2023, Volume 39, Number 3, Page(s) 169-178
Histopathologic Features for Overall Survival in Merkel Cell Carcinoma: A Case Series with Intact Mismatch Repair Protein Expression
Selin KESTEL, Betul OGUT, Mehmet Arda INAN, Ozlem ERDEM
Department of Pathology, Gazi University Faculty of Medicine, ANKARA, TURKEY
Keywords: Merkel cell carcinoma, Mismatch repair protein, Overall survival, Histopathology
In a study of Merkel cell carcinoma (MCC), a fusion transcript between MLH1 and SPATA4 was identified. This fusion has the
potential to generate the inactive or dominant-negative form of the protein. Therefore, we aimed to investigate whether mismatch repair protein
deficiency occurr in MCC cases or not, in addition to the overall survival association with histopathologic features.
Material and Method: A retrospective review of 15 patients diagnosed with a biopsy-proven Merkel Cell Carcinoma between 2012 and 2019 was
performed. Mismatch repair (MMR) protein expressions were evaluated by immunohistochemistry.
Results: The median follow-up time was 36 months (mean 41, range 2-103 months). Six (40%) patients died during follow-up. The overall survival
(OS) at 1 year, 2 years, 3 years, and 5 years were 87%, 80%, 62%, and 53%, respectively. The patients diagnosed at <60 years had an improved OS
compared to those ≥60 years of age (p=0.016). Patients in clinical stage I had better OS than patients in clinical stage IV (p=0.011). Cases with
pathological tumor stage (pT) 1 had better OS than pT3 and pT4 (p=0.045). Adjuvant radiotherapy or adjuvant radiotherapy+chemotherapy
treatment improved OS compared to adjuvant chemotherapy (p=0.003). MMR protein nuclear expression was intact in 12 cases available for
Conclusion: To the best of our knowledge, this is the second study that preferentially investigated the mismatch repair protein status of Merkel
Cell Carcinoma. No mismatch repair protein deficiency of MCC cases was identified in the current study.
Merkel cell carcinoma (MCC) is rare but one of the deadliest
cancers of the skin. Its incidence has increased in recent
. Merkel cell carcinoma has an estimated diseaseassociated
mortality of 33% to 46% 2
. In metastatic disease,
the overall survival is approximately 10 months 2,3
Toker initially described it in 1972 when he reported five
cases of trabecular carcinoma of the skin with a putative
origin of eccrine sweat gland 4
. Although MCC is rare,
its incidence has been rising due to the aging population,
increased sun exposure, and the use of immunosuppressive
. About 2000 people are diagnosed with
MCC annually in the United States 6
The cellular origin for Merkel cell carcinoma is still uncertain
7. The name implies immunohistochemical and
structural similarities between Merkel cells and Merkel cell
carcinoma. Historically Merkel cells were thought of as the
origin of MCC. However, current studies suggest four new candidates for the cellular basis: Epithelial progenitor cells,
fibroblast and dermal stem cells, hair follicle stem cells, and
pre/pro B cells 1,7,8. Merkel cells are postmitotic, highly
specialized cells located in the basal layer of the epidermis
and the external part of the hair follicle 8; they have low
sensitivity for oncogenic signals. Liu et al. have demonstrated
that Merkel Cell polyomavirus (MCV or MCPyV)
infects and proliferates within dermal fibroblasts under certain
conditions 9. Both MCC and B cells express paired
box 5 (PAX5), terminal deoxynucleotidyl transferase (TdT),
which is typically used for hematopoietic tumors 10,11.
There are two main pathogenic pathways for MCC development.
In 2008, Chang, Moore, and colleagues found that
80% of MCC is associated with MCPyV 12. The other
one, MCPyV negative, is related to UV exposure and a high
mutation burden. Tumor protein p53 gene (TP53), retinoblastoma
gene (RB) 13, and succinate dehydrogenase
D gene (SDHD) mutations 14 are also involved in the molecular pathogenesis of Merkel cell carcinoma. Clinically
it is a rapidly growing, painless, reddish-purplish nodule 15 (Figure 1). MCC diagnosis is based on histopathological
examination in most cases (Figure 2).
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|Figure 1: A) In this case, The tumor presented as a fast-growing 10 cm nodule with multifocally ulcerated, violaceous-colored overlying
skin located at the right thigh. B) The cut surface revealed a tumor with a firm, tan brown-colored, multinodular growth pattern in the
dermis and subcutis in the formalin-fixed excisional specimen.
