\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Near missed diagnosis of Merkel Cell Carcinoma in a young
immunocompetent woman with a recurrent left-arm mass: A case report}



\author[1]{fateme salemi}%
\author[2]{Seyed Mohammad Reza  Mortazavizadeh}%
\author[1]{Shokouh  Taghipour Zahir}%
\author[3]{Soroush  Shahrokh}%
\affil[1]{Shahid Sadoughi University of Medical Sciences and Health Services}%
\affil[2]{Islamic Azad University Yazd Branch}%
\affil[3]{University of Texas Medical School at Houston Department of Internal Medicine}%


\vspace{-1em}



  
  \date{May 23, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{INTRODUCTION}

Merkel Cell Carcinoma (MCC) is a rare, life-threatening tumor with
neuroendocrine features. Due of its extremely low occurrence worldwide,
epidemiological data on the disease is limited. (1). Commonly recognized
risk factors include fair skin, history of skin cancer, old age, chronic
immunosuppression, chronic ultraviolet (UV) light exposure, and Merkel
cell polyomavirus (MCPyV) infection (2). Amongst these factors, MCPyV
and UV exposure play a fundamental role with synergistic effects in the
pathophysiology of MCC (3). Despite being a part of normal skin flora in
most individuals, MCPyV DNA can clonally combine with the genome of
neoplastic cell precursors at the initial phases of carcinogenesis (4,
5). Concurrently, UV exposure elicits antigen-presenting dendritic cells
to produce inflammatory cytokines, leading to local immunosuppression
and creating an ideal environment for tumoral growth (6). Moreover,
immune hypersensitivity from UV exposure facilitates the viral
tumorigenic process (2).

Merkel cells cannot be derived from the MCC because they lack the
ability to proliferate. Merkel cell precursors (perhaps generated from
epidermal stem cells or hair follicle stem cells) and pre- and pro-B
cells appear to have histopathology, genetics, and molecular
characteristics with malignant cells instead (7).

MCC often presents as a single, asymptomatic erythematous or violaceous
nodule, often mistaken for cysts or abscesses. It usually originates
from the head or neck and generally spares the extremities (8).
Immunohistochemical (IHC) staining is required to validate
histopathological findings of small round cells that infiltrate
cutaneous or subcutaneous area. (7). Although MCC responds to the
combination of excisional surgery, radiotherapy, and chemotherapy, it
requires continuous follow-ups within the first year of diagnosis due to
the high recurrence rate (9).

Here, we present a 32-year-old Iranian (non-Caucasian) immunocompetent
female with a small nodule on her left arm at the disease onset finally
diagnosed as MCC. In this report, we aim to emphasize the significance
of early diagnosis and management of this cancer and highlight the
complications that a late diagnosis would entail for these patients.

\textbf{CASE REPORT}

A 32-year-old female with an unremarkable medical history presented to
the clinic with a small, non-tender, and erythematous nodule on the
dorsolateral aspect of her left arm, which initially appeared three
months before. Since then, the nodule had slowly darkened and grown to 1
cm \selectlanguage{ngerman}×1 cm in size. Her history and physical exam were insignificant
except for multiple warts on the dorsal aspect of the right hand.
(Figure 1). Initially, the patient was suspected of having an infectious
cyst and was treated with 10-days of antibiotics. However, she was
unresponsive to antibiotics and was evaluated by a surgeon, who
diagnosed the lesion as an abscess and surgically removed it.

After two weeks, a rapidly growing mass measuring 4 cm ×4 cm originated
from the incised area. The mass was surgically excised again but
reappeared within one week, measuring 5 cm ×5 cm, after which the
patient was referred to our hospital for further evaluation. The
magnetic resonance imaging (MRI11We first met the patient after her last
surgery. Unfortunately, the patient did not take any pictures from the
arm mass at the disease onset and intervals between surgeries.) of the
left arm with and without contrast showed multiple enhancing lesions at
the subdermal region of the posterolateral aspect of the left arm with
multiple enlarged axillary lymph nodes, the largest of which measured
approximately 17 mm, suggestive of metastasis. The tumor was radically
excised with negative surgical margins. Microscopic examination of the
lesion demonstrated a neoplastic round cell tumor with prominent foci of
necrosis (Figure 2). IHC staining revealed neoplastic cells with
positive expression for CD99, Ck20, and NSE (Figure 2), but no LCA,
Vimentin, CD3, CD20, and HMB45 expression consistent with MCC (Figure
3). Also, The MCPyV PCR real-time of the lesion was positive.

