Una Ercegovac
Rheumatology
July 2005
Rheumatologic Disease and Symptoms Associated with Malignancy
Case Presentation
The patient is a 61 year old woman referred by her PCP to Rheumatology for further evaluation of
possible rheumatoid arthritis. The patient complains of several years of polyarthritis, worsening over the
last year. Stiffness, pain, and swelling are predominant in the knees and ankles; no worse in the
morning than any other part of the day. She endorses an unintentional ten pound weight loss over
several months. She has a 45 pack year tobacco history. Denies fevers, chills, coughing or hemoptysis.
On examination, vital signs are stable and oxygen saturation is 97% on room air. The patient is a thin
woman in no acute distress. Temporal wasting is present. No lymphadenopathy in the cervical, axillary
or inguinal areas. Cardiac and lung exam are normal. Prominent clubbing is present in the finger nails.
Musculoskeletal exam notable for tenderness to palpation over thickened distal long bones including
radius and tibia. The laboratory data shows positive rheumatoid factor of 392 IU/mL (normal <13), and
moderately elevated inflammatory markers ESR 39 mm/hr (range 0-20) and CRP 18mL/L (range 0-10).
Introduction
For years, physicians have observed an association between rheumatic diseases and malignancy.
Many rheumatic diseases, listed in Table 1, are associated with an increased risk of developing
malignancies. Conversely various rheumatic symptoms and diseases are present more frequently in
underlying malignancy. The underlying malignancy, either directly by tumor or indirectly due to
remote effects of tumor (paraneoplastic syndromes), may produce rheumatic symptoms. The
association between rheumatic diseases and malignancy is complex and other factors can contribute
to this association. Medications used to treat rheumatic diseases or malignancy can lead to
development of malignancy or musculoskeletal symptoms respectively.
The case briefly presented above is instructive because it presents a classic case of musculoskeletal
manifestations of malignancy. It is a fine example for clinicians to keep the differential diagnosis
broad and to use the history, exam, laboratory data as well as imaging to come to the final diagnosis.
This paper will discuss a select few rheumatologic conditions associated with particular
malignancies, a few medications associated with developing malignancy, and musculoskeletal
symptoms that can clue the clinician towards certain malignancies.
Preexisting Rheumatic Disease and Associated Malignancy
A more comprehensive list of rheumatologic diseases and associated malignancies are listed in Table 1 (1, 2).
This paper will focus on several of the rheumatologic diseases: DM, SLE, and RA.
1
Table 1: Rheumatic Diseases or Symptoms Associated with Malignancy (1,2)
Rheumatic Disease
Malignancy
Associated Features
Miscellaneous
Rheumatoid Arthritis
Lymphoproliferative
disorders
Longer disease duration
Greater disease severity
Immunosuppression
Felty’s syndrome
Presence of paraproteinemia
Refractory, rapidly progressing flare
in RA- investigate for underlying
malignancy
SLE
Lymphoproliferative
disorders (NHL)
Discoid SLE
Squamous cell
epithelioma
Dermatomyositis
Ovarian, breast, gastric,
pancreatic, lung cancer
in Western populations.
NP in Asia.
Polymyositis
Sjogren’s Syndrome
Scleroderma
Vasculitis
Variety; solid and
lymphoproliferative
(NHL)
Lymphoproliferative
disorders
Alveolar cell ca
Possible breast ca
Nonmemelanoma skin
ca
Possible adenoca of
esophagus
Lymphoproliferative,
myeloproliferative and
solid tumors
Oldest plaques, >20 years after
onset of discoid lesions. Mostly
men 30-60 yo.
Ca-associated DM often with
normal creatinine kinase and
digital vasculitis. Less often
have myositis-specific
antibodies
Glandular: LAD, parotid/
salivary enlargement
Extra-glandular: purpura,
vasculitis, splenomegaly,
lymphopenia, cryoglobulins,
hypogammaglobulinemia
Pulmonary fibrosis, ILD
Near site of scleroderma
Areas of scleroderma and skin
fibrosis
Barrett’s metaplasia
Cutaneous vasculitis
Few with bowel involvement or
granulomatous features
Lymphomatoid
granulomatosis
Multicentric
reticulohistiocytosis
RS3PE
Age-appropriate cancer screening
High suspicion if worsening clinical
features; decline in rheumatoid factor
and IgM
Annual CXR after fibrosis detected
after 5th year
Breast exam and mammography
Change in skin or poor healing
Esophagoscopy and biopsy
Search for underlying cause of
vasculitis
Will develop in 13% patients
Lung, stomach, breast,
cervix, colon, ovarian ca
Osteomyelitis
Paget’s disease
Osteogenic sarcoma
Eosinophilic fasciitis
Lymphoproliferative
disorders
Palmar fibromatosis (or
Ovarian most common,
breast, gastric, pancreas,
lung, colon
fasciitis)
Higher incidence of cancer in DM
than PM
Lymphoma
Lymphoproliferative,
myelodysplasia,
endometrial adenoca.
