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\begin{document}

\title{Paraneoplastic Syndrome of Arthropathies as Presenting Sign for
Non-small Cell Lung Cancer}



\author[1]{Alexander Lee}%
\author[1]{Gurpreet Singh}%
\author[1]{Cleveland Lewis}%
\affil[1]{Garnet Health Medical Center}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Paraneoplastic syndrome is often not an obvious or common clinical
presentation, but this report demonstrates that migratory arthropathies,
may be the first presenting sign for non-small cell lung cancer (NSCLC).
This study showcases an example of paraneoplastic syndrome, so other
healthcare providers can be aware of early NSCLC manifestations.%
\end{abstract}%



\sloppy


\textbf{Paraneoplastic Syndrome of Arthropathies as Presenting Sign for
Non-small Cell Lung Cancer}

\textbf{Running head} : Paraneoplastic Syndrome of Arthritis in NSCLC

Alexander Kyle Lee D.O., Gurpreet Singh D.O., Cleveland W. Lewis Jr.
M.D.

Division of Thoracic Surgery, Department of Surgery, Garnet Health
Medical Center, Middletown, NY

\textbf{Keywords} : Paraneoplastic syndrome, Non-small Cell Lung Cancer,
Arthritis, Migratory Arthropathy

\textbf{Corresponding author and request for reprints} :

Cleveland W. Lewis Jr. M.D.

Division of Thoracic Surgery, Department of Surgery, Garnet Health
Medical Center, Middletown, NY

707 East Main St., Middletown, NY, 10940

Phone: (845) 333-7575

Email: clewis@garnethealth.org

\textbf{Conflicts of Interests and Sources of Funding}

The authors have no source of funding to disclose and have no financial
or proprietary interest in the subject matter of this article

\textbf{Consent Statement}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy

Abstract

Paraneoplastic syndrome is often not an obvious or common clinical
presentation, but this report demonstrates that migratory arthropathies,
may be the first presenting sign for non-small cell lung cancer (NSCLC).
This study showcases an example of paraneoplastic syndrome, so other
healthcare providers can be aware of early NSCLC manifestations.

(49 words)

\textbf{Paraneoplastic Syndrome of Arthropathies as Presenting Sign for
NSCLC}

\textbf{Introduction}

Lung and bronchus cancer is the third leading cancer in the United
States (US) and was the leading cause of cancer death in
2019.\textsuperscript{1} Deaths from lung and bronchus cancer also
accounted for 23\% of all deaths related to
cancer.\textsuperscript{2}Lung cancer is split up into four major types
of lung cancer that account for 88\% of primary lung cancer;
adenocarcinoma, squamous cell, small cell, and large cell, listed in
descending order.\textsuperscript{3} These non-small cell lung cancers
(NSCLC) makes up the majority of all lung cancers, however presentations
of these cancers range from a peripheral nodule, central mass, to widely
disseminated disease.\textsuperscript{3} The presentation of lung cancer
can sometimes be easily seen when incidentally found on imaging, other
times it is more subtle, like when presenting as a Paraneoplastic
syndrome. These syndromes can present as hypercalcemia (squamous cell),
SIADH (small cell), gynecomastia (large cell), or even connective tissue
syndromes such as clubbing and hypertrophic osteoarthropathy (HOA) which
are both most often associated with NSCLC.\textsuperscript{20}

In this article, we describe a patient who experienced joint pain in her
hands and pain in one knee, which later progressed to her other leg. She
was ultimately found to have NSCLC of squamous origin. A thorough
literature review on NIH Database has shown multiple case studies that
show the correlation between NSCLC and HOA involving large joints.
However, there are limited reports of singular joint involvement with
later progression to other joints. One case report showed a patient with
NSCLC who had 2 weeks of acute joint pain in all four extremities,
including his hands, fingers, knees, and ankles and was found to have
adenocarcinoma.\textsuperscript{4} Another retrospective study by
Cantini and associates did a study from the years 2000 to 2005 which
included patients with isolated knee monoarthritis as the initial
presenting sign.\textsuperscript{5} The study eventually found that five
out of 296 patients with isolated knee monoarthritis were found to have
NSCLC.\textsuperscript{5} This conclusion was again demonstrated in 2020
by a case report involving monoarthritis in the knee, a presenting sign
of HOA associated with NSCLC. However, the patient evaluated in this
article shows that this monoarthritis could spread to other joints,
which emphasizes the importance of watching for spreading arthropathies
as a presenting symptom of NSCLC and how surgery could be the definitive
treatment.

