PARANEOPLASICOS

1. Bulletin of the NYU Hospital for Joint Diseases 2012;70(2):109-14 109
Rheumatology and Oncology
An Updated Review of Rheumatic Manifestations of Malignancy
and Anti-Neoplastic Therapy
Abie Alias, D.O., Ernesto J. Rodriguez, M.D., Helen E. Bateman, M.D., Ashley G. Sterrett, M.D.,
and Joanne Valeriano-Marcet, M.D.
Abstract
Objective: Review of the literature addressing the rheumatic
manifestations of various malignancies as well as of common
chemotherapeutic agents.
Methods: A literature search was performed to identify
key articles regarding the association of rheumatic disease
with malignancy.
Results: Our review focused on the association of rheu-matic
disease with malignancy, paraneoplastic syndromes
with rheumatic manifestations, and chemotherapeutic
agents related to rheumatic syndromes. We have discussed
the importance of a newly described autoantibody that may
identify patients at risk for malignancy associated myositis.
Conclusion: Based on our literature review, recommenda-tions
are suggested regarding who and how patients should
be screened for malignancy when presenting with various
rheumatic symptoms.
Malignancy can be associated with a number of mus-culoskeletal
manifestations that may be caused
by direct tumor invasion into bones and joints,
as a paraneoplastic syndrome, and through altered immune
surveillance (Table 1). Paraneoplastic syndromes cause
manifestations at a site distant from the primary tumor with
the clinical course often paralleling that of the tumor. Im-mune
dysregulation can result in malignant transformation
of rheumatic disease and has been described as a late com-plication
of rheumatoid arthritis (RA), Sjogren’s syndrome,
systemic sclerosis, and systemic lupus erythematosus (SLE).
Antineoplastic drugs have been found to cause rheumatic
syndromes (Table 2), and conversely, antirheumatic therapy
can also induce malignancy.
This review focuses on rheumatic manifestations of ma-lignancy
as paraneoplastic disorders and also describes the
musculoskeletal manifestations of antineoplastic therapy.
Paraneoplastic Rheumatic Syndromes
Paraneoplastic rheumatic disorders are induced by malig-nancy
through hormones, peptides, autocrine and paracrine
mediators, antibodies and cytotoxic lymphocytes. Recogni-tion
of paraneoplastic disorders may lead to an earlier diag-nosis
of malignancy. Treatment of the underlying primary
neoplasm usually results in regression.1
Carcinomatous Polyarthritis
Carcinomatous polyarthritis is a seronegative inflammatory
arthritis that may precede the diagnosis of malignancy.
Features include late age at onset, a rapid presentation of
asymmetric oligoarthritis or polyarthritis, predominant in-volvement
of lower extremity joints, absence of rheumatoid
factor (RF), and a mildly inflammatory synovial fluid. There
are no distinctive pathologic or radiographic features. The
temporal relationship between the onset of carcinomatous
polyarthritis and the diagnosis of malignancy is typically less
than one year. It is most frequently reported in women with
carcinoma of the breast and in men with carcinoma of the
lung. The arthritis correlates well with tumor regression and
recurrence. The symptoms may respond to glucocorticoids
or nonsteroidal anti-inflammatory drugs (NSAIDS).2
Hypertrophic Osteoarthropathy
Hypertrophic osteoarthropathy (HOA) is characterized by
digital clubbing, periosteal proliferation, and an arthropa-thy
ranging from arthralgia to diffuse polyarthritis. This is
commonly associated with pulmonary malignancies, with
Abie Alias, D.O., Ernesto J. Rodriguez, M.D., Helen E. Bateman,
M.D., Ashley G. Sterrett, M.D., and Joanne Valeriano-Marcet,
M.D., are in the Department of Rheumatology, University of South
Florida, and James A. Haley VA Hospital, Tampa, Florida.
Correspondence: Helen E. Bateman, 13000 Bruce B. Downs
Blvd, Office of Rheumatology, Tampa, Florida 33612; Helen.
Bateman@va.gov.
Alias A, Rodriguez EJ, Bateman HE Sterrett AG, Valeriano-Marcet J. Rheumatology and oncology: an updated review of rheumatic manifestations of
malignancy and anti-neoplastic therapy. Bull NYU Hosp Jt Dis. 2012;70(2):109-14.

2. 110 Bulletin of the NYU Hospital for Joint Diseases 2012;70(2):109-14
resolution of the syndrome after tumor resection. HOA can
range from asymptomatic disease to incapacitating bone
pain, usually seen in those with aggressive malignancies.
