Pay attention to the man behind the curtain

Case Presentation

History of the Present Illness

In the winter of 2012, a 52 year old African American woman noted changes in the color of her fingers upon exposure to cold, characteristic of Raynaud's phenomenon. Her digital cold sensitivity worsened over the ensuing months. She then developed stiffness and pain in her hands and wrists that interfered with routine daily activities, including open jars or in making a fist. In March, 2012, she noticed swelling in both knees which led to difficulties in getting out of bed, up from a toilet seat, and in and out of a bathtub. She used naproxen, acetaminophen and topical Bengay (15% methylsalicylate and 10% menthol), each without symptomatic improvement. In April, red blotches appeared on her hands accompanied by hypopigmented patches on her cheeks and forehead. By the end of the month she developed new and severe heartburn and chest pain, alleviated by high-dose proton-pump inhibitor therapy.

In May, her primary care physician prescribed a 1-week course of prednisone @20 mg daily as treatment for a presumed rheumatoid arthritis flare, and on the third day, she noted substantial symptomatic and functional improvement. On day 8, the prednisone dose was decreased to 10 mg daily and she continued at this dose until she was evaluated in rheumatology consultation.

Past Medical History

The patient's past medical history was notable for smoking cigarettes 1 pack per day for 40 years, COPD, hypertension, hyperlipidemia, and coronary artery disease with stent placement 2 years earlier.

Social and Family History

There was no personal history of alcohol or illicit drug use. There was a family history positive for coronary artery disease and breast cancer. Her personal and family histories were notably negative for autoimmune rheumatic disorders.

Physical Examination

On examination, she was a pleasant, interactive woman with a small body habitus. She was afebrile and normotensive. There were subtle hypopigmented skin changes over the forehead and cheeks. Prominent telangiectasias (the reported ‘red blotches’) were present over the extensor and volar aspect of most digits and oral mucosa There was periungual erythema affecting the 3rd and 4^th fingers, bilaterally, as well as diffuse sclerodactyly. Tendon friction rubs were absent. There was no jugular venous distention. Breath sounds were clear to auscultation without crackles or wheezes. Heart sounds were regular without murmur, rub or gallop. The abdomen was soft and nontender without masses present. Her wrists were tender and warm; there was synovitis affecting the metacarpophalangeal and proximal interphalangeal joints, diffusely and bilaterally. There was no truncal skin thickening nor evidence of cutaneous sclerosis proximal to the metacarpophalangeal joints.

Review of systems

Review of systems was otherwise notable for an unintentional 13 pound weight loss over the preceding 6 month period.

Laboratory and radiologic evaluation

Laboratory studies revealed a WBC of 10.7/mm³, hematocrit of 40.5%, and platelet count of 433,000/mm³. The creatinine was 0.7 mg/dl with normal electrolyte levels, including calcium. Liver function tests were normal with an albumin of 4.2 g/dl. Serum protein electrophoresis revealed polyclonal hypergammaglobulinemia. Creatine kinase and aldolase were normal, at 64 U/L and 6.0 U/L, respectively.

ANA was positive at a high titer value of 1:640, in a nucleolar pattern. Rheumatoid factor was elevated at 47 IU/ml [NR 0-13.9], while anti-CCP antibodies were similarly detected at a high level of 107 units [strong positive >59]. In contrast, Scl70, dsDNA, RNP, Sm, Ro, La, anticardiolipin, and B2 glycoprotein antibodies were not detected. Lupus anticoagulant was absent by RVVT. RNA polymerase III antibody was strongly positive at a value of 127 units/ml [strong positive >80]. C3 and C4 complement levels were normal. Erythrocyte sedimentation rate was normal at 18 mm/hr.

Her prominent weight loss, history of smoking, and explosive onset of scleroderma raised a high index of suspicion for cancer. Consequently, CT scan imaging of the chest, abdomen, and pelvis with intravenous contrast was ordered, revealing a large hypodense mass measuring 4.8 × 4.2 cm occupying the aortopulmonary window (figure 1A). The mass abutted the inferior aspect of the aortic arch, the anterior aspect of the descending thoracic aorta, the lateral aspect of the esophagus, and the left main pulmonary artery(Figure 1B). On PET imaging, an intense rim of FDG uptake was detected in the mass(figure 1C).

Figure 1.

A: CT scan imaging of the chest, abdomen, and pelvis with intravenous contrast was ordered, revealing a large hypodense mass measuring 4.8 × 4.2 cm occupying the aortopulmonary window.

B: The mass abutted the inferior aspect of the aortic arch, the anterior aspect of the descending thoracic aorta, the lateral aspect of the esophagus, and the left main pulmonary artery.

