factor remained negative. The pattern of his arthropathy returned to its pretumor activity over the next month and he remained on his previous therapy. No further information was available. Carpal Tunnel Syndrome. The three patients with carpal tunnel syndrome had ovarian/gastric carcinoma and myeloma. Hypothroidism or diabetes were not present clinically or by laboratory parameters. Biopsy to rule out amyloid was not performed in the patient with an IgG myeloma. Endocrinopathies. An elderly male had a right upper lobe primary tumor diagnosed as an undifferentiated tumor by bronchoscopy. There were no symptoms but he had persistent hyponatremia for 6 months without head trauma or predisposing medications. Coincident medical problems and the extent of the tumor precluded surgery. Inappropriate antidiuretic hormone was attributed to the tumor. During a routine work-up for Cushing's syndrome, based on urinary steroid levels, weakness, and glucose and electrolyte abnormalities, a middle-aged white woman showed a pancreatic mass on abdominal ultrasound. She had had normal CPK and TSH levels and nornlal normal paralneters parameters of inflammation. A diagnosis of islet made at laparotolny. laparotomy. cell carcinoma was nlade paticnts in this group, clinical criteria established the diagnoses In two other patients temporal arteritis in two older white women. The of rheumatoid arthritis and tenlporal woman with telnporal temporal arteritis had a low sedilnentation sedimentation rate (60 Inm mm per hour) and no giant cells on biopsy. :v1onths Months after the diagnosis of rheumatoid arthritis was In"ade m-ade clinically and low-level rheumatoid factor was found, one woman's physician discovered a breast nodule that was proved to be malignant. In the other patient, a routine chest roentgenogram done at the patient's request for a cough she had not previously mentioned showed a lung primary (squamous). The last patient in development of D DIF this group had the rapid developlnent IF on chest radiograph 1 month after an initial chest radiograph was negative during a staging evaluation for a breast mass shown to be carcinoma. She had not been treated with chemotherapy or Inass drugs known to produce fibrosis previously and had just started chemotherapy. The diagnosis was established by biopsy, which was done to rule out infection. more likely due to the tumor than to chenlochemoThis rapid onset was believed to be Inore therapy by her physicians. In 35 other patients, there appeared to be no pathologic relationship between

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the musculoskeletal or connective tissue disease discase syndromes and the neoplastic disease (Table 5). No autoimmune syndromes were noted in this group. Twenty-two pattcrns of of these 35 patients had generalized osteoarthritis, with usual articular patterns involvement, gel phenomema, and relationship to use. There were six patients who had definite rheumatoid arthritis antecedent to the onset of their tumors; only one of these patients had antecedent therapy with a cytotoxic agent (1 year of azathioprine) 1 year before the diagnosis of chronic granulocytic leukemia. The three patients with gout had classic podagra, and two had pertinent family histories of gout. Low back pain 2 years before tumor diagnosis was the presentation in one patient who had a chronic degenerative lumbosacral disk problem, and bone scan was negative for pelvic metastases from colonic carcinoma. The single patient with a 10year history of ankylosing spondylitis and a hypernephroma had received only standard nonsteroidal anti-inflammatory agents, and had never undergone spinal irradiation. He presented with flank pain and hematuria without autoimmune or musculoskeletal features. His ankylosing spondylitis was inactive. There were no atypical features of clinical courses or responses to standard antirheulnatic antirheumatic therapy in these patients, and their CTD diagnoses were well established antecedent to tumor diagnoses.

The number of pathologic relationships in Tables 3 to 5 totals 99, and thus does not equal the number of patients (N == 91), because several individuals had osteoarthritis as a separate condition in addition to a direct or indirect manifestation of musculoskeletal disease and neoplasia. This was not unexpected in light of the age ranges accounting for most of the patients in this study. No significant predilection for a certain tumor type, degree of joint destruction, or pattern of joint involvement differentiated among this group.