High-resolution computed tomography (HRCT) Scan of the chest and
abdominopelvic area with and without contrast showed lymphadenopathy 39
mm×25 mm in the left axillary fossa along with a calcified lymph node
(6mm) in the abdominal cavity beyond the left abdominal muscle. She was
diagnosed with stage III MCC and subsequently treated with adjuvant
radiation to her left arm and axilla with 45.0 Grays (Gy) of radiation
in 35 fractions, followed by six cycles of chemotherapy with etoposide
and cisplatin. The patient's post-treatment PET/CT scan showed no
evidence of neoplastic disease and supported remission. However,
high-dose chemotherapy caused frequent myalgias and weakened immune
system. Unfortunately, she developed febrile neutropenia and expired due
to septic shock one month after the last chemotherapy course.

\textbf{DISCUSSION}

MCC is a rare, aggressive malignancy with an estimated annual incidence
rate of 0.01 to 0.13 per 100,000 people globally. It predominantly
affects the elderly (probably due to chronic UV radiation from the sun
exposure), Caucasian males, and chronically immunocompromised patients,
especially recipients of organ transplants, those with
lymphoproliferative disorders, and untreated HIV infection (1).
Specifically, in the United States, more than 8 in 10 individuals
diagnosed with MCC are older than 70 years old, and more than 95\% are
Caucasian. Furthermore, males are twice more likely to be diagnosed with
MCC than females (10). When MCC occurs in a younger population, it often
involves children and is extremely rare in middle-aged adults (11).

Because of its low incidence, particularly in non-Caucasian populations,
asymptomatic nature, and indistinguishable clinical presentation, MCC
has a high rate of misdiagnosis (12). A retrospective analysis of 195
patients diagnosed with MCC found that less than 1\% were suspected of
having MCC on clinical evaluation, leading to a median delay of more
than three months from the initial appearance of the nodule to biopsy
sampling (13). Similarly, our patient was initially suspected of having
an infectious lesion rather than MCC, which significantly delayed her
initial presentation until her diagnosis. This case was further
complicated by the absence of any risk factors in our patient. The most
commonly recognized modifiable risk factors include MCPyV and long-term
UV radiation exposure, with more than half of primary MCC lesions
originating from the head and neck region (14). Despite the presence of
MCPyV in her arm lesion and multiple warts on the dorsal aspect of both
hands, she had none of the previously mentioned risk factors.

The clinical presentation of MCC is often variable and nonspecific. MCC
often presents as a tender, erythematous red to the violet-colored
lesion on sun-exposed skin regions, most commonly the head and neck, but
less commonly on the trunk or the extremities (15). The only
distinguishing characteristic of MCC is its rapid growth rate.
Otherwise, the lesion may or may not have central ulceration and may
present with superimposing infection, resulting in its misdiagnosis as
an abscess (16, 17). Tender or non-tender painless local or distant
lymphadenopathy may also be present in case of lymph-node metastasis or
superimposed infection (18).

Barreira et al. reported a 70-year-old immunocompromised woman with
painless inguinal lymphadenopathy. Further evaluations revealed a pink
plaque in the left knee whose histopathology confirmed MCC with lymph
node metastasis. Like our patient, she died due to a high tumor stage
and metastasis at the disease onset. However, palliative treatment was
indicated for this patient since she was dealing with underlying medical
problems such as nephrectomy due to renal tuberculosis and non-Hodgkin's
lymphoma~ (19). Similarly, Agut-Busquet E et al. reported a young white
woman with a well-defined subcutaneous mass measuring 3 cm × 2.5 cm in
size located in the dorsal aspect of the left arm. Nevertheless, MCC was
diagnosed before the tumor spread, resulting in more effective treatment
and complete remission one year after the diagnosis~(20).

