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\begin{document}

\title{Parapharyngeal tuberculoid mass: a rare complication of Bacillus
Calmette-Gue\selectlanguage{english}rin therapy for urothelial carcinoma in situ\selectlanguage{english}}



\author[1]{Karolina Plonowska}%
\author[1]{Monica Fung}%
\author[1]{Christine Glastonbury}%
\author[2]{Patrick Ha}%
\affil[1]{University of California San Francisco}%
\affil[2]{University of California San Francisco School of Medicine}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Bacillus Calmette-Gue\selectlanguage{english}rin (BCG) is commonly used in treating superficial
urothelial carcinoma. Though rare, local and systemic disseminated BCG
infections are important to recognize as they require prolonged
antimicrobial therapy and surveillance. We present an unusual case of a
parapharyngeal space mass as manifestation of disseminated BCG following
urothelial carcinoma treatment.%
\end{abstract}%



\sloppy


\textbf{Title:} Parapharyngeal tuberculoid mass: a rare complication of
Bacillus Calmette-Gue\selectlanguage{english}rin therapy for urothelial carcinoma \emph{in situ}

\textbf{Authors:} Karolina A. Plonowska, MD,\textsuperscript{1} Monica
Fung, MD,\textsuperscript{2} Christine Glastonbury,
MD,\textsuperscript{1,3} Patrick K. Ha, MD*\textsuperscript{1,4}

\textbf{Author Affiliations:}

\textsuperscript{1} Department of Otolaryngology-Head and Neck Surgery,
University of California-San Francisco, San Francisco, CA.

\textsuperscript{2} Department of Medicine -- Infectious Disease,
University of California-San Francisco, San Francisco, CA.

\textsuperscript{3} Department of Clinical Radiology, University of
California-San Francisco, San Francisco, CA.

\textsuperscript{4} Division of Head and Neck Surgical Oncology,
Department of Otolaryngology-Head and Neck Surgery, University of
California-San Francisco, San Francisco, CA.

\textbf{*Corresponding Author:}

Patrick K. Ha, MD

550 16th. Street, Rm 6765

UCSF Box 3213

San Francisco, CA 94158

Patrick.Ha@ucsf.edu

\textbf{Author disclosures:} The authors report no relevant disclosures.
PKH did serve on advisory boards for Loxo/Bayer Oncology and received
research/educational funding from Stryker, Synthes, and Medtronic.

\textbf{Key terms:} parapharyngeal mass, Bacillus Calmette-Gue\selectlanguage{english}rin,
mycobacterial infection, tuberculoid mass; mycobacterium bovis; BCG

\textbf{Key Clinical Message:}

Local and systemic complications of Bacillus Calmette-Gue\selectlanguage{english}rin therapy are
important to recognize as they require prolonged antimicrobial therapy;
molecular genomic testing may be key to diagnosis when culture data is
inconclusive.

\textbf{Manuscript word count:} 783

\textbf{Parapharyngeal tuberculoid mass: a rare complication of Bacillus
Calmette-Guerin therapy for urothelial carcinoma \emph{in situ}}\selectlanguage{english}

Karolina A. Plonowska, MD, Monica Fung, MD, Christine Glastonbury, MD,
Patrick K. Ha, MD

\textbf{Abstract}

Bacillus Calmette-Gue\selectlanguage{english}rin (BCG) is commonly used in treating superficial
urothelial carcinoma. Though rare, local and systemic disseminated BCG
infections are important to recognize as they require prolonged
antimicrobial therapy and surveillance. We present an unusual case of a
parapharyngeal space mass as manifestation of disseminated BCG following
urothelial carcinoma treatment.

\textbf{Key Clinical Message}

\textbf{Introduction}

Bacillus Calmette-Gue\selectlanguage{english}rin (BCG), a live-attenuated stain
of\emph{Mycobacterium bovis} , has been successfully used as
intravesical immunotherapy in superficial (muscle-sparing) bladder
cancer for over 40 years.\textsuperscript{1} It is the treatment of
choice in patients with urothelial carcinoma \emph{in situ} (Tis) and
early-stage disease (Ta-T1), and has been shown to reduce both its
recurrence and progression.\textsuperscript{2} While its precise
mechanism of action remains poorly defined, BCG infection of the
urothelium stimulates a cytokine-mediated immune response and confers
anti-tumor activity by cytotoxic T lymphocytes.\textsuperscript{3}

Local and systemic infectious complications of BCG intravesical therapy
are rare; the most common of these is BCG cystitis, but reported
manifestations include orchitis, sepsis, granulomatous hepatitis,
pneumonitis, osteomyelitis, arthritis, and mycotic aneurysms. In this
report, we describe a rare case of a 71 year old male with bladder
carcinoma \emph{in situ} treated with two courses of intravesical BCG
who presented with development of a parapharyngeal mass, ultimately
found to be distant mycobacterial infection.