Lack of Specific Autoantibodies in Patients with Neoplasia Several studies have reported a variable incidence of positive autoan23 . 25 Usually, these are lowtibody tests in patients with different tumors. 23, titer positives, most often detected on the rat liver or mouse kidney autoantibody substrates. Since a patient with systemic manifestations of a malignancy can be a clinical mimic of a systemic inflammatory disease, the co nfuexistence of positive autoantibodies tests can be a source of major confuTable 5.

Independent Pathologic Relationship between Neoplasia and Musculoskeletal Syndromes (N=35)

NO ANTECEDENT ASSOCIATION WITH NEOPLASIA

NUMBER OF PATIENTS

Osteoarthritis, generalized

22

Rheumatoid arthritis Gout Osteoarthrosis, localized Degenerative disk disease Ankylosing spondylitis

6 3 2

1

1

TUMOR TYPES

Lung (6), colon (4), breast (3), prostate (3), uterine (2), lymphoma (2), esophogeal (2) Breast (2), lung (2), prostate (1), CML (1) Lung (2), uterine (1) Lung (1), breast (1) Colon Hypernephroma

*Total number of patients in Tables 3 to 5 is greater than 91 because several patients had both directly and indirectly associated syndromes.

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AUTOIMMUNITY AND MALIGNANCY

sion to the clinician. The newer substrates such as human epithelial cells (HEp-2) are very reactive and detect a wider range of autoantibodies in patients with connective tissue diseases than the tissue section 25 ,, 42 To determine the incidence of high- and low-titer autoantisubstrates. 25 bodies in patients with neoplasia, serum was obtained from many of the F ANA, with determination of spepatients in this study, and a screening FANA, cific precipitin autoantibodies, was performed (Table 6). It is apparent that both low- and high-titer speckled patterns occur in the sera of patients with neoplasia; however, none of the sera from these patients contains the specific autoantibodies that occur in 30 to 60 per cent of patients with idiopathic isolated connective tissue diseases not related to the neoplasia. 21-23, 21-23, 25-27, 25--27, 42 The specific autoantibodies and their profiles are noted in the connective tissue disease section of Table 6. These specific autoantibodies also do not occur in the sera of normal controls, and in some connective tissue diseases are specific enough to be considered mark42 Several examples are Sm, disorder.42 Srn, RnP, Scl-70, Ro and reers for the disorder. lated antigens antigens..1,1, 2 In the tumors, the autoantibodies are nonspecific and in most instances are not known to be related to a tumor-specific antigen 21- 23 , 25-27, 25--27, 42 None had antibody to proliferating cell nuclear antigen system 21 leulo(PCNA), a lupus-related entity,27 or to specific cells such as the leuko42, 76 Variation in titer with tumor burden as reduced by cancer cyte. 27 , 42, Table 6. Occurrence of Autoantibodies by Immunofluorescence or Precipatory Antibodies to Nuclear Extracts in Selected Patients with Neoplastic Diseases, Connective Tissue Diseases, and Normal Controls IgG ANA ANA (HEp-Z) (HEp-Z) IgG

TUMORS

NUMBER NUMBER

Lymphomas Hodgkin's 6 Non-Hodgkin's 4 Myeloma 4 Leukemia 2 Lung 23 Breast 18 Prostate 7 11 Colon Ovarian 2 Cervical 2 Esophogeal 2 Connective Tissue Diseases SLE 72 RA PSS PMIDM PM!DM OA Normals

-=absent

60 35 25 60 80

Negativel Negative! Low Titer 140

High Titer >1640

5 3 3 1 21 15 6 9 1 1 2

1 1 1 1 2 3 1 2 1 1 0

12

60

48 5 22 58 79

12 30 3 2 1

PRECIPITINS TO TO PRECIPITINS RTE!CTE RTE/cTE

Sm/RNP Sm!RNP Ro/La Ro!La

25% 250/0 10%

Se! 70 Scl Jo-l Jo-1

20% lOo/Cl 10%

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chemotherapy or by surgical debulking has been reported and theoretically 42 . 45 This is important to autoantibody could recur with metastatic disease. 42, the clinician because most of the autoantibodies in connective tissue diseases do not change with disease activity. 42, 42. 45, 45. 78