Diagnostic imaging, including regional lymph nodes ultrasonography, CT
scan, MRI, and PET-CT scan, are often used for clinical staging and
monitoring a patient's prognosis. Early clinical detection is essential,
and the possibility of MCC should be considered in patients with rapidly
evolving skin lesions unresponsive to antibiotic therapy. However,
neither clinical evaluation nor imaging can accurately diagnose MCC,
with histopathologic evaluation and IHC studies the gold standard
diagnostic approach (18). Histopathology generally displays small,
uniformly rounded blue neoplastic cells with scanty cytoplasm. Even
larger pleomorphic cells with increased proliferation rate, broad tissue
infiltration, and lymphatic involvement may be detected. MCC-specific
IHC markers should confirm the diagnosis since they distinguish this
cancer from other small round cell tumors. The malignant cells show
positive immunoreactivity for CK20, CK8, CK18, CK19, synaptophysin,
HIP1, P36, TTF1, ASH1, S100B, and CK7, while Vimentin does not stain in
the IHC of MCC (21).

Clinical manifestations of patients easily distinguish between basal
cell carcinoma (BCC) and metastatic cell carcinoma (MCC). In pathology,
BCC neoplastic cells display size variability and stretched nuclei with
marked peripheral palisading. Unlike BCC, local lymph node metastasis
and intradermal spreading are characteristic of MCC. Nevertheless,
atypical cases of these two malignancies share similarities, including
the presence of mucin or amyloid in the stroma and peripheral slits
located in the tumor borders. Therefore, IHC plays a significant role in
differentiating these challenging samples. In contrast to BCC, MCC
stains with CK20 and epithelial membrane antigen~(22).

Small cell melanoma is a subtype of cutaneous melanoma that displays the
intraepidermal pagetoid spread in which round or atypical dendritic
melanocytes gather in nests. Despite expressing S100, the presence of
keratins and NSE differentiates this skin cancer from MCC (23). Although
lymphoma a presents quick indistinct inflammation with prominent small
cells in histology, its hematolymphoid markers, such as PAX5, TdT, and
immunoglobulins, are not detected in IHC staining of MCC (24). Also,
lymphoma lacks most IHC markers of MCC, such as CD45, CD3, and CD20
(25). Also, MCC and primary cutaneous Ewing sarcoma share similarities.
Small tumor cells that may be positive for keratin, CD99, FLI-1, and NSE
may be seen in both types of tumors. CK20 and dot-like keratin are not
found in Ewing Sarcoma while EWSR1 translocation defect is specifically
detected in this malignancy (26).

Imaging techniques, including ultrasonography of regional lymph nodes,
CT scan, MRI, and PET-CT scan associated with sentinel lymph node
biopsy, are essential for clinical staging, prognosis, and patient
follow-up. The mainstay treatment of MCC is radical surgical excision
accompanied by wide-field adjuvant radiotherapy in patients with lymph
node invasion (7). Chemotherapy indicated for systemic eradication of
neoplastic cells often fails to restrain tumor invasion and acts as
palliative care (27). Furthermore, retrospective analyses showing
inconsistent results on the effects of post-operative chemoradiation on
patient survival outcomes. Likewise, immune-check-point inhibitors
against pathways involved in pathogenesis is reserved for advanced-stage
cases unresponsive to chemotherapy (28).

In summary, we present a case of MCC with unspecific skin involvement
who was misdiagnosed at first and then underwent multiple complicated
surgeries. This report focused on the adverse effects of mismanagement
in MCC that led to its spread and made all the therapeutic options
ineffective. It underlined the consequences of delayed diagnosis in
aggressive skin tumors, as higher stages are associated with dismal
prognosis despite multidisciplinary approach and patient
immunocompetency. Therefore, in rapidly growing and recurrent cutaneous
lesions, prompt histopathologic assessment is required to improve the
patient's overall survival and minimize side effects.