Cervical, bladder,
gastric, lung, breast,
renal ca, cutaneous and
pulmonary SCC
SCC
Sarcoidosis
If adenopathy, masses or weight loss
develop, suspect NHL. Splenic
enlargement may represent lymphoma
Poorly healing lesion should be
further evaluated
Classic features plus fever,
weight loss and poor response
to glucocorticoid therapy
Highest incidence in first 4
years after detection of
granulomas
Chronic osteo with cutaneous
ulcer
Severe pain
Increases with age
Suspect if aplastic anemia,
thrombocytopenia, Hodgkin’s
disease
Polyarthritis may accompany
fibrosis
Flexion deformities of fingers
“woody hands”
2
Malignant tumors can lead to sarcoid
like tissue reactions resulting in
mistaken diagnosis of sarcoid
Arises in proliferating edges of
cutaneous ulcer, then invades bone
Swelling and bone destruction in preexisting Paget’s may be sarcoma;
consider biopsy
Long-term follow up
Appears similar to Dupuytren’s
contracture
Malignancy not related in all cases
SLE= systemic lupus erythematosus. NHL= Non-Hodgkin’s lymphoma. NP= nasopharyngeal. ILD= interstitial
lung disease. RS3PE=Remitting seronegative symmetric synovitis with pitting edema. SCC= squamous cell
carcinoma.
Inflammatory myopathy: Dermatomyositis (DM) and Polymyositis (PM)
The exact association between inflammatory myopathy, conditions where immune-mediated
inflammation results in muscle weakness, and malignancy is still not clear. It is not known if
myopathy precedes malignancy or if it represents a paraneoplastic process. The frequency of cancer
in these patients has been reported between 7-30%, and a stronger association with DM than PM has
been published (3). Various malignancies have been implicated including hematologic (non-Hodgkin
lymphoma), gastrointestinal, pancreatic, ovarian, breast, lung tumors, and malignant melanoma;
reflecting malignancies found in age-matched population (2,4). There may be an increased
occurrence of ovarian cancer associated with DM, and one study concluded that patients with DM
have a higher rate of mortality from cancer (5). Studies of Asian populations with DM have
suggested an association with nasopharyngeal carcinomas (2,3). The time course of developing
cancer is also unclear, although there seems to be an increased risk of developing cancer in the first
five years after diagnosis of DM (6). Further large, long-term, prospective trials are needed to obtain
conclusive evidence regarding this association. Further evaluation for malignancy is indicated in
patients with unusual presentations of DM or particularly refractory cases in addition to the standard
age-appropriate cancer screening measures.
Systemic Lupus Erythematosus (SLE)
Case reports and few studies report an increased incidence of solid tumors or lymphoproliferative
disorders (especially NHL) associated with SLE. A recent multisite international cohort study of
cancer in SLE confirms an increased risk of cancer, particularly hematologic (NHL), lung, and
hepatobiliary cancer (7). There is an increased risk of NHL in SLE patients, 3-4 fold greater than in
the general population (7). The underlying etiology is not well understood, nor are there predictive
features that may suggest occult malignancy.
Rheumatoid Arthritis (RA)
There is data suggesting that underlying RA is associated with an increased risk of developing certain
lymphoproliferative disorders and a decreased risk of developing colorectal tumors. The risk of
developing lymphoma (HL, NHL) and leukemia is 2-3 times increased in patients who have pre3
existing RA. The underlying etiology may be due to immune dysregulation and/or chronic immune
activation. The use of methotrexate (MTX) for treatment of RA and whether this potentiates the
development of lymphoma have been studied. A number of studies have shown no excessive risk of
developing lymphoma (1). In 1997, Georgescu et al. reviewed the literature and discussed possible
oncogenic mechanisms of MTX in the development of lymphoma.
The authors found most
lymphoproliferative cases presented with features of immunosuppression-associated lymphoma,
possibly due either to underlying RA itself or actions of MTX. Risk factors for developing lymphoma
in RA patients on MTX include severe disease, intense immunosuppression, genetic predisposition,
decreased apoptosis of infected B cells, decreased natural killer cell activity, and an increased
frequency of latent infection with prooncogenic viruses such as Epstein-Barr virus (8). It is still not
clear if MTX itself increases the likelihood of developing lymphoma or whether it is the combination
of RA/MTX, a “combined immunodeficit” mechanism that is to blame. The risk of developing
lymphoma is also studied for TNF-inhibitors. There appears to be an increased risk of developing
lymphoma in RA patients treated with TNF-inhibitors on the order of three times the risk of the
general population (9, 10). However, it is unclear if the higher risk is due to the drug itself or that
patients with more severe RA [conferring] and higher risk of lymphoma, are receiving TNFinhibitors (10). The current data is not sufficient to make conclusive statements about a causal
relationship between RA therapies and development of lymphoma.