C: On PET imaging, an intense rim of FDG uptake was detected in the mass.

Bronchoscopic evaluation

Bronchoscopy showed hypervascular mucosa in the distal trachea, proximal left mainstem bronchus and proximal left lower lobe, with intrinsic compression of the distal trachea by the large presumptive malignancy. Subsequently, bronchoscopic biopsy confirmed histologic evidence of a poorly differentiated adenocarcinoma of the lung, with diagnostic immunohistochemistry staining (TIFF-1 and napsin-A; Figure 2A-D); a K-ras mutation was also demonstrated.

Figure 2.

A-D: Bronchoscopy showed hypervascular mucosa in the distal trachea, proximal left mainstem bronchus and proximal left lower lobe, with intrinsic compression of the distal trachea by the large presumptive malignancy. Subsequently, bronchoscopic biopsy confirmed histologic evidence of a poorly differentiated adenocarcinoma of the lung, with diagnostic immunohistochemistry staining ; a K-ras mutation was also demonstrated.

Case Summary

A 52 year-old African American woman with a 40 year smoking history, COPD, hypertension, hyperlipidemia, and coronary artery disease, presented with a profound decline in health status. Over a period of 6 months, she developed progressive functional impairment, beginning with digital cold sensitivity, followed by inflammatory polyarthritis, unintentional weight loss of 13 pounds and an examination notable for facial and forehead hypopigmentation, diffuse digital telangiectasias, and sclerodactyly. Laboratory studies revealed a positive RNA polymerase III antibody, as well as seropositivity for CCP antibody and rheumatoid factor. CT of the chest showed a large mediastinal mass which proved upon histologic examination to be a non-small cell lung cancer.

Differential Diagnosis

A key priority is to interpret and reconcile the predominant clinical features of the patient's course together with the multiple positive autoantibodies and the ultimate tissue-proven diagnosis of lung cancer.

Raynaud's phenomenon can be associated with various autoimmune diseases, including systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis and scleroderma, but may also occur with underlying vascular abnormalities (arterial occlusive disease, thromboangiitis obliterans), blood dyscrasias (cryoglobulinemia, myeloproliferative disorders, multiple myeloma), and local factors (thoracic outlet syndrome), but the presence of dilated nailfold capillaries narrows the differential. Prominent nailfold capillary dilatation is classically seen in scleroderma and dermatomyositis (1).

Our patient had no evidence of hepatic insufficiency on physical exam that could account for the diffuse telangiectasias, and their rapid development ruled out Osler-Weber-Rendu syndrome. Inflammatory polyarthritis has a wide differential diagnosis which includes rheumatoid arthritis, systemic lupus, Sjogren's syndrome, seronegative spondyloarthropathies, crystal arthritides, an overlap syndrome and paraneoplastic arthritis, and can infrequently be seen in scleroderma. Nevertheless, the combined phenotypic features of sclerodactyly, Raynaud's phenomenon, nailfold capillary dilatation, diffuse telangiectasias, inflammatory polyarthritis and gastroesophageal reflux disease, we believe, are best explained by a unifying diagnosis of scleroderma. The diagnosis was further supported by a scleroderma-specific antibody, namely RNA polymerase III. There were, however, atypical features of the case which prompted screening for an underlying malignancy.

Telangiectasias are a specific manifestation of scleroderma skin disease. They represent dilated postcapillary venules without evidence of inflammation and are observed in both the limited and diffuse subsets of scleroderma (2). Interestingly, the number of telangiectasias increases with disease duration, even in cases when the disease seems clinically quiescent (3). Our patient developed prominent telangiectasias of her hands and oral mucous membranes which evolved over a period of only 2 months. Notably, a telangiectasia score was recently developed among a cohort of 147 patients with scleroderma to assess the correlation between the number of telangiectasias, duration of disease and presence of pulmonary hypertension (4). The body areas assessed included the face, hands, arms, chest and abdomen, back, legs, and feet. For each body area, telangiectases were scored as 0 if no telangiectases were present, 1 if there were fewer than 10 telangiectases, and 2 if 10 or more telangiectases were counted. The total possible telangiectasia score was 22. In this cohort, a telangiectasia score of 4-7 was seen in 34% of patients with mean disease duration of 8.4 years. Though not yet validated in a separate published cohort, application of this scoring system to our patient would yield a telangiectasia score of 6. Distinct from the evolving diagnosis of scleroderma, reports of secondary telangiectasias resulting from an internal malignancy have been similarly reported as a marker for undifferentiated bronchogenic carcinoma (5), carcinoid tumors (6), malignant angioendotheliomatosis (7), adenocarcinoma of the hepatic duct, and breast cancer (8). Thus, in addition to the significant exposure to longstanding cigarette smoking, the rapid evolution of pronounced telangiectasias necessitated consideration and a prompt diagnostic evolution for an occult malignancy.