Click Here to Zoom
|Figure 2: In this example (A,B), subepidermal edema and dermal lymphatic invasion were evident. Uniform basophilic tumor cells
formed nests and diffuse sheets surrounding the adnexal structures. Dissection of collagen and some crushing artifacts accompanied
tumor cells (C). Paranuclear dot-like cytokeratin 20 stainings (D). MLH1 (E) and PMS2 (F) nuclear stainings were intact with internal
controls. (Hematoxylin and Eosin stain, magnifications 40X [A, B], 200X [C], immunohistochemical stainings, magnifications 200X
[CK20], 100X [MLH1, PMS2]).
Traditional drug development strategies are mostly based
on tumor type or a biomarker within a tumor type. In 2017,
the U.S. Food and Drug Administration (FDA) approved
the Anti-Programmed cell death-1 [PD-1] antibodies-
Pembrolizumab as the first tissue-agnostic drug for the
treatment of microsatellite instability-high or mismatch
repair-deficient, unresectable or metastatic solid tumors
in adult and pediatric patients 16. Although currently,
tissue-agnostic drug therapies are few, patients, even in the
pediatric age group with life-threatening solid tumors, may
benefit from tumor-agnostic treatments selected based on
the microsatellite-high/DNA mismatch repair-deficient
biomarker or other few biomarkers, regardless of tumor
histology or location. In a study of MCC including nextgeneration
sequencing techniques, a fusion transcript
between the mutL homolog 1 gene (MLH1) and spermatogenesis-
associated 4 gene (SPATA4) was identified, and
this fusion has the potential to generate the inactive or
dominant-negative form of the protein 17.
In the present study, we investigated whether mismatch
repair (MMR) protein deficiency also occurred in Merkel
cell carcinoma cases at our center or not with immunohistochemical
staining for MMR proteins (MLH1, PMS2
[postmeiotic segregation increased 2], MSH2 [mutS homolog
2], and MSH6 [mutS homolog 6]) expression. We also
aimed to define known or new clinicopathological features
for overall survival in Merkel cell carcinoma.
A retrospective review of 15 patients diagnosed with a biopsy-
proven MCC between 2012 and 2019 was performed
). The histopathological slides were reviewed.
The following primary data were extracted: age, gender,
tumor site, tumor size, lymph node status, types of treatments received, recurrence, overall survival, the primary
or metastatic status of the tumor sample, ulceration, tumor
thickness, lymphovascular invasion, perineural infiltration,
mitotic rate, tumor-infiltrating lymphocytes (TILs), growth
pattern, necrosis, adnexal infiltration, desmoplasia, nuclear
chromatin pattern, and immunohistochemical studies
done at the time of diagnosis (Cytokeratin 20, synaptophysin,
chromogranin). When possible, additional findings,
such as the patients’ medical history, were obtained from
the electronic medical records or directly from the patients
themselves or their relatives by a phone call. The pathological
tumor stage was retroactively determined when possible
using the extent of disease from the pathology reports
and using the tumor size and invasion to the deep extra
dermal structures according to the classification protocol
developed by the American Joint Committee on Cancer,
8th edition. The correlation between clinicopathologic factors
and overall survival was evaluated.
Additionally, formalin-fixed paraffin-embedded (FFPE)
tissue blocks of twelve MCC cases were retrieved from
the pathology archives of our institution. Immunohistochemical
expression of MMR proteins was examined using
the ultraview Universal DAB detection kit on a Ventana
Benchmark automated staining system. The following
monoclonal antibodies were tested on immunohistochemistry:
Anti-MLH-1 (clone M1, Roche), anti-MSH2 (clone
G219-1129, Roche), anti-MSH6 (clone 44, Roche), and
anti-PMS2 (clone EPR3947, Roche). Internal controls were
positive for all cases. Only nuclear staining was scored as
positive. The nuclear staining threshold required for an
“intact expression” result was accepted as more than 5%.
Institutional research ethics board approval was obtained
for the study.
The overall survival data was calculated as the months
from diagnosis to death from any cause or to the last follow-
up for surviving patients (censored). Statistical analyses
were calculated using the Statistical Package for the
Social Sciences (SPSS) version 23 (IBM Corp., Armonk,
NY). Descriptive statistics were calculated as mean, median,
and standard deviation for quantitative variables like
age, tumor size, tumor thickness, mitoses per millimeter
square, and months since diagnosis. Survival analysis was
calculated using the Kaplan-Meier method. Differences
between survival functions were analyzed by the log-rank
test. The statistically significant difference between groups
was determined as p < 0.05.