Vascular endothelial growth factor has been suggested to
play a role in the pathogenesis of HOA.3
Relapsing Seronegative Symmetric Synovitis
with Pitting Edema
Relapsing seronegative symmetric synovitis with pitting
edema (RS3PE) is characterized by involvement of the
hands and feet, elevated acute phase reactants, negative RF,
and absence of radiographic erosions.4 Yao and colleagues4
performed a literature review from 1985 to 2008 and found
32 case reports of malignancy in RS3PE , including 18 solid
tumors, 11 hematologic malignancies, and 3 additional
malignancies of unknown sites. The malignancy rate associ-ated
with RS3PE was found to be as high as 54%. Patients
with malignancy associated RS3PE have more dramatic
symptoms, tend to respond poorly to glucocorticoid therapy,
and improve with treatment of the underlying malignancy.
Currently, there are no data supporting the cost-effectiveness
of screening for underlying malignancy in patients with
RS3PE; however, it may be appropriate to screen individuals
at high risk and those who fail to respond to therapy.
Palmar Fasciitis and Arthritis
Palmar fasciitis and polyarthritis syndrome is characterized
by progressive bilateral digital contractures, inflammatory
fasciitis, fibrosis, and inflammatory polyarthritis. The syn-drome
typically precedes the tumor presentation. It has been
described most commonly with ovarian carcinoma but has
also been reported with endometrial, gastric, pancreatic,
prostate, and breast carcinoma, as well as in chronic lym-phocytic
leukemia and Hodgkin’s disease. Cases have also
been described without underlying malignancy.1 Steroids,
NSAIDs, or hand therapy have little effect; while successful
treatment of the underlying tumor can improve symptoms.
Women who present with inflammatory palmar fasciitis or
palmar fibromatosis should have a thorough malignancy
work-up including gynecologic examination.5
Inflammatory Myopathy
Inflammatory myopathies have been associated with malig-nancy
but are most frequently seen with dermatomyositis
(DM) and polymyositis (PM). Hill and associates6 used
national databases and found malignancy in approximately
30% of DM and 15% of PM cases, with most malignancies
diagnosed within 1 year of the development of myositis.
The risk of developing malignancy persisted over 5 years in
patients with DM. The most common malignancies identified
were ovarian, lung, pancreatic, stomach, bladder, colorectal
Table 1 Rheumatologic Manifestations of Malignancy
Direct tumor invasion into joints
Leukemia
Lymphoma
Multiple myeloma
Skeletal metastasis
Metastatic carcinomatous arthritis
Arthropathies
Carcinomatous polyarthritis*
Hypertrophic osteoarthropathy*
Relapsing seronegative symmetric synovitis with pitting
edema*
Palmar fasciitis and arthritis*
Gout
Rheumatoid-arthritis like syndrome
Multicentric reticulohistiocytosis
Panniculitis-arthritis
Muscular Disorder
Inflammatory myopathies*
Lambert-Eaton myasthenic syndrome
Vasculitic Syndrome
Vasculitis*
Cutaneous leukocytoclastic vasculitis presenting after
age 50*
Atypical polymyalgia rheumatica*
Scleroderma and Scleroderma Mimicks
Systemic scleroderma
Eosinophilic fasciitis
Other
Erythromelalgia*
Raynauds syndrome presenting after age 50
Lupus-like syndrome
Sjogren syndrome with monoclonality
Antiphospholipid antibody syndrome*
Chronic regional pain syndrome
Relapsing polychondritis
Erythema nodosum lasting more than 6 months
*Discussed in detail.
Table 2 Rheumatic Syndromes Caused by Anti-
Neoplastic Therapy
Rheumatic Syndrome Anti-Neoplastic Therapy
Raynauds Bleomycin
Vinblastine
Vincristine
Cisplatin
Skin thickening Bleomycin
Graft-versus-host disease
Arthralgias, myalgias
(post-chemo rheumatism)
Interleukin-2
Aromatase Inhibitors
Cisplatin
5-Fluorouracil
Cyclophosphamide
Methotrexate
Tamoxifen
SLE-like/RA-like
syndromes
Interferon
Polymyositis Graft-versus-host disease
Osteoporosis Aromatase Inhibitors
Anti-androgens
Reactive Arthritis Bacillus Calmette-Guerin

3. Bulletin of the NYU Hospital for Joint Diseases 2012;70(2):109-14 111
cancers, and non-Hodgkin’s lymphoma (NHL). Features
suggesting malignancy include older age, male gender,
rapid onset of skin or muscle symptoms, skin necrosis, and
periungual erythema.7
Antisynthetase syndrome is characterized by the presence
of antihistidyl tRNA synthetase (Jo-1) antibody, interstitial
lung disease (ILD), Raynaud’s phenomenon, arthralgia/
arthritis and “mechanic’s hands.” It is thought to have a
negative association with malignancy. However, case reports
have shown a positive association with malignancy.8
Chinoy and coworkers9 found that patients without
myositis-specific and myositis-associated autoantibodies, in-cluding
anti-Jo-1, anti-PM-Scl, anti-U1-RNP, anti-U3-RNP,
anti-Ku antibodies, had an increased risk of malignancy.