\textbf{Case Presentation}

This patient was a 56-year-old female who presented to a local urgent
care due to persistent cough that she had had for about a week. The
cough was dry in nature (no hemoptysis) and her only other complaints at
the time were severe joint pain, requiring NSAID use, and swelling of
her fingers. While she was there, she was tested for COVID, which was
negative, and had a CXR which was read after the patient left the urgent
care. Of note, this patient had minimal past medical history but did
have a 55-pack year smoking history with cessation of tobacco products 2
years prior. Patient does vape daily. After the urgent care visit, she
was sent home with azithromycin for suspected community acquired
pneumonia but was later called for a suspicious lesion found on the CXR
located near the right lateral pleural space. This lesion was not seen
on CXR that she had 5 years prior, for an unrelated issue.

She was then referred to a pulmonologist for evaluation of the
persistent cough and CXR finding. The pulmonologist did a thorough work
up for the right lower lobe lung mass, which included a CT of the
abdomen/pelvis, pulmonary function tests, and a PET scan of her body,
with plans to biopsy the mass (Figure 1). A CT guided biopsy of the mass
was diagnostic for invasive poorly differentiated squamous cell
carcinoma. PET CT scan and MRI of the spine revealed the mass to be
without metastases. However, the imaging did reveal right posterolateral
chest wall involvement.

At this time, she was sent to thoracic surgery for pre-operative
evaluation. Upon presentation to our clinic, patient states she was
taking ibuprofen for left knee pain that started about a year ago and a
few months after the onset the pain migrated to other sites, including
her right knee, right ankle, and left foot. She had also noticed
progressive swelling in her phalanges and metacarpal bones bilaterally
at the time she developed the nonproductive cough.

After appropriate clearances patient underwent a flexible bronchoscopy,
right posterolateral thoracotomy with a right lower lobectomy with en
bloc chest wall resection of posterior ribs 7-8, and a mediastinal lymph
node dissection. Patient was discharged on post op day 4 without
complications and was seen again in the clinic for a 1 week follow. The
final pathology demonstrated an 11 cm, T4 N0 M0 Stage IIIB squamous cell
carcinoma. During the visit she noted that her joint pain and swelling
had significantly improved. She then continued on to her post operative
adjuvant chemotherapy and her follow up surveillance appointments,
according to the NCCN guidelines; 6 month follow up PET-CT showed no
evidence of active neoplastic disease (Figure 2).

\textbf{Discussion}

HOA is a syndrome with stages in the disease process, most often
starting with clubbing of fingers and progressing to other symptoms such
as joint pain, periostosis, etc.\textsuperscript{6} These symptoms can
differ in severity from patient to patient, making the diagnosis of HOA
challenging.\textsuperscript{6} There are several proposed theories on
the pathogenesis of HOA; the exact physiology still remains unclear. One
popular theory includes release of platelet derived growth factors
(PDGF), prostaglandin E, and vascular endothelial growth factor (VEGF)
by megakaryocytes that have bypassed the pulmonary capillary
network.\textsuperscript{7} These growth factors lead to fibroblast
proliferation, distal clubbing, vascular hyperplasia, and new bone
formation. Patients with HOA have been shown to have significantly
higher levels of PDGF and VEGF.\textsuperscript{7} Although the
diagnosis is a clinical one, bone scintigraphy is a useful adjunctive
for detection. Characteristic findings on scintigraphy include bilateral
increased uptake in long bones, with periostitis being the hallmark of
hypertrophic pulmonary osteoarthropathy.\textsuperscript{8}

Various treatments of HOA have been studied, however, treatment with
surgical resection of the primary tumor results in rapid long-term
remission of symptoms.\textsuperscript{9} This was evident in our case
with almost complete resolution of our patient's joint pain and swelling
during her 1 week follow up. Other treatments that have shown to provide
relief in HPO include bisphosphonates\textsuperscript{10} and
octreotide\textsuperscript{11}. One case was also treated with an EGFR
inhibitor, gefitinib.\textsuperscript{12} It is important to understand
that conventional analgesics, including NSAIDs have limited efficacy on
HOA. Utilizing these alternative medications for refractory cases of HOA
can help symptomatic relief in many patients.

HOA can also be a sign of a multitude of different organ systems being
affected which makes this a syndrome that all physicians should be aware
of. According to the study by Martinez-Lavin, the majority of cases will
only show manifestations of clubbing in the
fingers.\textsuperscript{6}However, although the patient in this report
did have clubbing in her fingers during examination, her main complaint,
and first to manifest, was the migratory arthritis. This presentation of
arthritic pain in her left knee is unusual to appear prior to clubbing
of her fingers and the length of time from onset of arthritis to
respiratory symptoms are unusual. This patient presentation stresses the
importance of always having lung cancer on the differential diagnosis in
the setting of any symptom associated with HOA. It also shows
monoarthritis that spread to other joints is a potential symptom
heralding adenocarcinoma of the lung.

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\textbf{Hosted file}

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