Late Diagnosis Merkel Cell Carcinoma

with History of Basal Cell Carcinoma

Adelia Hanung Puspaningtyas

, Lydia Kurniasari

, Renni Yuniati

, Buwono Puruhito

, Puji Sriyani

Department of Dermatovenereology,

Department of Surgery Faculty of Medicine

Diponegoro University / Dr. Kariadi General Hospital

Keywords: Merkel Cell Carcinoma, Basal Cell Carcinoma, Excision, Split Thickness Skin Graft, Chemotherapy

Abstract: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor. The etiopathogenetic remains

unclear, associated with Merkel cell polyomavirus.

MCC presents as an asymptomatic lesion or dome-

shaped nodules that clinically benign. Diagnosis is based on histopathology and immunohistochemistry

assay. This therapy includes excision, radiotherapy, immunotherapy, and chemotherapy. This case report is

aimed to give more understanding of the diagnosis and management of MCC. A 47-year-old man presented

with multiple pale-reddish tumors for eight months previously. Initially, the clinical feature was reddish,

scaly, and dry patches spread over the extremities. The biopsy two years ago showed BCC. There was no

regional lymph node involvement. Physical examination found verrucous tumors, with the largest size of 5

centimeters, erythematous macules, papules, erythematous plaques, crusts, and scales on the right elbow and

leg. Excision was followed by split-thickness skin graft and chemotherapy. One month post-surgery, the

patient had tetraparesis, and he died due to distant metastases one month later. The diagnosis of MCC was

established on history, clinical, histopathological, and immunohistochemistry examinations.

Sun exposure,

elderly age, and fair-skin type are the major factors that can cause MCC. Patient sustains advanced stage

and distant metastatic with a mortality rate between 33%- 46 %. MCC generally occurs on elderly fair-

skinned men with high UV exposure and poor prognosis at an advanced stage.

1 INTRODUCTION

Merkel cell carcinoma is a rare and aggressive

neuroendocrine tumor (Schadendorf et al, 2017;

Harms, 2017), high risk of metastasis, recurrence,

and death (Schadendorf et al, 2017; Pulitzer, 2017),

known as the second largest cause of death from

skin cancer after melanoma (Harms, 2017).

Although MCC is rarely found, it is estimated that

around 1500 new cases are found every year in the

United States with incidence rate tripled than the

same cases in the last 20 years (Schadendorf et al,

2017). The aetiopathogenesis of MCC is still

unclear, with tumor cells showing similar

histological and morphological features with Merkel

cell even though Merkel cells are postmitotic cells

and mostly located in the area of palms and soles,

oral and genital mucosa, and nail plates (not

predilection areas of MCC) (Xue et al, 2019). MCC

is associated with Merkel cell polyomavirus

(MCPyV) infection tumor (Schadendorf et al, 2017;

Harms, 2017) which is found in 80% cases of MCC,

exposure to ultraviolet light, and

immunosuppression condition (Xue et al, 2019;

Femia et al, 2018). Several factors that are thought

to increase the risk of MCC include sunlight,

prolonged exposure to UV light and

photochemotherapy, 81% MCC occurs in the sun-

exposed area (Tegeder et al, 2017). Human

polyomavirus infection is usually asymptomatic,

except in immunocompromised individuals, with

symptoms of progressive multifocal neuropathy or

leukoencephalopathy (Femia et al, 2018). The latest

pathogenesis model divided MCC into two groups:

positive virus group (80% found in the northern

hemisphere) and negative virus groups found most

frequently in the southern hemisphere (Schadendorf

et al, 2017; Harms, 2017). In the positive virus

group, MCPyV will encode the modifying gene (T

antigen), so that tumor cell proliferation occurs,

whereas in the negative virus group UV light is

thought to induce genetic changes and acts as a

driver mutation (Xue et al, 2019; Femia et al, 2018).

The risk of MCC is influenced by ethnicity, age,

Puspaningtyas, A., Kurniasari, L., Yuniati, R., Puruhito, B. and Sriyani, P.