However, the presence of autoantibodies specifically directed
to the N‐terminal fragment of the Mi‐2β antigen has an as-sociation
with malignancy.10 Additionally, the presence of the
antibody against 155 kDa and 140 kDa protein (anti-155/140
antibody) has been found to be a significant risk factor for
malignancy associated DM. Given the positive predictive
value, the antip155 antibody is useful in detecting occult
malignancy in patients with DM but is difficult to obtain in
clinical practice.9
Currently, there is no consensus concerning who to
screen for malignancy, what type of screening should be
done, and how often it should be repeated. We recommend
age, gender, and ethnic specific cancer screening, which
should begin with careful history and physical including
gynecologic examination. Routine laboratory testing should
include: complete blood count, erythrocyte sedimentation
rate (ESR), routine biochemistry, urinary cytology, and fe-cal
occult blood test. Special testing with tumor markers is
more controversial but may be indicated. Imaging such as
mammography, computed tomography (CT), and ultrasound
of the chest, abdomen, and pelvis should be completed.11
FDG-PET/CT, a single imaging study for diagnosing occult
malignancy, was found to be comparable to broad conven-tional
screening but is not yet widely used.12
Vasculitides
Vasculitis syndromes may predate, follow, or occur concur-rently
with malignancy and are more commonly associated
with hematologic malignancies. In contrast to a traditional
paraneoplastic syndrome, malignancy appears to be a vascu-litis-
triggering factor characterized by a disassociation of the
clinical courses. In his analysis of 60 patients with vasculitis
associated with malignancy, Fain and colleagues13 found cu-taneous
leukocytoclastic vasculitis (LV), polyarteritis nodosa
(PAN), Churg-Strauss syndrome, microscopic polyangiitis,
Wegener’s granulomatosis, and Henoch-Schonlein purpura
(HSP) to be triggered by malignancy. Of these, LV (45%)
and PAN (36.7%) were most commonly seen.
Fain and colleagues also described that investigation
for occult malignancy may be needed when the vasculitis
becomes chronic, treatment is no longer effective, or the
disease is uncontrollable. Elderly males with HSP and joint
involvement were shown to have an increased risk for solid
tumors, less often hematologic malignancies, and should
be screened for cancer. Tumor relapse or cytologic trans-formation
should be considered when vasculitis develops
in a patient being followed for a malignancy.13
There have been conflicting data regarding the incidence
of malignancy associated with giant cell arteritis (GCA).
In their population-based case-control study, Kermani and
associates14 indicated that GCA patients had significantly
fewer malignancies prior to the diagnosis as compared
with controls. In a population based study, Myklebust and
coworkers15 found no differences in frequencies or types
of malignant neoplasms between patients with GCA and
population controls. However Liozon and colleagues16 re-ported
that 7.4% of patients with GCA were diagnosed with
a concurrent malignancy within one year, most commonly
solid tumors and hematologic malignancies.
Atypical Polymyalgia Rheumatica
Patients with classical polymyalgia rheumatica (PMR) have
not been shown to have increased frequency of malignancy.15
However, a PMR-like syndrome, with atypical features
including age greater than 50 years, limited involvement of
only one traditional site, asymmetric involvement, additional
painful joints, an ESR of less than 40 or greater than 100
mm/h, and lack of improvement on prednisone 10 mg/day
has been shown to be associated with malignancy. Patients
with atypical PMR may benefit from a workup for malignant
involvement of bones and joints.17
Erythromelalgia
Erythromelalgia is characterized by recurrent attacks of
burning pain and warmth and erythema of the extremities,
and it can be associated with myeloproliferative disorders
and thrombocythemia. Onset of may be gradual or abrupt,
and exacerbated by exercise, heat, or dependency of limbs.
Treatment consists of analgesia, such as aspirin, and control
of the underlying disease.18
Antiphospholipid Antibodies
There is a higher prevalence of antiphospholipid antibod-ies
(aPL) in patients with solid tumors and hematologic
malignancy compared to those in the general population.