Another dimension of the patient's course that was atypical, or at least relatively uncommon among large cohorts of scleroderma, was the intense component of inflammatory arthritis in association with both rheumatoid factor and CCP-antibody seropositivity. For example, in a multicenter European study that included 1132 patients with scleroderma, the convergence of systemic sclerosis and rheumatoid arthritis was seen in only 11 patients, or as few as 1% of this large cohort (9). Further, the clinical expression of rheumatoid arthritis usually follows the onset of scleroderma by 1-16 years (10); it is highly unusual for the features of rheumatoid arthritis to precede those of scleroderma: this occurs in 0% - 14% of cases (10, 11). Thus, in a Hungarian cohort of 22 patients with both disorders, a diagnosis of rheumatoid arthritis preceded that of scleroderma in only 3 (14%) of the patients (10). Further, those patients with the scleroderma-rheumatoid overlap syndrome demonstrated an increase in prevalence of several HLA haplotypes (e.g., HLA-DR3, HLA-DR7, HLA-DR11 and HLA-DRw53) than was observed among those with either disorder alone, suggesting a distinct genetic profile to the overlap syndrome. Yet, these studies may underestimate the true prevalence of a rheumatoid arthritis overlap, since erosive arthropathy was detected in 24 of 103 (23%) consecutive patients with scleroderma when systematically evaluated using serial radiographs (12).

To date, there have been contradictory reports regarding the nature of a scleroderma-rheumatoid arthritis overlap. Specifically, in a Japanese cohort the overlap syndrome was associated with generalized skin sclerosis, seropositive erosive polyarthritis, pulmonary fibrosis, antitopoisomerase-I antibodies, and HLA haplotype DR4 (13). In contrast, among a large Hungarian cohort of 22 patients manifesting a scleroderma-rheumatoid arthritis overlap syndrome, limited skin fibrosis predominated; further, 23% of these patients were seropositive for antitopoisomerase-I antibodies, no higher than in the broader Hungarian cohort of scleroderma from which this overlap series was derived (10). In our patient, the presence of high titer anti-CCP and RF positivity in the setting of diffuse inflammatory polyarthritis observed was consistent with a true overlap syndrome of scleroderma and rheumatoid arthritis.

In addition to her seropositivity for rheumatoid factor and CCP antibody, our patient was also seropositive for RNA polymerase III. Notably, the presence of RNA polymerase III antibodies is associated with the diffuse cutaneous subset of scleroderma and heightened risk to develop renal crisis (14,15) . Further, in one American cohort consisting of 6 patients with RNA polymerase antibodies and cancer, these six uniformly manifested the diffuse cutaneous subset of scleroderma (16). However, our patient demonstrated sclerodactyly only, indicative of the limited subset of disease. It should be noted that our patient was early on in her disease course, and while limited cutaneous involvement was present at the time of diagnosis, she could have progressed to diffuse scleroderma with time.

There is as yet no direct causal relationship of cancer with scleroderma that has been demonstrated, and no cancer screening besides age appropriate guidelines are recommended by the EULAR guidelines for scleroderma (17), although compelling new data is emerging which may change this approach (18). Nevertheless, in the setting of ongoing anorexia and weight loss, as well as prominent 40 year history of cigarette smoking, this combination of worrisome and compelling clinical features in the context of an underlying newly established diagnosis of scleroderma with seropositivity to RNA polymerase III, prompted an expeditious malignancy workup, which ultimately yielded the diagnosis of lung cancer.

Discussion

The first reported association of an autoimmune disease with cancer date back to 1916, nearly a century ago, when two case reports describing the occurrence of inflammatory myopathy in association with gastric cancer and breast cancer, respectively, were published (19)(20). Since then, the inflammatory myopathies, including dermatomyositis and polymyositis, have become the paradigm of paraneoplastic rheumatic disorders. Notably, among large population-based studies, cancer has been detected in 30% and 15% of patients with underlying dermatomyositis and polymyositis, respectively, a clearly heightened risk compared to the background general population (21). Patients with systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome similarly experience an increase in risk of developing cancer, particularly lymphoma, with a disproportionately higher risk in Sjogren's syndrome; the latter risk is quantified as being 16-fold higher relative to the general population (22).