Late Diagnosis Merkel Cell Carcinoma with History of Basal Cell Carcinoma.

DOI: 10.5220/0009989203710374

In Proceedings of the 2nd International Conference on Tropical Medicine and Infectious Disease (ICTROMI 2019), pages 371-374

ISBN: 978-989-758-469-5

371

gender, and history of treatment (Harms, 2017).

More than 95% of MCC patients have light skin

type, occur in men, age above 50 years (Xue et al,

2019).

MCC is characterized as a soft red or violet

nodule, overgrowing, in sun-exposed area (Harms,

2017). Crusting and ulceration are rarely found in

the early stages of the disease (Xue et al, 2019).

Abbreviations of AEIOU are used to show clinical

changes in MCC: asymmetrical, expanding rapidly,

immune system suppression, older than 50, UV-

exposed site in light-skin patients (Schadendorf et al,

2017; Harms, 2017), with 89% of patients show 3 or

more characteristics of AEIOU (Schadendorf et al,

2017).

Based on their histological features, MCC is

divided into 3 subtypes: trabecular, intermediate,

and small cell. The trabecular type is usually found

in mixed tumors, and the standard type is the most

common type characterized by a basophilic nucleus

with high mitotic activity. While the small cell type

is undifferentiated and indistinguishable from small

cell carcinoma in other locations. Histopathological

features in MCC include the hyperchromatic nucleus

and high mitotic activity (Schadendorf et al, 2017;

Tegeder et al, 2017). Immunohistochemical

examination show positive staining for cytokeratin

20 and neuron-specific enolase and gives negative

results for thyroid transcription factor-1

(Schadendorf et al, 2017; Ko et al, 2016; Harms et

al, 2016).

Staging MCC based on AJCC (American

Joint Committee on Cancer) criteria with four

significant division stages based on tumor size,

lymph node involvement, and presence/absence of

metastases (Harms et al, 2016).

Several treatments for MCC include surgery,

radiotherapy, chemotherapy, and immunotherapy

tumor (Schadendorf et al, 2017; Harms, 2017; Femia

et al, 2018; Cassler et al, 2016; Tello et al, 2018). In

cases with primary lesions are generally performed

wide excision and SLNB (Sentinel Lymph Node

Biopsy) with 1-2 cm free margin. In high-risk tumor

conditions (location of the head and/or neck, size

more than 1 cm, positive excision margin,

lymphovascular invasion) or high-risk patient

(immunocompromised condition) (Xue et al, 2019;

Femia et al, 2018) surgery is followed by 50Gy to

66Gy radiotherapy in the primary lesions and

regional lymph nodes as an adjuvant after the wound

healing process (Xue et al, 2019; Femia et al, 2018).

In small primary tumor lesions (less than 1 cm), no

involvement of lymph nodes, lymphovascular

invasion, or immunosuppression, postoperative

radiotherapy is not recommended (Krispinsky et al,

2018). Radiotherapy can be used as monotherapy in

conditions that surgical therapy cannot be

performed, either due to unresectable tumors, patient

rejection or due to the risk of morbidity in surgery

(Femia et al, 2018). Chemotherapy can be useful as

palliative therapy in conditions of patients who are

not operable or in metastatic conditions.

Chemotherapy regimens for MCC based on the

protocol for small cell lung cancer by giving

carboplatin / cisplatin-etoposide as the first line (Xue

et al, 2019; Femia et al, 2018). However, in the case

of patients who have received surgical therapy or

radiotherapy or both, chemotherapy as an adjuvant is

not recommended because it can increase morbidity

(associated with neutropenia) and mortality,

decreased quality of life, resistance to

chemotherapy, and suppressing the immune system

(Tegeder et al, 2017). Although chemosensitive, the

effectiveness of chemotherapy in MCC cases tend

not to be durable (Xue et al, 2019).

The aim of this case report is to give more

understanding of the diagnosis and management of

Merkel cell carcinoma.