Similarly, there is a higher rate of thromboembolic events
in aPL positive cancer patients compared to controls who
have the same malignancy without aPL. Manifestations of
antiphospholipid syndrome (APS) in patients with malig-nancy
are similar to those in classic APS and catastrophic
antiphospholipid syndrome (CAPS).19
There is no consensus on the management of patients with
aPL and malignancy. Given the increased risk of thrombo-embolic
events in patients with aPL and malignancy, prophy-lactic
anticoagulation should be considered. In healthy aPL
carriers, evaluation for underlying hematologic malignancy

4. 112 Bulletin of the NYU Hospital for Joint Diseases 2012;70(2):109-14
may be indicated.19 In the case of CAPS, malignancy should
be considered as a precipitating factor.20
Rhumatic Complications of Cancer
Therapies
Post-Chemotherapy Rheumatism
A newly recognized but poorly defined syndrome, post-chemotherapy
rheumatism is a non-inflammatory, migratory,
and usually self-limited arthropathy of less than 1 year.
Symptoms often develop several weeks to months after
completion of chemotherapy and include severe myalgias
and morning stiffness. Arthralgias and periarticular swell-ing
typically involve hands, ankles, and knees. Antinuclear
antibody and RF are not diagnostic, and radiographs do
not usually reveal erosion. Symptoms are best treated con-servatively
with NSAIDs. Recurrent carcinoma or other
inflammatory conditions should be excluded.21
Although the underlying pathogenesis of this process is
as yet unknown, proposed mechanisms include premature
menopause and complications of immune reconstitution
after completion of treatment.22-24 The most frequently
associated chemotherapeutics include cyclophosphamide,
5-fluorouracil, tamoxifen, methotrexate, and cisplatin.25
While post-chemotherapy rheumatism has been best de-scribed
in patients treated for breast cancer, it has also been
reported in other malignancies including ovarian cancer and
non-Hodgkin lymphoma.21
Aromatase Inhibitors and Anti-androgen Therapy
The aromatase inhibitors (AIs) are increasingly being used
as adjuvant therapy in the management of hormone receptor
positive breast cancer. Its use has been associated with an
increased risk for musculoskeletal complications such as ar-thralgias
and bone mineral density (BMD) loss. Studies have
shown that approximately 47% describe joint symptoms that
either develop or worsen within 2 to 3 months of initiating
AIs.26 Wrists, hands, and knees are disproportionately affect-ed
with associated pain and morning stiffness. The majority
of patients describe mild to moderate symptoms; however
in one study, 5% of patients reported a marked decline in
quality of life necessitating withdrawal from treatment.27
Studies have also shown an increased trend toward
osteoarthritic changes in the hands, as well as functional
disabilities.28 Markers of inflammation are usually normal.
The etiology, time course, and treatment for AI-induced
arthralgias are not well understood and may be related to
estrogen deprivation. Current recommendations include
mild analgesics, topical medications, NSAIDs, and regular
exercise, but these may not be fully effective. Spontaneous
symptom resolution on AI therapy is rare. Discontinuation
of therapy or switching to a selective estrogen receptor
modulator (SERM), such as tamoxifen, is an alternative in
patients with debilitating symptoms and usually alleviates
pain within weeks.29
Data from clinical trials of third generation aromatase
inhibitors (anastrozole, letrozole, and exemestane), have
shown a modest reduction in BMD, increased bone turnover,
and an increased risk of fragility fractures when compared
to standard tamoxifen therapy.30 In premenopausal women
with breast cancer, hypogonadism develops in at least 63%
of patients who receive adjuvant chemotherapy. With ovar-ian
failure, a significant decline in bone density can be seen
within 6 months.31
According to American Society of Clinical Oncology
(ASCO) guidelines, postmenopausal women treated with
AIs are at increased risk for osteoporosis. Current recom-mendations
include annual surveillance with DXA scans,
weightbearing exercise, and initiation of osteoporotic treat-ment
for those with T-scores less than -2.5.32
Other chemotherapeutic agents, including anti-androgens
for prostate cancer, may also induce osteoporosis.33 Cur-rently,
no medications have been approved for the prevention
of chemotherapy-induced bone loss.