In contrast, patients with systemic sclerosis have a 1.5–5-times increased risk of developing solid malignancies (23–26). Lung cancer was the most frequent type of solid tumor observed in these studies, followed by breast and esophageal cancer and then lymphomas (26). No correlation was found between anti-centromere or anti-topoisomerase I serologic status and risk for developing malignancy (24). In contrast, RNA polymerase III antibodies have a unique and close temporal relationship between cancer diagnosis and scleroderma onset, typically with the detection of cancer shortly preceding the clinical onset of scleroderma (16,27). RNA polymerase III antibodies were first described in 1993 as a highly specific marker for scleroderma, one strongly associated with the diffuse cutaneous subset of disease (28). They are found in 5–23% of SSc patients, with significant geographic variability that is a characteristic of the serologic profile of scleroderma patients (29). For example, anti-RNA polymerase III antibodies seem to be distinctly rare in some European cohorts, with a decreasing North to South gradient, (highest described prevalence in Sweden of 22%((30), down to 5% in Poland (31)). Their 6% prevalence in Japan (32) and 3% in South Korea (33) is much lower than the 25% prevalence described in Pittsburgh (31). Besides their distinctive association with malignancies, anti-RNA polymerase III antibodies also carry a 25% increase in risk of developing scleroderma renal crisis, compared with a 2% risk in the absence of this antibody (34).

The underlying pathophysiologic mechanism which links autoimmunity and cancer continues to elude the scientific community despite rapid advances in knowledge of cancer biology. The dogma that autoantibody size precludes intracellular entry has limited the scientific approach to antibodies targeting membrane-bound antigens and antigens released during cell death. This paradigm has now changed and antibodies targeting intracellular oncogenes have been shown to affect tumor growth and metastasis by B-cell dependent intracellular uptake and effects (35). When oncoproteins essential to the survival of cancer cells (PRL-3 (phosphatase of regenerating liver 3), EGFP (enhanced green fluorescent protein), and mT (polyomavirus middle T)) were targeted by their respective exogenous antibodies or by antigen-induced host antibodies in a mouse model, it was noted that rates of tumor growth and metastasis were reduced, prolonging murine survival (35). Interestingly, Shah et al have found a unique, nucleolar staining pattern for RNA polymerase III expression in breast and ovarian cancer tissue from RNA III polymerase antibody positive scleroderma patients (27), suggesting that autoantigen expression in the cancer and the autoantibody response are associated with each other. This brings us to the main question: could the RNA polymerase III antibodies be an expected and beneficial host immune response to cancer, the role of which is intracellular blockade of tumor synthesis of 5S rRNA, tRNA and other small RNAs which are essential for cancer growth and propagation? Further research is needed to answer this question, but recent data showing that the POLR3A locus is genetically altered in cancers from most patients with antibodies to RNA polymerase III, but not in cancers from scleroderma patients with other autoantibody specificities (18), strongly supports this theory.

Another intriguing feature of this case is the described patient's severe inflammatory arthritis associated with high titer anti-CCP antibody and rheumatoid factor. The clinical significance of these antibodies in systemic sclerosis is not well understood since they lack the specificity and sensitivity they have in rheumatoid arthritis. Surprisingly, anti-CCP was found in ∼12% and RF in 30% of 78 patients with scleroderma in a Brazilian cohort; while CCP seropositivity was related to prevalence of arthralgia, an association with overt inflammatory arthritis was not demonstrable (36). Moreover, none of the 9 CCP-positive patients in this scleroderma cohort had radiographic evidence of erosive disease. In contrast, among an Italian cohort of 75 consecutive patients with scleroderma, anti-CCP antibodies measured using the same methodology, were associated with arthritis and marginal erosions and were deemed the crucial laboratory marker of a true RA/scleroderma overlap (37).

Patient's Course

The above described patient had an unresectable stage III poorly differentiated adenocarcinoma of the lung as evidenced by mediastinal invasion and both esophageal and tracheal compression, hence the role of surgery was limited in the management of her disease. Treatment with chemoradiation was offered as a reasonable therapeutic alternative. She received 7 courses of weekly paclitaxel and carboplatin which she tolerated remarkably well. Thereafter, she underwent consolidation chemotherapy with four cycles of carboplatin and pemetrexed administered once every 21 days.

Final Diagnosis

RNA polymerase III autoantibody- positive scleroderma associated with poorly differentiated adenocarcinoma of the lung in a 52 year old woman with marked telangiectasias, and a CCP antibody-positive and rheumatoid factor-positive scleroderma-rheumatoid arthritis overlap syndrome.