2 CASE

A 47-year-old Chinese male came with complaints

of pale-reddish tumor in his right arm and leg eight

months ago. Soft rapidly enlarged and quickly bled

tumor, in some parts covered with pus and foul-

smelling, painful (+). Initially, skin disorders were

reddish, scaly, and dry patches spread over the

extremities. At his initial disease, he denied having a

fever, fatigue, weakness in limbs, unintentional

weight loss, and other systemic symptoms. Two

years ago, the patient had taken a surgery on the

right hand with biopsy result showed basal cell

carcinoma. History of sunlight exposure (+) because

he was a foreman. History of family members with

the malignant disease was denied.

Generalist status: the patient was compos mentis,

good nutritional status with 167 cm height, 75 kg

body weight, 120/80 mmHg blood pressure, pulse 80

x/minute, respiratory frequency 18 x/minute, and

C axillary temperature. From dermatological

status, there was a variety size of verrucous tumors,

the largest tumor was 5 cm, with crust, papules,

erythematous macules, scally, erythematous plaques

on the elbow and right leg. There was no

involvement of regional lymph nodes. Blood

laboratory test showed mild anemia; gamma GT 108

U / L; urea 41 mg / dL; creatinine 1.6 mg / dL;

chloride 108 mmol / L; non-reactive anti HIV

screening; ASTO qualitative negative, HsCRP 1.28

ICTROMI 2019 - The 2nd International Conference on Tropical Medicine and Infectious Disease

372

mg/L; HBsAg negative; anti HCV 0.15. From

peripheral blood smear testing, erythrocytes were

obtained: mild anisocytosis (normocytic,

microcytic), mild poikilocytosis (ovalocyte, pear

shape, teardrop), polychromatic +; leukocytes:

normal amounts estimation, monocytosis,

neutrophilia, atypical lymphocytes +; platelets:

estimated quantities are difficult to analyze,

clumping ++, were dominated by normal forms,

large forms +.

Biopsy specimens showed fragments of tumor

tissue coated with a flattened squashed epithelium,

keratinized, some of them were ulcerative with

swollen and hyperemic connective tissue stroma

caused of lymphocytes, leukocytes, histiocytes

contained tumor masses in the form of nests of

malignant cells with pleomorphic, hyperchromatic

round, oval nuclei, provide salt and pepper picture,

some vesicular, eosinophilic cytoplasm, arranged

molding, uninterrupted, in rows around blood

vessels, and also groups of cells with a pseudo

rosette structure. Immunohistochemical staining

showed the most positive cells for synapthopicin,

NSE, CK 7, and CK 20. Differential diagnosis

included basal cell carcinoma (BCC) and squamous

cell carcinoma (SCC).

Excision was followed by split-thickness skin

graft and chemotherapy using cisplatin 50 mg and

paclitaxel 300 mg/50 cc protocol. One month after

surgery, the patient had tetraparesis, and he died due

to distant metastases one month later.

Figure 1. A. The verrucous flesh-red tumor partially is

covered by crust, painless in suppression, soft on touch; B.

Mass of tumor cells after excision; C. Post split-thickness

skin graft surgery

3 DISCUSSION

The incidence of Merkel cell carcinoma correlates

with exposure to UV light in light-skin individuals

along with age and mostly found at the location of

the head, neck, and upper extremities (Schadendorf

et al, 2017)About 10% of patients are found younger

than 50 years old. (Tegeder et al, 2017) The UV

exposure is thought as a cause of cellular mutations

which is resulting in uncontrolled proliferation,

especially in the virus-negative group.(Kneiling et

al,2011) MCC more often attacks men (62%) than

women (38%). (Harms et al,2017).

MCC lesions mostly appear as nodules that are

red-violet, soft, rapidly enlarged, and painless in

suppression. (Schadendorf et al, 2017) In the patient

has found 3 characteristics of abbreviation AEIOU

(asymptomatic, expanding rapidly, and lesions at the

location of the body exposed to UV) show suspicion

towards MCC. (Schadendorf et al, 2017). 65% of

MCC patients only have limited skin disease, 26%

of patients are accompanied by regional lymph node

involvement and 8% of patients with distant

metastases.(Xue et al,20019; Harms et al,2017).

