Thoughts on the Etiology of Cherubism.

Cherubism is nowadays classified as an autoimmune disease and was first described in 1933. Although suspected at that time to be the result of defective tooth development, it was primarily classified as a bone disease caused by a mutation in the SH3BP2 gene. Despite a knock-in mouse model, phenotypic signs in the jaw area were not reproducible in this model. The features of classical cherubism can be attributed to a disturbed formation of the dental placode of the second molar. Since 2019, it has become clear that inhibition of the WNT pathway leads to the accumulation of SH3BP2 via tankyrase inhibition. As the dental placode is triggered via WNT (in epithelia) and MSX1 (in mesenchyme), aplasia of the second and third molars occurs due to a block in the WNT pathway. The mesenchymal part, which occurs prior to the body plan regulation of the WNT/MSX1 pathway, remains unaffected and provides the substrate for the giant cell granuloma. Considering macrophage polarization and the role of the extracellular matrix in general, cherubism is situated in the field of tension between autoimmune diseases and cancer. In this sense, we see the cause of cherubism in a WNT-related dysregulation, which can be proven postnatally in the neural crest-related tooth development of the replacement tooth ridge, both genotypically and phenotypically.

Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes - an immunohistochemical study.

BACKGROUND: It is largely accepted that specific immunological parameters in solid malignancies are associated with patient's prognosis. Recently a correlation of macrophage polarization with histomorphological parameters could also be shown in oral squamous cell carcinoma (oscc). The observed tumor derived peripheral immune tolerance could be associated with the macrophage polarization in regional tumor draining lymph nodes.So far there are no studies analyzing the macrophage polarization in cervical lymph nodes of oscc patients. In the present study we aimed to correlate macrophage polarization in different anatomical lymph node compartments of patients diagnosed with oscc with histopathologic parameters of the primary tumor (T-, N-, L-, V-, Pn-status, grading). METHODS: Tumor free (n = 37) and metastatic (n = 17) lymph nodes of T1 and T2 oscc patients were processed for immunohistochemistry to detect CD68, CD11c, CD163 and MRC1 positive cells. Samples were digitized using whole slide imaging and the number of cells expressing the aforementioned markers in the region of interest quantitatively analyzed. RESULTS: The malignancy of the primary tumor (defined by T-, L-, Pn-status, grading) correlated with the lymph node macrophage polarization. L1 and Pn1 tumor cases displayed a significantly (p < 0.05) decreased M1 and increased M2 polarization in the sinus of the lymph nodes. G3 cases presented a significantly (p < 0.05) increased M2 polarization in the sinus compared to G2 cases. T2 tumors had significantly (p < 0.05) increased M2 polarization in the interfollicular zone of regional lymph nodes compared to T1 tumors. Metastatic and non-metastatic lymph nodes did not differ regarding their macrophage polarization. CONCLUSIONS: The current study revealed for the first time an influence of oscc on the macrophage polarization in regional lymph nodes. Markers of malignant behavior in the primary tumor were associated with a shift of macrophage polarization in lymph nodes from the anti-tumoral M1 type to the tumor-promoting M2 type. As tumor free and metastatic lymph nodes did not differ in terms of their macrophage polarization pattern, there must be other factors influencing the location for lymph node metastasis formation.

Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages--an immunohistochemical analysis.

BACKGROUND: In solid malignancies the influence of immunological parameters - especially of macrophages - on invasiveness, metastatic potential and prognosis has been shown. There are no studies quantitatively analysing the macrophage polarization in oral squamous cell carcinoma (oscc). The aim of this study was to correlate macrophage polarization in the epithelial and stromal compartment of oscc with histopathologic parameters. METHODS: T1 and T2 oscc samples (n = 34) were used. Automated immunohistochemical staining detected CD68, CD11c, CD163 and MRC1 positive cells. All samples were completely digitalized using whole slide imaging and the number of stained cells per area was assessed quantitatively. RESULTS: Primary tumours with lymphogenic metastasis (N+) showed a significantly (p < 0.05) increased count of CD68, CD11c, CD163 and MRC1 positive cells in the epithelial fraction compared to N0 tumours. The ratio of CD163 positive cells (M2 macrophages) to CD68 positive cells (M1 and M2 macrophages) was significantly (p < 0.05) increased in N+ tumours. CONCLUSION: An increased macrophage infiltration and an increased M2 polarization in primary oral squamous cell carcinomas with lymphogenic metastasis was shown. Macrophages that migrated into the epithelial tumour fraction seem to be of special biological importance. The results indicate a central role of macrophages in the progression of oscc.