\textbf{AUTHOR CONTRIBUTIONS}

\textbf{Fateme Salemi:} Conceptualization, Methodology, Investigation,
Writing- Original Draft, Writing - Review \& Editing,
Visualization;\textbf{Seyed Mohammad Reza
Mortazavizadeh:}Conceptualization, Methodology, Investigation, Data
curation; Project administration; Resources;\textbf{Shokouh Taghipour
Zahir:} Conceptualization, Methodology, Resources, Writing - Review \&
Editing, Supervision; \textbf{Soroush Shahrokh:} Review \& Editing.

\textbf{ACKNOWLEDGMENTS}We thank Dr. Henry Ashworth, Medical student at
Harvard Medical school for his helpful comments in revising the
manuscript.

\textbf{FUNDING INFORMATION}

This case report study was not financially supported by any
organization.

\textbf{CONFLICT OF INTEREST STATEMENT}

The authors declare no conflict of interest.

\textbf{DATA AVAILABILITY STATEMENT}

The case report data is not publicly available, but it could be
available from the corresponding author with a reasonable request.

\textbf{CONSENT}

Written informed consent was obtained from the patient for publication
of this case report and any accompanying images.

.

\par\null

\textbf{REFERENCES}

1. Schadendorf D, Lebbé C, zur Hausen A, Avril M-F, Hariharan S, Bharmal
M, et al. Merkel cell carcinoma: epidemiology, prognosis, therapy and
unmet medical needs. European Journal of Cancer. 2017;71:53-69.

2. Becker JC, Stang A, DeCaprio JA, Cerroni L, Lebbé C, Veness M, et al.
Merkel cell carcinoma. Nature Reviews Disease Primers. 2017;3:17077.

3. Higaki-Mori H, Kuwamoto S, Iwasaki T, Kato M, Murakami I, Nagata K,
et al. Association of Merkel cell polyomavirus infection with
clinicopathological differences in Merkel cell carcinoma. Human
pathology. 2012;43(12):2282-91.

4. Church CD, Nghiem P. How does the Merkel polyomavirus lead to a
lethal cancer? Many answers, many questions, and a new mouse model. The
Journal of investigative dermatology. 2015;135(5):1221-4.

5. Wong SQ, Waldeck K, Vergara IA, Schröder J, Madore J, Wilmott JS, et
al. UV-associated mutations underlie the etiology of MCV-negative Merkel
cell carcinomas. Cancer research. 2015;75(24):5228-34.

6. Lunder EJ, Stern RS. Merkel-cell carcinomas in patients treated with
methoxsalen and ultraviolet A radiation. New England Journal of
Medicine. 1998;339(17):1247-8.

7. Amaral T, Leiter U, Garbe C. Merkel cell carcinoma: epidemiology,
pathogenesis, diagnosis and therapy. Reviews in Endocrine and Metabolic
Disorders. 2017;18(4):517-32.

8. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. Journal of
clinical oncology. 2002;20(2):588-98.

9. McAfee WJ, Morris CG, Mendenhall CM, Werning JW, Mendenhall NP,
Mendenhall WM. Merkel cell carcinoma: treatment and outcomes. Cancer.
2005;104(8):1761-4.

10. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in
the United States. Journal of the American Academy of Dermatology.
2003;49(5):832-41.

11. Llombart B, Requena C, Cruz J. Update on Merkel cell carcinoma:
epidemiology, etiopathogenesis, clinical features, diagnosis, and
staging. Actas Dermo-Sifiliográficas (English Edition).
2017;108(2):108-19.

12. Linjawi A, Jamison WB, Meterissian S. Merkel cell carcinoma:
important aspects of diagnosis and management. The American surgeon.
2001;67(10):943.

13. Oh SI, Jin US, Chang H, Kwon ST, Minn KW. A retrospective analysis
of eight cases of Merkel cell carcinoma. Archives of Craniofacial
Surgery. 2013;14(1):41-5.

14. An KP, Ratner D. Merkel cell carcinoma in the setting of HIV
infection. Journal of the American Academy of Dermatology.
2001;45(2):309-12.

15. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken
SW. Multimodality treatment of Merkel cell carcinoma: case series and
literature review of 1024 cases. Annals of surgical oncology.
2001;8(3):204-8.

