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Der „Basalzellenkrebs“




E. Krompecher, 1903
1894                   Today
Illustration P.G. Unna   Photography W. Neuse
1895                     Today
Illustration G. Thibierge   Photography W. Neuse
BASAL CELL CARCINOMA
                  INCIDENCE


Australia    up to 2 % per year


USA          White population      407 / 100 000 / year
             1 million cases in 2005
             Half of all cancers
             80 % of all NMSC


Worldwide     Increasing incidence
BASAL CELL CARCINOMA
               RISK FACTORS

Skin type I – II
Ionising radiation
Burns
As, Tar, Smoking
Immunosuppression
Age > 60
Previous BCC: RR 10x
Gene mutations
Ultraviolet !
BASAL CELL CARCINOMA
          AND IONIZING RADIATION




Multiple BCCs 20 yrs after irradiation of Hodgkin´s disease
BASAL CELL CARCINOMA
    DISTRIBUTION



Head/Neck      60 %
     Nose      14 %

Trunk          30 %

Extremities    10 %
BASAL CELL CARCINOMA
                  PATHOGENESIS

                      UV

 Immuno-                              DNA
Suppression
                    Mutations        Repair




                     BCC
                                    Genetic
  Skin type                      Predisposition
NEVOID BASAL CELL CARCINOMA-
          SYNDROME (NBCCS)


Autosomal dominant

Multiple BCCs at young age

Skin, CNS, Skeletal involvement

Predisposition to malignancy
(medulloblastoma)

PTCH germ line mutations
THE SONIC HEDGEHOG PATHWAY

 Shh

                     extracellular
 Ptch    Smoh
                     intracellular

                    PTCH
         Gli1/2
                     HIP
Sufuh
                     CCNB1/D2
         Gli1/2
                    FOXM1/FOXE
        Nucleus
                      BCL2
PTCH

Human homolog of the Drosophila - Gene patched




            Wild type          PTCH Mutant

Drosophila: segmental development
Function:     Receptor for the hedgehog protein
              Tumor suppressor
ANALYSIS OF SHH PATHWAY GENES
          IN SPORADIC BCCs


   PTCH mutations:                            28/42 (67%)
   SMOH mutations:                            4/42      (10%)
   SUFUH mutations:                           2/42      (22%)
   GLI1/GLI2 overexpression:                  42/42 (100%)


In 70% of BCCs somatic mutations of Shh genes

Shh pathway is constitutively activated in all BCCs

                         Wolter et al., Cancer Res 57: 2581-2585, 1997
                         Reifenberger et al., Cancer Res 58: 1798-1803,1998
                         Reifenberger et al., Br J Dermatol: 43-51, 2005
PTCH+/- MOUSE MODEL


Model of human NBCCS

Body size increased

Medulloblastomas (15%)

                           Medulloblastoma



BCCs after repetitive
     UVB exposure


                          UVB induced BCCs
„MOUSE SOLARIUM“
GDC-0449
SMALL MOLECULE SMO-INHIBITOR
von Hoff et al., N Engl J Med 2009
PHOTODYNAMIC THERAPY (PDT)




                          PDD with
                         Wood-Light
Topical application of     417 nm
                                      PDT with
ALA 20 % (3 - 5 h)                    red light
                                       634 nm
PHOTODYNAMIC THERAPY
           OF NBCCS




Before therapy      After 4x PDT
FLUORESCENCE DIAGNOSIS




Pre-operative determination of tumor margins
And I told him,
put some cream on
UV PROTECTION
OBC | New development in the therapy of basal cell carcinoma
OBC | New development in the therapy of basal cell carcinoma
OBC | New development in the therapy of basal cell carcinoma
OBC | New development in the therapy of basal cell carcinoma
OBC | New development in the therapy of basal cell carcinoma
OBC | New development in the therapy of basal cell carcinoma
OBC | New development in the therapy of basal cell carcinoma

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OBC | New development in the therapy of basal cell carcinoma

  • 2. 1894 Today Illustration P.G. Unna Photography W. Neuse
  • 3. 1895 Today Illustration G. Thibierge Photography W. Neuse
  • 4. BASAL CELL CARCINOMA INCIDENCE Australia up to 2 % per year USA White population 407 / 100 000 / year 1 million cases in 2005 Half of all cancers 80 % of all NMSC Worldwide Increasing incidence
  • 5. BASAL CELL CARCINOMA RISK FACTORS Skin type I – II Ionising radiation Burns As, Tar, Smoking Immunosuppression Age > 60 Previous BCC: RR 10x Gene mutations Ultraviolet !
  • 6.
  • 7.
  • 8. BASAL CELL CARCINOMA AND IONIZING RADIATION Multiple BCCs 20 yrs after irradiation of Hodgkin´s disease
  • 9. BASAL CELL CARCINOMA DISTRIBUTION Head/Neck 60 % Nose 14 % Trunk 30 % Extremities 10 %
  • 10.
  • 11.
  • 12.
  • 13.
  • 14. BASAL CELL CARCINOMA PATHOGENESIS UV Immuno- DNA Suppression Mutations Repair BCC Genetic Skin type Predisposition
  • 15. NEVOID BASAL CELL CARCINOMA- SYNDROME (NBCCS) Autosomal dominant Multiple BCCs at young age Skin, CNS, Skeletal involvement Predisposition to malignancy (medulloblastoma) PTCH germ line mutations
  • 16. THE SONIC HEDGEHOG PATHWAY Shh extracellular Ptch Smoh intracellular PTCH Gli1/2 HIP Sufuh CCNB1/D2 Gli1/2 FOXM1/FOXE Nucleus BCL2
  • 17. PTCH Human homolog of the Drosophila - Gene patched Wild type PTCH Mutant Drosophila: segmental development Function: Receptor for the hedgehog protein Tumor suppressor
  • 18. ANALYSIS OF SHH PATHWAY GENES IN SPORADIC BCCs PTCH mutations: 28/42 (67%) SMOH mutations: 4/42 (10%) SUFUH mutations: 2/42 (22%) GLI1/GLI2 overexpression: 42/42 (100%) In 70% of BCCs somatic mutations of Shh genes Shh pathway is constitutively activated in all BCCs Wolter et al., Cancer Res 57: 2581-2585, 1997 Reifenberger et al., Cancer Res 58: 1798-1803,1998 Reifenberger et al., Br J Dermatol: 43-51, 2005
  • 19. PTCH+/- MOUSE MODEL Model of human NBCCS Body size increased Medulloblastomas (15%) Medulloblastoma BCCs after repetitive UVB exposure UVB induced BCCs
  • 22.
  • 23. von Hoff et al., N Engl J Med 2009
  • 24.
  • 25.
  • 26.
  • 27. PHOTODYNAMIC THERAPY (PDT) PDD with Wood-Light Topical application of 417 nm PDT with ALA 20 % (3 - 5 h) red light 634 nm
  • 28. PHOTODYNAMIC THERAPY OF NBCCS Before therapy After 4x PDT
  • 30.
  • 31. And I told him, put some cream on