DISCUSSION

Rheumatic manifestations can accompany both primary and metastatic neoplastic diseases as shown by this systematic study of 91 well-characterliterature,3. 6-8, 6--8, 47, 48, 52 The major conized patients and as reviewed in the literature,3, clusions from the data can be summarized: 1. Lung, breast, colon, prostate carcinomas, and lymphomas were the most common neoplasia in order of decreasing frequency. 2. Lung, prostate, colon, uterine, and breast carcinomas were most commonly autoimnlune, musculoskeletal, and connective tissue disease sympassociated with autoimmune, toms, in order of decreasing frequency. non-Hodgkin's lymphomas and myelomas were the hema3. Hodgkin's Hodgkin>s and non-Hodgkin>s tologic to logic malignancies associated with autoimmune and connective tissue disease, but rarely musculoskeletal symptoms; these tumors occurred more commonly in study patients than in the Oncology Registry overall. 4. Bone pain was the most common musculoskeletal syndrome directly related to neoplasia, and was indicative of metastatic disease in breast, lung, colon, myeloma, prostate, gastric, and ovarian tumors, in order of decreasing frequency. 5. Lumbosacral spine, rib, and long bone involvement was noted in metastatic disease; hypertrophic osteoarthropathy was not noted in this series. 6. The most common autoimmune autoimlllune and connective tissue disease syndromes svndromes indirectly related to neoplasia were (a) myoneuropathy, seen with lung, lymphoma, breast, and embryonal cell tumors, and (b) lupus-like syndromes, seen in Hodgkin's lymphoma, lung, colon, and myeloma. 7. Connective tissue disease syndromes indirectly related to neoplasia were (a) myopathy, seen with colon, breast, and chronic granulocytic leukemia, (b) secondary gout, seen with lung and uterine neoplasia, and (c) carcinomatous polyarthritis, seen with lung and colon neoplasia. 8. The most common musculoskeletal and connective tissue disease syndromes independent of neoplasia were osteoarthrosis, rheumatoid arthritis, and gout; autoimmune syndromes per se were absent in this group. 9. Serologic characterization, including second-level autoantibody determinations can be helpful in defining autoimmune autoimlllune or connective tissue disease syndromes related to neoplasia, versus those related to idiopathic connective tissue disease, when clinical symptomatology is confusing.

Regarding the musculoskeletal symptoms that are usually related to the neoplasia, and manifested as bone pain, the data are consistent with that reviewed by Caldwell in the prominence of metastatic disease. The skeletal metastases were usually asymmetric. This may also reflect the fact that even with many pulmonary tumors, hypertrophic osteoarthropathy was not seen even when looking for it radiographically, and this condition is more commonly associated with a symmetric polyarthritis. With metastatic disease, ribs and vertebral bodies were involved more commonly than small joints of the hands, which has been reported in lung, breast and colon neoplasia. In our study none of the patients with vertebral involve-