Malignancy and rheumatic symptoms as a complication of treatment
Medications for various rheumatic syndromes are typically immunomodulatory agents and may be
associated with the subsequent development of malignancy. Already discussed above was the
association between MTX and TNF-inhibitors for RA therapy and the development of lymphoma.
Other medications that may potentiate development of malignancies include cyclophosphamide
(bladder cancer, skin cancer, and hematologic malignancy), azathioprine (lymphoma, leukemia and
nonproliferative cancers), cyclosporine (lymphoproliferative disorders), leflunomide, and steroids
(predispose to osteonecrosis).
Various treatments for cancer can cause post chemotherapy
rheumatism. These agents include bleomycin (associated with scleroderma or Raynaud
phenomenon), and taxanes (paclitaxel or docetaxel) associated with myalgias and arthralgias.
Radiation therapy can cause myalgias, stiffness, and elevated serum CK; this can follow radiation up
to months to years after.
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Rheumatic symptoms of underlying malignancy
Musculoskeletal or rheumatic symptoms can manifest either directly, by primary tumor or metastasis
disease, or indirectly, as a paraneoplastic process. Metastases are most often to the spine and pelvis
and the tumors most commonly associated include prostate, thyroid, lung, breast, and kidney (2).
Metastases can result in arthritis, by direct sensorial implantation or involvement of surrounding
bone, and arthralgia, most often monoarticular and affecting the knee. Rheumatic symptoms, most
commonly bone pain and stiffness, can develop in multiple myeloma lymphoproliferative and
myeloproliferative disorders.
Arthropathy is most often seronegative, and arthritis, although
uncommon, can be monoarticular or polyarticular.
Paraneoplastic syndromes frequently result in musculoskeletal manifestations. These syndromes
cause hormonal, neurologic, hematologic or biochemical disturbances that are not directly related to
tumor or metastases. Table 2 includes some of the paraneoplastic syndromes that present with
musculoskeletal manifestations. This paper will focus on hypertrophic osteoarthropathy as it relates
to the presented case.
Table 2: Paraneoplastic Syndromes
Arthropathy
Miscellaneous Presentations
Hypertrophic osteoarthropathy (secondary)
Lupus-like syndrome
Amyloidosis
Necrotizing vasculitis
Secondary gout
Cryoglobulinemia
Carcinomatous polyarthritis
Immune complex disease
Jacoud’s type arthropathy
Reflex sympathetic dystrophy syndrome
(RSDS)
Shoulder-hand syndrome
Palmar fibromatosis (or fasciitis)
Polymyalgia rheumatica
Panniculitis
Hypertrophic osteoarthropathy (formerly known an hypertrophic pulmonary osteoarthropathy) is a
syndrome characterized by abnormal proliferation of skin and osseous tissue in distal extremities and
of long bones (periostosis of tubular bones), clubbing of the fingers and/or toes (refer to Image 1),
and oligo/polysynovitis. The secondary form is most often bilateral, symmetric, rapidly progressive,
and associated with malignancy or infection (11). Often painful arthropathy can be confused with
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inflammatory arthritis. In adults, intrathoracic infections and malignancies are most common. In 111
patients diagnosed with lung cancer, by pathology, 29% had clubbing; clubbing was present more
commonly in woman than men (40% versus 19%), and it was more common in patients with nonsmall cell lung carcinoma compared to those with small cell carcinoma (35% verses 4%) (12).
Laboratory testing commonly features elevated erythrocyte sedimentation rate, normal complement
levels, and elevated alkaline phosphatase levels if there is presence of new periostial bone formation.
Image 1: Clubbing
QuickTime™ and a
TIFF (U ncompressed) decompressor
are needed to see t his picture.
(www3.nbnet.nb.ca/ normap/clubbingphoto.JPG)
Case Revisited
The patient presented at the beginning of the paper has convincing evidence for hypertrophic
osteoarthropathy. The prominent digital clubbing, thickening of distal long bones, several month
history of weight loss in association with 45 pack year smoking history made us suspicious for a
primary lung process, likely malignancy. A chest radiograph revealed a 3.2 x 2.4 cm mass in the left
upper lobe. Chest CT confirmed a 4.5 x 3 cm spiculated mass in the apical posterior segment of the
left upper lung with surrounding infiltrate and cavitary lesion. Lymphadenopathy or bony erosions
were not present. Further laboratory data confirmed absence of rheumatoid arthritis with a negative
anti-CCP. Alkaline phosphatase, basic chemistries and coagulation profile are normal; fibrinogen
elevated at 631 mg/dL (reference high is 400). At the time of paper submission, the patient is
awaiting a transthoracic biopsy of the lung mass to include histology as well as AFB culture of the
cavitary lesion. Incidentally, patients who have successful treatment of the primary condition may
expect symptoms and signs of arthropathy to subside rapidly.
This case illustrates how various musculoskeletal manifestations can give clues to underlying
malignancy. The first part of the paper outlined several rheumatic diseases that have been shown in
association with development of certain malignancies. The awareness of these associations with and
predispositions to malignancy may lead physicians to recognize occult malignancy earlier.
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