There were 9 (60%) female and 6 (40%) male patients. The
median follow-up time was 36 months (mean 41, range
2-103 months). Patients in this study had a mean survival
of 66.3 months. Six (40%) patients were deceased during
follow-up. The overall survival (OS) at 1 year, 2 years, 3
years, and 5 years were 87%, 80%, 62%, and 53%, respectively
). The mean age at diagnosis was 65 years
(median 59, range, 52-91 years). The patients diagnosed
at <60 years had an improved OS compared to those ≥60
years of age (p=0.016) (Figure 3B
). Two tumors belonged to metastatic tissue, whereas 13 tumors presented with primary
MCC. However, primary site and diagnosis time were
known for one of the patients. Regarding their past medical
history, one patient had kidney transplantation due to
familial polycystic kidney disease; one patient had partial
nephrectomy due to renal cell carcinoma, papillary type 2;
two patients had a history of kidney stones and one of these
underwent radical nephrectomy due to atrophy. In addition,
two patients developed neoplasm after MCC diagnosis:
one of them was ovary cancer, and the other was breast
cancer. Clinical and histopathologic variables were present
in Tables II
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|Figure 3: Kaplan-Meier overall survival curves for Merkel cell carcinoma patients compared for variables by age (B), clinical-stage (C),
pathological tumor stage (pT) (D), adjuvant treatment (E), tumor thickness (F).
Click Here to Zoom
|Table II: Univariate Analysis of Clinical Variables for Overall Survival time (months) in Merkel Cell Carcinoma, Calculated From
Kaplan-Meier Analysis With Comparisons Performed With the Log-Rank Test.
Click Here to Zoom
|Table III: Univariate Analysis of Histopathologic Variables for Overall Survival time (months) in Merkel Cell Carcinoma,
Calculated From Kaplan-Meier Analysis With Comparisons Performed With the Log-Rank Test.
In terms of anatomical location, extremities (upper extremity
n=6, 40%; lower extremity n=6, 40%) was the most common,
followed by trunk (n=1, 7%), and face (n=1, 7%).
Additionally, one metastatic MCC to the brain was present
without a known primary site. One of the cases belonged
to the lymph node metastatic MCC of the primary ankle
MCC patient. Ulceration was present in 2 cases (18%).
The mean tumor size was 57 mm (range, 18-100 mm).
The mean tumor thickness was 20 mm (range, 5-60 mm).
The mean number of mitoses per 1 mm² was 14 (range,
1-50). Lymphovascular invasion was present in 10 cases
(72%). Perineural invasion was seen in 5 cases (38%).
Tumor-infiltrating lymphocytes were present in 12 cases
(86%). The growth pattern was nodular in 9 cases (64%), and
infiltrative in 5 cases (36%). Necrosis was extensive in
3 (19%) cases, focal in 8 (50%) cases, and not present in 5
(31%) cases. Desmoplasia was detected in 12 cases (86%).
Adnexal involvement was evident in 9 (75%) tumors. The
nuclear chromatin pattern was vesicular in 3 tumors (21%),
salt and pepper in 4 (29%), and hyperchromatic in 7 (50%)
tumors. Lymph node metastasis was histopathologically
present in 2 (25%) of 8 MCC cases. MCC cases were pathologically
staged as pT1 in 5 patients, pT2 in 2, pT3 in 3, and pT4 in 1 (Figure 3D). Patients were mostly diagnosed at
clinical stage III. Patients in their clinical stage I had better
OS than patients in clinical stage IV (Figure 3C). MMR
protein nuclear expression was intact in 12 cases available
for immunohistochemical study. Cytokeratin 20, chromogranin,
and synaptophysin stainings were characteristically
positive in 14, 13, and 12 cases, respectively. The patients
were treated by surgery only in 4, surgery with adjuvant
radiotherapy (RT) in 5, surgery with adjuvant chemotherapy (CT) in 1, and surgery with adjuvant chemoradiotherapy
(CRT) in 4 patients. Adjuvant radiotherapy or
adjuvant radiotherapy+chemotherapy treatment had a better
prognostic impact on OS than adjuvant chemotherapy (p=0.003) (Figure 3E). There was no recurrence in 7 cases,
whereas 3 cases recurred at 12, 16, and 20 months after the
MCC is mostly seen in elderly male patients and in the head
and neck regions 18
. Heath et al. have reported 195 MCC
cases, 168 of which were primary skin lesions. The most
common location was the head and neck (n=56, 29%), followed
by the lower limb (n=46, 24%), upper limb (n=40,
21%), trunk (n=16, 8%), buttock (n=9, 5%), and vulva
(n=1, 0.5%) 15
. In our case series, patients were mostly
elderly, and extremities were the most common location.