Oral cancer treatment and immune targets - a role for dendritic cells?

Treating a patient suffering from an advanced oral cavity carcinoma by peritumoural injections of mistletoe preparation resulted in a surprising partial response. At the same time an early metastasis, located at the kidney, however remained unaffected. The main difference in treatment being peritumoural versus systematic application supports the hypothesis of immune surveillance. The impact of mistletoe extract in direct contact with the tumour tissue might be explained as activation of macrophage polarization followed by induced cytotoxicity. No direct contact is resulting in no direct macrophage activation. At present there is no clinical trial outlined to test this hypothesis, but as a beginning we would like to encourage submission of case reports with similar clinical experience.

Bisphosphonate-associated osteonecrosis of the jaw is linked to suppressed TGFß1-signaling and increased Galectin-3 expression: a histological study on biopsies.

BACKGROUND: Bisphosphonate associated osteonecrosis of the jaw (BRONJ) implies an impairment in oral hard- and soft tissue repair. An understanding of the signal transduction alterations involved can inform therapeutic strategies. Transforming growth factor ß1 (TGFß1) is a critical regulator of tissue repair; galectin-3 mediates tissue differentiation and specifically modulates periodontopathic bacterial infection. The aim of this study was to compare the expression of TGFß1-related signaling molecules and Galectin-3 in BRONJ-affected and healthy mucosal tissues. To discriminate between BRONJ-specific impairments in TGFß1 signaling and secondary inflammatory changes, the results were compared to the expression of TGFß1 and Galectin-3 in mucosal tissues with osteoradionecrosis. METHODS: Oral mucosal tissue samples with histologically-confirmed BRONJ (n = 20), osteoradionecrosis (n = 20), and no lesions (normal, n = 20) were processed for immunohistochemistry. Automated staining with an alkaline phosphatase-anti-alkaline phosphatase kit was used to detect TGFß1, Smad-2/3, Smad-7, and Galectin-3. We semiquantitatively assessed the ratio of stained cells/total number of cells (labeling index, Bonferroni-adjustment). RESULTS: TGFß1 and Smad-2/3 were significantly decreased (p < 0.032 and p(0.028, respectively) in the BRONJ samples and significantly increased (p < 0.04 and p <0.043, respectively) in the osteoradionecrosis samples compared to normal tissue. Smad-7 was significantly increased (p < 0.031) in the BRONJ group and significantly decreased (p < 0.026) in the osteoradionecrosis group. Galectin-3 staining was significantly (p < 0.025) increased in both the BRONJ and the osteoradionecrosis (p < 0.038) groups compared to the normal tissue group. However, Galectin-3 expression was significantly higher in the BRONJ samples than in the osteoradionecrosis samples (p < 0.044). CONCLUSION: Our results showed that disrupted TGFß1 signaling was associated with delayed periodontal repair in BRONJ samples. The findings also indicated that impairments in TGFß1-signaling were different in BRONJ compared to osteoradionecrosis. BRONJ appeared to be associated with increased terminal osseous differentiation and decreased soft tissue proliferation. The increase in Galectin-3 reflected the increase in osseous differentiation of mucoperiosteal progenitors, and this might explain the inflammatory anergy observed in BRONJ-affected soft tissues. The results substantiated the clinical success of treating BRONJ with sequestrectomy, followed by strict mucosa closure. BRONJ can be further elucidated by investigating the specific intraoral osteoimmunologic status.

Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue-etiopathology considerations respecting jaw developmental biology-related unique features.