16. Xue Y, Thakuria M. Merkel cell carcinoma review. Hematology/Oncology
Clinics. 2019;33(1):39-52.

17. Becker JC, Stang A, DeCaprio JA, Cerroni L, Lebbé C, Veness M, et
al. Merkel cell carcinoma. Nature reviews Disease primers.
2017;3(1):1-17.

18. Tello TL, Coggshall K, Yom SS, Yu SS. Merkel cell carcinoma: An
update and review: Current and future therapy. J Am Acad Dermatol.
2018;78(3):445-54.

19. Barreira JV, Valejo Coelho MM. Unknown primary Merkel cell carcinoma
with cutaneous spread. 2019;12(2).

20. Agut-Busquet E, Yebenes M, Luelmo J. Stony-Hard Subcutaneous Mass on
the Arm of a Young Woman. Actas dermo-sifiliograficas.
2016;107(2):149-50.

21. Leroux-Kozal V, Lévêque N, Brodard V, Lesage C, Dudez O, Makeieff M,
et al. Merkel cell carcinoma: histopathologic and prognostic features
according to the immunohistochemical expression of Merkel cell
polyomavirus large T antigen correlated with viral load. Human
pathology. 2015;46(3):443-53.

22. Panse G, McNiff JM, Ko CJ. Basal cell carcinoma: CD56 and
cytokeratin 5/6 staining patterns in the differential diagnosis with
Merkel cell carcinoma. Journal of cutaneous pathology. 2017;44(6):553-6.

23. Kontochristopoulos GJ, Stavropoulos PG, Krasagakis K, Goerdt S,
Zouboulis CC. Differentiation between merkel cell carcinoma and
malignant melanoma: An immunohistochemical study. Dermatology (Basel,
Switzerland). 2000;201(2):123-6.

24. Battifora H, Silva EG. The use of antikeratin antibodies in the
immunohistochemical distinction between neuroendocrine (Merkel cell)
carcinoma of the skin, lymphoma, and oat cell carcinoma. Cancer.
1986;58(5):1040-6.

25. Sur M, AlArdati H, Ross C, Alowami S. TdT expression in Merkel cell
carcinoma: potential diagnostic pitfall with blastic hematological
malignancies and expanded immunohistochemical analysis. Modern pathology
: an official journal of the United States and Canadian Academy of
Pathology, Inc. 2007;20(11):1113-20.

26. Fernandez-Flores A, Suarez-Penaranda JM, Alonso S. Study of
EWS/FLI-1 rearrangement in 18 cases of CK20+/CM2B4+ Merkel cell
carcinoma using FISH and correlation to the differential diagnosis of
Ewing sarcoma/peripheral neuroectodermal tumor. Applied
immunohistochemistry \& molecular morphology : AIMM. 2013;21(5):379-85.

27. Becker JC, Lorenz E, Ugurel S, Eigentler TK, Kiecker F, Pföhler C,
et al. Evaluation of real-world treatment outcomes in patients with
distant metastatic Merkel cell carcinoma following second-line
chemotherapy in Europe. Oncotarget. 2017;8(45):79731.

28. Nghiem P, Bhatia S, Lipson EJ, Sharfman WH, Kudchadkar RR, Brohl AS,
et al. Durable tumor regression and overall survival in patients with
advanced Merkel cell carcinoma receiving pembrolizumab as first-line
therapy. Journal of Clinical Oncology. 2019;37(9):693.

\emph{}

\textbf{Figures}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1.} multiple warts on dorsal aspect of the patient's
right hand.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2.} Hematoxylin and Eosin (H\&E) staining of the
cutaneous lesion showing tumoral cells (10x) (a), (40x) (b).

\emph{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3.} IHC staining, the tumoral cells are positive for
synaptophysin, (40x) (a), focally positive for S-100 (40x) (b), positive
for AE1/AE3 (40x) (c), negative for Vimentin (10x) (d), positive for
CD56 (40x) (e), positive for Ki67 (10x) (f), and negative for CD45 (40x)
(g).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

