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.