\textbf{Case Report and Discussion}

This study was exempt from review by the UCSF Institutional Review
Board. A 71 year old man presented to clinic with a six month history of
a left-sided soft, compressible neck mass. He denied any associated pain
or dysphagia, compressive symptoms, hoarseness, or globus. His past
surgical history was notable for a childhood adenotonsillectomy;
urothelial carcinoma \emph{in situ} status post two transurethral
resections of bladder tumors and two therapeutic courses with one
maintenance intravesical immunotherapy with BCG. His treatment was
complicated by BCG cystitis, for which the patient was treated with a
three weeks of isoniazid and rifampin, and his symptoms resolved. The
last intravesical BCG therapy was completed six months prior to
developing a neck mass and 12 months prior to presentation in clinic.

Outside hospital workup of the mass included an ultrasound of the neck
and an MRI. These showed a left level II/III 6.6 x 2.8 cm complex cystic
mass with a mural soft tissue component and an unusually thick
septation. The patient had undergone two fine-needle aspirations, which
yielded purulent material with neutrophils but no observed growth on
bacterial, fungal, and acid-fast bacilli cultures. A multidisciplinary
review of this case favored additional imaging with computed tomography
of the neck and chest (Figure 1). This demonstrated a left lateral neck
non-calcified fluid collection with a thick rim and enhancing internal
septation. There were no associated calcifications, no surrounding
inflammatory changes, and the collection displaced the carotid and
jugular vessels anteriorly. Chest CT revealed calcifications within
mediastinal lymph nodes and spleen, indicating prior granulomatous
infection.

The infectious disease service was consulted for diagnostic workup and
management. QuantiFERON-TB Gold Plus returned negative. The patient also
tested negative for human immunodeficiency virus, which confers a higher
incidence of tuberculous lymphadenitis with
co-infection.\textsuperscript{4} Additional antibody and antigen testing
for \emph{Histoplasma capsulatum} , \emph{Coccidioides immitis}
,\emph{Coxiella burnetii} , \emph{Bartonella} and \emph{Brucella}
species was unremarkable. The patient was started empirically on
isoniazid, rifampin, and ethambutol given high clinical suspicion for
disseminated BCG infection. 16S ribosomal RNA sequencing of FNA specimen
ultimately detected \emph{mycobacterium tuberculosis} complex. Specimen
was sent to the California State Laboratory for pyrosequencing, which
detected DNA of \emph{M. bovis} and confirmed susceptibility to
isoniazid and rifampin. On therapy, patient initially experienced
paradoxical worsening of the left neck mass before improvement. At most
recent follow-up in March 2020, the patient had nearly completed planned
six months of antimicrobial therapy with a persistent small area of
nodular hyperpigmentation at the neck mass site.

A parapharyngeal space lesion is a rare complication of BCG treatment
for urothelial carcinoma. Risk of disseminated mycobacterial infection
is increased in individuals with foreshortened time between surgical
treatment and intravesical instillation of BCG. Reported onset of
symptoms can vary from 3 months to 1 year following BCG
treatment.\textsuperscript{5}

Disseminated BCG infections may not require surgical intervention, but
should be treated with extended courses of medical therapy and undergo
surveillance for treatment response. A suggested duration of therapy is
three to six months with a multidrug regimen of rifampin, isoniazid, and
ethambutol. A close review of the patient's medical history and
exposures is needed to raise suspicion for this rare etiology. Molecular
diagnostics, such as 16S rRNA sequencing, may be key to diagnosis in
cases where serology and culture-based testing is inconclusive.

\textbf{Author contributions:}

KAP performed patient chart review, literature review for prior reported
BCG therapy sequalae, and authored the manuscript. PKH and MF were
involved in the clinical care for the case patient presented and
contributed to the final manuscript. CG reviewed and interpreted imaging
studies for the case, identified representative imaging findings, and
contributed to the manuscript text.

\textbf{Acknowledgements:}

None

\textbf{References:}

1. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus
Calmette-Guerin in the treatment of superficial bladder tumors. \emph{J
Urol} . 1976;116(2):180-183.

2. Han RF, Pan JG. Can intravesical bacillus Calmette-Guerin reduce
recurrence in patients with superficial bladder cancer? A meta-analysis
of randomized trials. \emph{Urology} . 2006;67(6):1216-1223.

3. De Boer EC, De Jong WH, Steerenberg PA, et al. Induction of urinary
interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during
intravesical immunotherapy with bacillus Calmette-Guerin in superficial
bladder cancer. \emph{Cancer Immunol Immunother} . 1992;34(5):306-312.

4. Hill AR, Premkumar S, Brustein S, et al. Disseminated tuberculosis in
the acquired immunodeficiency syndrome era. \emph{Am Rev Respir Dis} .
1991;144(5):1164-1170.

5. Gonzalez OY, Musher DM, Brar I, et al. Spectrum of Bacille
Calmette-Gu\selectlanguage{ngerman}érin (BCG) Infection after Intravesical BCG
Immunotherapy.\emph{Clinical Infectious Diseases} . 2003;36(2):140-148.

\textbf{Figure Captions:}

\textbf{Figure 1.} (A) Axial and (B) sagittal contrast-enhanced computed
tomography demonstrating an elongated thick-walled, irregular fluid
density collection deep to the sternocleidomastoid muscle, displacing
carotid vessels anteriorly. There were no associated calcifications or
infiltration of adjacent tissues.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
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\end{document}

