Department of Plastic Surgery University of Helsinki
Finland
MERKEL CELL CARCINOMA
EPIDEMIOLOGICAL STUDY WITH SPECIAL REFERENCE TO POLYOMAVIRUS AND VASCULAR FACTORS IN PATHOGENESIS
Heli Kukko
ACADEMIC DISSERTATION
To be presented, with the permission of the Faculty of Medicine of the University of Helsinki, for public examination in the Lecture Hall
of Töölö Hospital, Helsinki, on 13 May 2011, at 12 noon.
Helsinki 2011
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INTRODUCTION
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REVIEW OF THE LITERATURE
1. NORMAL SKIN
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Figure 1. Normal skin structure (¤ Terese Winslow)
2. MERKEL CELL
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3. SKIN CANCERS
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4. MERKEL CELL CARCINOMA
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4.1. ETIOLOGY
4.1.1. Ultraviolet radiation
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4.1.2. Immunosuppression
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4.1.3. Merkel cell polyomavirus
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Figure 2. A rapidly grown Merkel cell carcinoma in the deltoid area of a 68-year old man. Two months earlier a small lump was excised at a primary health care center. The scar is visible in the middle of the tumor. The black spots are marks for sentinel node biopsy.
4.5. HISTOPATHOLOGICAL DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
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Table 1. Differential diagnosis of Merkel cell carcinoma by immunohistochemistry (Modified from McKee et al. 2005b, Llombart et al. 2005, Hanly et al. 2000, Koljonen et al. 2005, Goessling et al. 2002, Poulsen et al. 2004, Bichakjian et al. 2007, Mott et al. 2004).
CK-20 (%)
TTF-1 (%)
LCA (%)
S-100 (%)
NFP (%)
NSE (%)
SYP (%)
ChrA (%)
NCAM
MCC 89-100 0 0 0 50-100 80 95 80-
100 100
SCLC 3-33 83-100 0 0 0 64
Lymph 0 98 6 0 11
SCM 0 0 0 97 0 71
BCC 0
Figure 3a. MCC in HE staining. Original magnification x200.
Figure 3b. Positive CK-20 staining. Original magnification x200.
4.6. STAGING AND PROGNOSIS
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Table 2. Memorial Sloan-Kettering Cancer Center staging system (Allen et al. 2005)
Stage MCC 5-year disease specific survival (%)
I Local disease <2cm 81
II Local disease t2cm 67
III Regional nodal disease 52
IV Distant metastatic disease 11
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Table 3. American Joint Committee on Cancer consensus staging system for MCC (AJCC 2010)
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor (e.g. nodal/metastatic presentation without associated primary tumor)
Tis In situ primary tumor
T1 d2 cm maximum tumor dimension
T2 >2 cm but d5 cm maximum tumor dimension T3 >5 cm maximum tumor dimension
T4 Primary tumor invades bone, muscle, fascia or cartilage
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis
cN0 Nodes negative in clinical examination (no histopathological examination performed)
pN0 Nodes negative by histopathological examination N1 Metastasis in regional lymph node(s)
N1a Micrometastasis (diagnosed after sentinel or elective lymphadenectomy) N1b Macrometastasis (clinically detectable nodal metastases confirmed by CLND
or needle biopsy)
N2 In transit metastasis
Distant metastases (M)
M0 No distant metastasis
M1 Metastasis beyond regional lymph nodes
M1a Metastasis to skin, subcutaneous tissues or distant lymph nodes
M1b Metastasis to lung
M1c Metastasis to all other visceral sites
Anatomic stage / prognostic groups
Stage 0 Tis N0 M0
Stage IA T1 pN0 M0
Stage IB T1 cN0 M0
Stage IIA T2/T3 pN0 M0
Stage IIB T2/T3 cN0 M0
Stage IIC T4 N0 M0
Stage IIIA Any T N1a M0
Stage IIIB Any T N1b/N2 M0
Stage IV Any T Any N M1
4.7. TREATMENT
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5. TUMOR BIOLOGY
5.1. ANGIOGENESIS IN TUMOR GROWTH AND METASTASES
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Table 4. Patient and tumor characteristics of 181 patients (Study I)
Value
No. of patients
% Sex
female 125 69.1
male 56 30.9
Age (years)
mean 75.9
median 78
range 27-100
0–50 6 3.3
51–74 58 32.1
75–100 117 64.6
Tumor location
head and neck 102 53.3
trunk 22 12.2
upper extremity 27 14.9
lower extremity 22 12.2
primary unknown 8 4.4
Tumor size (cm)
mean 1.78
median 1.4
range 0.3–8.5
Table 5. Stage at presentation and tumor size by sex
Females (n=125)
Males (n=56)
All (n=181) Stage I
tumor size (mean, mm)
80 (64%) 10.8
28 (50%) 9.9
108 10.6 Stage II
tumor size (mean, mm)
32 (26%) 28.8
15 (27%) 34.7
47 30.7 Stage III
tumor size (mean, mm)
10 (8%) 32.4
8 (14%) 31.0
18 31.8 Stage IV
tumor size (mean, mm)
3 (2%) 24.7
5 (9%) 13.0
8 18.8
(LYMPHO)VASCULAR INVASION (STUDY II)
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Figure 4. Lymphovascular invasion. Staining with CD31 (a) and D2-40 (b). A cluster of tumor cells within a lymph vessel (L). Endothelial cells of an artery (A) stained with CD31, but remained negative with D2- 40 staining. Original magnification x200.