Histopathological features of MCC at low

enlargement in the form of large nodules that are

infiltrating the dermis or subcutaneous, with stromal

changes including mucin, inflammation, and

increased vascularity. At high magnification, the

tumor consists of small round cells with a few

cytoplasms and pale, smooth neuroendocrine

chromatin (salt and pepper image), can also be found

hyperchromasia, accompanied by epidermal

involvement in the form of scattered pagetoid

images, also rosette. (Schadendorf et al, 2017;

Harms et al,2017). In addition to histopathological

examination with hematoxylin-eosin staining,

enforcement of the diagnosis of MCC requires

immunohistochemical staining including keratin-20

(CK 20), thyroid transcription factor-1 (TTF-1), CD

56, chromogranin A, synaptophysin, and

neurofilament protein (NFP). CK 20 is a sensitive

marker for MCC, with positive results are found in

89% -100% cases of MCC. (Femia et al, 2018)

addition to CK-20, the presence of at least one

marker which is derived from neuroendocrine

differentiation (ex synaptopodin) can confirm

neuroendocrine tumor origin. (Pulitzer, 2017) MCC

and BCC provide similar morphological features

caused by mucin in stromal or intratumor, but the

presence of CK20 and dotlike keratin expression can

distinguish MCC from BCC. (Pulitzer, 2017;

Harms,2017). In SCC with strong neuroendocrine

differentiation, it is often difficult to distinguish

from MCC because of the discovery of CK20 and

neuroendocrine granules that are also positive for

SCC biopsy. However, SCC always gives negative

results for MCV. (Pulitzer, 2017)

Late Diagnosis Merkel Cell Carcinoma with History of Basal Cell Carcinoma

373

Patients were referred to the plastic surgery

department for excision and split-thickness skin

graft. The choice of therapy in MCC cases is based

on several characteristics of the disease, including

clinical stage, the involvement of regional lymph

nodes, comorbid factors, and general condition of

the patient. Surgical excision with 1-3 cm borders at

the location of the primary tumor is the foremost

step in the treatment of MCC, where patients with

high-risk tumors should be followed by radiotherapy

as an adjuvant. (Schadendorf et al, 2017; Xue et al,

2019; Femia et al, 2018) Split thickness skin graft is

a skin-tight technique to cover the defect of

extensive skin and epithelial failure. The donor

location is usually chosen from the lateral thighs,

with the skin to be draped with holes using No. 11

and sewn to the side of the wound. This technique

provides faster healing results (between 4-6 weeks)

and a more acceptable appearance.(Kneiling et

al,2011;Yi et al,2015) Clinical output in MCC

patients with the latest therapy is still weak, with the

incidence of disease progression and metastasis

occur in the first three years after the diagnosis is

established. The size of the primary tumor is the

most reliable indication of the occurrence of

metastases, where small tumor (less than 1 cm) has a

risk of metastases 10-20% (Harms,2017). The most

common metastases are lymph node glands,

followed by metastases at a distant location of the

skin, lungs, nervous system center, bone, and liver.

Chemotherapy with carboplatin / cisplatin-etoposide

is recommended for stage IV MCC. (Schadendorf et

al, 2017; Xue et al, 2019;Harms,2017; Femia et al,

2018) 5-year survival rates are 51% for patients with

localized disease, 35 % in diseases with lymph node

involvement, and only 14% in distant metastatic

disease (Harms,2017).

4 CONCLUSION

A case of Merkel cell carcinoma has been reported

in a 47-year-old male Chinese patient, with a

dermatological examination in variety size of

verrucous tumor, the largest tumor is 5 cm,

accompanied by crusting, papules, erythematous

macules, squares, erythematous plaques on the

elbows and right foot, without the involvement of

regional lymph nodes. The results of

histopathological and immunohistochemical

examination supported the diagnosis of Merkel cell

carcinoma. Therapy modalities of this patient are

excision surgery and split-thickness skin graft

followed by cisplatin-paclitaxel chemotherapy, but

the patient died due to distant metastases to the

central nervous system.

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