Our series included slightly more female patients, similar
to another Turkish case series of MCC patients 19
Liang et al. have reported the 2-year and 5-year OS rates as
53.9% and 32.8% in 87 MCC patients over 30 years (20).
The 2-year and 5-year OS rates were 80% and 53% in our
series, respectively. The two cm primary tumor size threshold
did not statistically significantly affect the survival in
Liang et al. and Ciążyńska et al.’s studies 20,21. In our
research, less than 12 mm tumor thickness had better OS
than tumors equal to or more than 12 mm (Figure 3F),
although this did not reach the exact level of statistical significance.
Several proofreading mechanisms are necessary to have
a DNA replication system with high fidelity. A mismatch
is an incorrect base pairing between an incoming deoxyribonucleoside
triphosphate and the DNA template. DNA
polymerase has 5’-to-3’ polymerization ability and intrinsic
3’-to-5’ exonucleolytic proofreading to prevent and correct
mismatches. The third system for correcting these errors
in the DNA helix from the misfit between noncomplementary
base pairs is strand-directed mismatch repair. Two
proteins function as heterodimers for mismatch repair in
both bacteria and eukaryotes. Human MutS heterodimers
(MSH2/MSH6 and MSH2/MSH3 complexes) bind specifically
to a mismatched base pair. Then, human (h) MutL
heterodimers (hMLH1/hPMS2, hMLH1/hPMS1, and
hMLH1/hMLH3) specifically recruit proteins to remove
the newly synthesized strand back through the mismatch
and resynthesize DNA 22.
DNA repair is impaired when one or more mismatch
repair proteins lose their function (deficient mismatch
repair-dMMR). As a result, spontaneous genetic mutations
accumulate in the genome leading to an increased
risk of developing an increasing number of neoplasms;
some are associated with familial cancer syndromes 23.
Lynch syndrome is the familial cancer syndrome associated
with a mono-allelic germline mutation in an MMR
gene 24. Lynch syndrome is related to an increased risk of
developing colon, rectum, endometrium, stomach, ovary, ureter, renal pelvis, brain, small bowel, and hepatobiliary
tract cancers 25. Muir Torre syndrome is another familial
cancer syndrome caused by mutations in the DNA mismatch
repair genes with a combination of skin neoplasms
(mostly sebaceous neoplasms but also keratoacanthoma)
and a visceral malignancy (usually colorectal, endometrial,
small intestine, and urothelial) 26. Regardless of the
syndromic status, deficiency in mismatch repair proteins
have been described in uterine corpus endometrial carcinoma,
colon adenocarcinoma, stomach adenocarcinoma,
rectal adenocarcinoma, adrenocortical carcinoma, uterine
carcinosarcoma, cervical squamous cell carcinoma, endocervical
adenocarcinoma, Wilms tumor, mesothelioma,
esophageal carcinoma, breast carcinoma, renal clear cell
carcinoma, ovarian serous cystadenocarcinoma, cholangiocarcinoma,
thymoma, hepatocellular carcinoma, head and
neck squamous cell carcinoma, sarcoma, cutaneous melanoma,
cutaneous squamous cell carcinoma, lung squamous
cell carcinoma, prostate adenocarcinoma, lung adenocarcinoma,
bladder carcinoma, pediatric neuroblastoma, lowergrade
glioma, chronic lymphocytic leukemia, glioblastoma,
pancreatic adenocarcinoma, thyroid carcinoma, and uveal
melanoma 27-33. Accompanying renal cell, breast, and
ovary cancers to MCC in our case series also led to searching
for the MCC and deficient MMR protein relationship.
Gambichler et al. have studied microsatellite instability
in 56 MCC cases for the first time 34. Nine patients had
a low level of at least one MMR protein (MLH1, PMS2,
MSH2, MSH6) expression. One of them was found to have
microsatellite instability-high by multiplex PCR combined
with high-resolution capillary electrophoresis. They also
revealed an association between low expression of mismatch
repair proteins and negative MCPyV status. Nevertheless,
there was no association with MMR expression and
the outcome of the patients such as disease relapse or death
34. In our study, all tumors had intact expressions that
were diffuse nuclear positive for MMR proteins.