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Figure 5. Blood vascular invasion. Staining with CD31 (a), and D2-40 (b). A cluster of tumor cells within a blood vessel (B) identified by CD31 staining. The endothelial cells remained negative in D2-40 staining.
Original magnification x200.
Table 6. Clinical characteristics of Merkel cell carcinoma patients at diagnosis (Study II)
No of patients (n=126) % Sex
female 90 71.4
male 36 28.6
Age (years)
mean 77.6
median 79
range 50–100
Tumor location
head or neck 73 57.9
upper extremities 21 16.7
trunk 14 11.1
lower extremities 18 14.3
Tumor size (cm)
mean 1.86
median 1.5
range 0.3–8.5
Stage at diagnosis
I Local only <2cm 75 59.5
II Local only t2cm 36 28.6
III Nodal* 11 8.7
IV Distant metastatic 4 3.2
*nodal disease assessed by palpation or histological evaluation (when performed)
MERKEL CELL POLYOMA VIRUS (STUDY III)
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Table 7. Patient and tumor characteristics of 114 patients (Study III)
No. of patients % Sex
female 80 70.2
male 34 29.8
Age (years)
median 78
range 35–100
Tumor location
head and neck 58 50.9
trunk 17 14.9
limb 39 34.2
Tumor size (cm)
median 1.6
range 0.3–8.5
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I 61 53.5
II 39 34.2
III 10 8.8
IV 4 3.5
VEGFR-2 AND ENDOSTATIN (STUDIES IV-V)
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Table 8. Patient and tumor characteristics of VEGFR-2 and the endostatin study (Studies IV-V)
VEGFR-2 study (n=21) Endostatin study (n=19) Sex (number of patients)
female 12 10
male 9 9
Age (years)
median ( range) 78 (59–100) 78 (59–100)
Tumor size (cm)
median (range) 2.0 (0.8–6.0) 2.0 (0.8–6.0)
Stage at presentation
I 10 9
II 8 8
III 1 1
IV 2 1
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RESULTS
EPIDEMIOLOGICAL-CLINICAL STUDY (STUDY I)
INCIDENCE
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TREATMENT OF DISEASE AT PRESENTATION
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RECURRENCE
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SURVIVAL
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Table 9. Treatment of the primary lesion and subsequent recurrences in Merkel cell carcinoma patients presenting with clinically local disease (Stage I-II) with known primary tumor (n=155)
Excision margin status No. of patients (100%)
Recurrence No. of patients (%) Only local Nodal (+/-
local)
Distant (+/- local or nodal)
Overall
Intralesional exc. 27 7 (26%) 6 (22%) 1 (4%) 14 (52%)
Intralesional exc.
+RT
6 0 2 (33%) 0 2 (33%)
Marginal exc. 81 10 (12%) 10 (12%) 8 (10%) 28 (35%)
Marginal exc. +RT 13 0 2 (15%) 2 (15%) 4 (31%)
Wide exc. 18 2 (11%) 4 (22%) 1 (6%) 7 (39%)
Wide Exc +RT 2 0 0 1 (50%) 1 (50%)
Unknown 7 2 (29%) 1 (14%) 0 3 (43%)
Unknown+RT 1 0 0 0 0
Total 155 21 (14%) 25 (16%) 13 (8%) 59 (38%)
exc. = excision RT = radiotherapy
Table 10. Site of first recurrence among the 59 patients with Stage I-II disease with a recurrence.
Number of
patients %
Median time months (range)
Local 35 59.3 3 (1-61)
In-transit 3 5.1 7 (4-34)
Regional lymph node 19 32.2 8 (2-56)
Distant 2 3.4 9 and 27
Table 11. Five-year relative survival ratio (%) among 180* Merkel cell carcinoma patients, with 95% confidence interval, by sex and stage (closing date Dec. 31, 2007).
Men Women All
Stage I 57.7 (30.5–85.6) 71.5 (55.0-–86.6) 68.7 (54.0–81.8)
Stage II 28.5 (7.0–60.4) 88.0 (56.7–114) 67.0 (44.3–88.6)
Stage III 0 28.7 (4.4–66.2) 16.5 (2.7–43.7)
Stage IV 0 0 0
All 35.7 (20.3–53.5) 69.4 (56.0–81.9) 59.2 (49.0-70.0)
* One 100-year-old patient was dropped because the population life table did not go beyond the age of 99 years.
(LYMPHO)VASCULAR INVASION IN MERKEL CELL CARCINOMA (STUDY II)
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Table 12. Development of regional or distant metastases in cases with only local disease at the time of diagnosis (N= 111)
LVI+, BVI+ LVI+, BVI- LVI-, BVI+ LVI-, BVI-
N= 26 N= 73 N= 3 N= 9
Regional lymph node 3 (11.5%) 14 (19.2%) 0 0
Regional and distant 2 (7.7%) 2 (2.7%) 0 0
Distant only 1 (3.8%) 3 (4.1%) 1 (33.3%) 0
Total 6/ 26 19/ 73 1/ 3 0/ 9
LVI + = lymphovascular invasion detected LVI = lymphovascular invasion not detected BVI + = blood vascular invasion detected BVI = blood vascular invasion not detected
MERKEL CELL POLYOMA VIRUS (STUDY III)
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Figure 6. Kaplan-Meier analysis of the survival of patients whose tumors contained (+) Merkel cell polyoma virus DNA or lacked it (-).
A) Merkel cell carcinoma specific survival, B) overall survival