ACTOIMl\IUNITY AND MALIGNANCY ~lALIGNANCY AUTOIMl\fUNITY

611

ment had a spondylytic-like picture. Leukemia was not associated with leukemic synovitis; one of our patients with chronic granulocytic leukemia had a chloroma in bone, giving localized pain. There were no instances of synovial reaction to adjacent bone tumors. The entity of carcinomatous polyarthritis should be suspected with a seronegative rheumatoid-type polyarthritis and is associated with solid tumors. A summary of the salient clinical points is available in Caldwell's review.6-8 review.&--8 The few patients with this entity in the study did have solid tumors with a rheumatoid arthritis-like seronegative process in temporal &--8. 61-63 None N one had an explosive onset of systemic relationship to their tumor. 6-8, features such as fevers and rashes, and their laboratory studies and lack of splenomegaly or lymphadenopathy did not suggest adult-onset juvenile rheumatoid arthritis or a systemic infection. Because the patients for this review were chosen on the basis of musculoskeletal-, autoimmune-, or connective tissue disease-like symptoms prominent enough to be listed as a coded separate diagnosis and to prompt rheumatologic consultation, it is surprising that more patients were not identified with carcinomatous polyarthritis. An informal review of the development of solid tumor malignancies among our rheumatic disease service clinics did not reveal patients whose patterns are suggestive of carcinomatous polyarthritis, so the failure to identifY identify more patients with this entity is more likely representative of the fact that they have idiopathic connective tissue diseases and not undiagnosed carcinomas. The high incidence of breast carcinoma in older female patients suggested that a high incidence of carcinoma polyarthritis might exist in this group, as has been noted in previous studies. 88 However, of our 18 patients with breast neoplasia, most had musculoskeletal pain due to direct bony metastases, and only one had rheumatoid arthritis which was considered to be indirectly related to the breast neoplasia because of its temporal relationship. This patient did not have the aforementioned features of carcinomatous polyarthritis. Only three of the breast neoplasia patients had high FANA F ANA titers, but had no other lupus-related autoantibodies, nor clinical laboratory findings associated with SLE74 such 25. 35, 35. 38, 38. 41 as isolated thrombocytopenia, thrombocytosis, or leukopenia. 19,. 25, The major area of confusing symptomatology symptornatology and serologic studies relates to the coincidence of neoplasia and connective tissue diseases such as SLE. Most of the patients with lymphomas had symptoms indirectly related to the neoplasia, the lupus-like syndromes, with autoantibodies, and the other features detailed previously. This study reemphasizes the care in clinical history, physical examination for subtle signs of connective tissue diseases, and the utility of complete autoantibody characterization in the differentiation of these patients. The occasional occurrence of autoantibodies in patients with hypernephroma or lymphoma which change in titer relative to tumor burden or with re~ponse rellPonse to specific antitumor therapy is an intriguing example of the clinical and laboratory overlap that can be confusing to the physician. 23, 23. 25, 30, 45 45 The fine line between autoimmunity and lymphoproliferation suggests abnormalities among several common pathways of regulation of the immune system. 31 , 30 Most often, SLE precedes the lymphoproliferative process or is coincident in onset with lym3o, 31, 41 The relationship of cytotoxic therapy to subsequent develphoma. 30 opment of neoplasia in SLE is a point on which it is difficult to offer firm

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statistics. When SLE is associated with neoplasia, it appears to be similar in terms of systemic symptoms, serositis, and generalized musculoskeletal and autoimmune features, except the exact incidence of renal disease is unclear. Many of the early literature case reports did not include detailed serologic or clinical laboratory data that would permit comparisons in an attempt to define exact incidences of serologic abnormalities. Diagnosing and treating complications such as serositis and fever will continue to be a series of diagnoses of exclusions. In general, standard treatment of the malignancy is pursued even with a connective tissue disease, but in some instances, specific therapy for the rheumatic component may be needed.68, 45, 73

The present study did not find isolated cases of other, less common types of autoimmune or connective tissue disease syndromes that have been reported to occur in conjunction with various neoplasia, such as associated autoimmune thyroiditis, thymoma, and cryoglobulinemia. 37 , 67 In addition, relapsing polychondritis, panniculitis, tumoral osteomalacia, scleroderma syndromes, eosinophilic fasciitis, and vasculitis of all types were absent in this patient population. 25, 34, 53, 67, 49, 79 These less common presentations should be considered, however, among the numerous rheumatic manifestations of neoplasia. Research on chemical messengers in the immune system such as the interleukins, the thymus and cellular immunity, and humoral aspects of immunoregulation may help to delineate their roles in the genesis of autoimmunity and neoplasia. 4, 30, 40, 64-66 ACKNOWLEDGMENTS

The author wishes to recognize the contributions of Carol B. Moran and Joanne P. Tucker in the preparation of this manuscript.

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