Miner et al. have reported that 13 patients of cytokeratin
20-negative MCC were also negative for MCPyV by polymerase
chain reaction. They also showed at least one of
three cytokeratins, including cytokeratin-7, AE1/AE3, and
Cam 5.2 immunoreactivity in CK20-negative MCC cases
35. Iwasaki et al. have reported additional CK20-negative
MCCs. They concluded that the negativity of both cytokeratin
20 and MCPyV might be associated with poorly differentiated
MCC features pertaining to their previous study
that demonstrated severe nuclear atypia and pleomorphism
in MCPyV-negative MCCs compared to MCPyV-positive
MCCs 36,37. However, they did not find a significant relationship between CK20 negativity and MCC-specific
death. Cytokeratins are intermediate-sized filament proteins
found in most epithelial cells. Cytokeratin 20 (CK20)
is a type I (acidic), low molecular weight cytokeratin 38.
In normal Merkel cells of the skin, the CK20 arrangement
is loose, leading to diffuse cytoplasmic staining 7. However,
in Merkel cell carcinoma, there is a characteristic but
not pathognomic CK20 staining for paranuclear collection
of intermediate filaments described as paranuclear whirls,
or dot-like or globoid in appearance 39,40. Some intermediate-
sized filaments are immunoreactive for neurofilament
in MCC 40-42. The differences in the arrangement,
interaction, and regulation of intermediate filament proteins
might be a candidate reason for cytokeratin-20 negativity
in addition to damage of the antigenic determinants
by the formaldehyde fixative.
Studies have demonstrated that MCPyV, like some other
polyomaviruses, is serologically present in most adult populations.
It was thought that exposure to this virus occurred
during childhood 43. Furthermore, the skin microbiota
also includes MCPyV, isolated from different parts of the
skin surfaces by Schowalter et al. 44. MCC’s etiological
relation to MCPyV and asymptomatic infection with
MCPyV in healthy individuals was explained by the MCC
tendency in immunocompromised subjects 12,44.
Chang et al. reported that recurrence was observed in 6 of
13 clinically node-negative and clinically followed-up MCC
patients 45. Another three node-negative patients who
underwent sentinel lymph node biopsy did not experience
recurrence. They emphasized that wide surgical excision
and initial sentinel lymph node biopsy (SLNB) are essential
for improved survival outcomes in early MCC. In our
study, 2 of 3 recurrent MCC cases had undergone SLNB
with a positive result prior to the recurrence experience.
In the present study, the patients whose treatment history
was obtained were primarily treated with surgery. When
we compare adjuvant treatments, radiotherapy had an
improved OS compared to chemotherapy, and RT+CT
also had better OS than CT. Despite best cytotoxic chemotherapy,
advanced MCC patients have 6 to 9 months
of median overall survival 46. Ciążyńska et al. reported
no significant impact of radiotherapy on the survival of 31
MCC patients 21. On the other hand, avelumab, an antiprogrammed
death-ligand-1 monoclonal antibody, was
the first approved immune checkpoint inhibitor for metastatic
MCC in 2017 by FDA 47. In 2018, pembrolizumab,
an anti-programmed death-1 monoclonal antibody, was
approved for locally advanced and metastatic MCC 47.
Ciążyńska et al. found female gender, local disease, tumorfree
resection margin as independent prognostic factors
for MCC 21. Since our sample is small and Cox multiple
regression analysis models were insignificant, we could
not test the independence of variables. However, the clinical
stage was similarly significant for OS in our study on
univariate analysis. All stage IV patients were deceased,
and stage I patients’ prognosis was excellent, similar to our
The study’s main limitations were the limited number of
cases and retrospective nature. The results would be more
generalizable if similar studies were performed with more
cases. However, the scarcity of MCC diagnoses somehow
limits this process. Multi-institutional studies may provide
a solution to this problem. Another limitation was the diagnosis
at an advanced stage and short follow-up time due
to the deceased patients. There was no information for the
MCPyV status of the patients.
In conclusion, this is the second study that preferentially
investigates Merkel cell carcinoma’s mismatch repair protein
status to the best of our knowledge. Mismatch repair
deficiency was not identified in our research. Additional
prognostic findings related to OS in this study were age,
clinical-stage, pathological tumor stage, and adjuvant treatment.
Conflict of Interest
The authors declare no conflict of interest.
Concept: SK, MAI, OE, Design: SK, MAI, OE, Data collection or
processing: SK, BO, MAI, OE, Analysis or Interpretation: SK,
BO, MAI, OE, Literature search: SK, BO, MAI, OE, Writing: SK,
Approval: SK, BO, MAI, OE.
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