Bacillus Calmette-Guerin (BCG)
Musculoskeletal manifestations have been described in ap-proximately
0.5% to 5% of patients receiving intravesical
administration of live attenuated Bacillus Calmette-Guerin
(BCG) for superficial bladder cancer. Typical manifestations
include bland arthralgias or aseptic arthritis. Although rare,
most cases occur after 2 to 4 weeks of BCG therapy and
present as an oligoarthritis involving knees and ankles.34
Additional symptoms suggestive of an associated reactive
arthritis (ReA) include concomitant urinary tract symptoms,
sacroiliitis, dactilytis, keratoconjunctivitis sicca, and signs of
ocular inflammation. Symptoms typically remit with cessa-tion
of BCG therapy, and complete clinical recovery within
6 months. Chronic cases have been described in patients
who are HLA-B27 positive. Therapy, with variable response,
includes NSAIDs, corticosteroids, hydroxychloroquine,
isoniazid, and rifampin.35
Another rare complication of intravesical BCG admin-istration
is vertebral osteomyelitis (Pott’s Disease), which
requires 9 to 12 months of anti-tuberculous medications.36
Miscellaneous Cancer Therapies
Several other chemotherapeutic agents have been linked with
the development of rheumatic manifestations.
Raynaud’s phenomenon, with its characteristic skin
color changes and pain in response to cold exposure, has
been well described with the use of bleomycin, vinblastine,
vincristine, and cisplatin in the treatment of lymphomas
and germ cell tumors.37 The proposed mechanisms include
direct vascular toxicity leading to endothelial dysfunction
versus neurotoxicity causing an aberrant sympathetic arterial
vasoconstrictive response.38
Bleomycin has also been associated with the development
of a scleroderma-like disease characterized by skin thicken-ing,
pulmonary fibrosis, and Raynaud’s phenomenon.39 This
should be distinguished from scleroderma mimics, which

5. Bulletin of the NYU Hospital for Joint Diseases 2012;70(2):109-14 113
can include graft-verses-host disease (GVHD). Unlike pri-mary
scleroderma, GVHD skin thickening usually spares
the fingers, has a limited distribution, and is not associated
with Raynauds’s phenomenon. A typical case may occur
after bone marrow transplantation.40
Granulocyte and granulocyte-macrophage colony stimu-lating
factors (G-CSF/GM-CSF) used in conjunction with
chemotherapy may lead to the development of an acute
symmetric inflammatory arthropathy. Symptoms often oc-cur
within hours or days of treatment with the stimulating
factor.41
Cytokine based immunotherapy, such as interferon-alpha
(INF-alpha) and interferon-gamma (INF-gamma), used in
the treatment of lymphoproliferative malignancies, have
been associated with the development of autoimmune dis-orders
such as a lupus-like syndrome.42 Most reported cases
have shown a reduction in antibody titers, marked clinical
improvement, or remission upon cessation of therapy. Other
potential complications of INF therapy include exacerbation
of pre-existing hepatitis C virus-related arthritis and the
induction of a RA-like symmetric polyarthralgia.42,43
Interleukin-2, used in the treatment of metastatic malig-nant
melanoma and renal cell carcinoma, has been reported
to induce the development of psoriatic arthritis, ankylosing
spondylitis, RA, ReA, and an inflammatory necrotizing
myositis, as well as causing exacerbations of pre-existing
scleroderma.42,44 Discontinuation of treatment generally
leads to symptomatic improvement.
Another complication of cancer therapy is PM which has
been described in association with graft-versus-host disease.
One center reported 12 cases of PM over a 30 year period in
patients with chronic GVHD who received allogeneic stem
cell transplantation.45
Conclusion
The delineation of an underlying malignancy from a primary
rheumatic disease can be a challenge for the astute clinician.
There is currently no consensus on which patients or how
extensively to screen for malignancy in rheumatic syn-dromes.
It is neither practical nor cost effective to perform
an extensive search for malignancy in most patients with
rheumatic conditions, unless they have features suggesting
an occult neoplasia including:
• Personal or family history of malignancy,
• Exposure to carcinogens or medications known to
cause malignancy,
• Severe or atypical presentation,
• Asymmetric or explosive onset arthritis in the el-derly,
• Constitutional features out of proportion with the
degree of arthritis,
• Paraneoplastic syndrome,
• Failure to respond to traditional therapies, or
• Presence of serologic markers of malignancy (tumor
markers and autoantibodies).
Early diagnosis of malignancy through awareness of these
associations can lead to improved patient outcomes. In the
case of paraneoplastic syndromes, the severity of symptoms
can be used as a guide to the response of tumor therapy, since
treating the underlying tumor will often resolve the paraneo-plastic
features. Additionally, knowledge of the association
of rheumatic symptoms with various chemotherapeutic
agents is essential to differentiate from primary rheumatic
disease.
Disclosure Statement
No funding was received for this review and authors do not have
any financial interests. A portion of this review was presented at
the American College of Rheumatology Annual Scientific Meeting
in November 2010 by Dr. Valeriano-Marcet.
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