BACKGROUND: Bone-destructive disease treatments include bisphosphonates and antibodies against the osteoclast differentiator, RANKL (aRANKL); however, osteonecrosis of the jaw (ONJ) is a frequent side-effect. Current models fail to explain the restriction of bisphosphonate (BP)-related and denosumab (anti-RANKL antibody)-related ONJ to jaws. Msx-1 is exclusively expressed in craniofacial structures and pivotal to cranial neural crest (CNC)-derived periodontal tissue remodeling. We hypothesised that Msx-1 expression might be impaired in bisphosphonate-related ONJ. The study aim was to elucidate Msx-1 and RANKL-associated signal transduction (BMP-2/4, RANKL) in ONJ-altered and healthy periodontal tissue. METHODS: Twenty ONJ and twenty non-BP exposed periodontal samples were processed for RT-PCR and immunohistochemistry. An automated staining-based alkaline phosphatase-anti-alkaline phosphatase method was used to measure the stained cells:total cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed on ONJ-affected and healthy jaw periodontal samples (n = 20 each) to quantitatively compare Msx-1, BMP-2, RANKL, and GAPDH mRNA levels. RESULTS: Semi-quantitative assessment of the ratio of stained cells showed decreased Msx-1 and RANKL and increased BMP-2/4 (all p < 0.05) expression in ONJ-adjacent periodontal tissue. ONJ tissue also exhibited decreased relative gene expression for Msx-1 (p < 0.03) and RANKL (p < 0.03) and increased BMP-2/4 expression (p < 0.02) compared to control. CONCLUSIONS: These results explain the sclerotic and osteopetrotic changes of periodontal tissue following BP application and substantiate clinical findings of BP-related impaired remodeling specific to periodontal tissue. RANKL suppression substantiated the clinical finding of impaired bone remodelling in BP- and aRANKL-induced ONJ-affected bone structures. Msx-1 suppression in ONJ-adjacent periodontal tissue suggested a bisphosphonate-related impairment in cellular differentiation that occurred exclusively jaw remodelling. Further research on developmental biology-related unique features of jaw bone structures will help to elucidate pathologies restricted to maxillofacial tissue.

Stromal laminin chain distribution in normal, hyperplastic and malignant oral mucosa: relation to myofibroblast occurrence and vessel formation.

BACKGROUND: The contribution of stromal laminin chain expression to malignant potential, tumour stroma reorganization and vessel formation in oral squamous cell carcinoma (OSCC) is not fully understood. Therefore, the expression of the laminin chains alpha2, alpha3, alpha4, alpha5 and gamma2 in the stromal compartment/vascular structures in OSCC was analysed. METHODS: Frozen tissue of OSCC (9x G1, 24x G2, 8x G3) and normal (2x)/hyperplastic (11x) oral mucosa was subjected to laminin chain and alpha-smooth muscle actin (ASMA) immunohistochemistry. Results were correlated to tumour grade. The relation of laminin chain positive vessels to total vessel number was assessed by immunofluorescence double labelling with CD31. RESULTS: Stromal laminin alpha2 chain significantly decreases and alpha3, alpha4, alpha5 and gamma2 chains and also ASMA significantly increase with rising grade. The amount of stromal alpha3, alpha4 and gamma2 chains significantly increased with rising ASMA positivity. There is a significant decrease in alpha3 chain positive vessels with neoplastic transformation. CONCLUSIONS: Mediated by myofibroblasts, OSCC development is associated with a stromal up-regulation of laminin isoforms possibly contributing to a migration promoting microenvironment. A vascular basement membrane reorganization concerning alpha3 and gamma2 chain laminins during tumour angioneogenesis is suggested.

Expression of Snail is associated with myofibroblast phenotype development in oral squamous cell carcinoma.

Snail is a regulator of epithelial-mesenchymal transition (EMT) and considered crucial to carcinoma metastasis, myofibroblast transdifferentiation, and fibroblast activation. To investigate the role of Snail in oral squamous cell carcinoma (OSCC), its immunohistochemical expression was analysed in 129 OSCC samples and correlated to nodal metastasis, histological grade, E-cadherin, and alpha smooth-muscle-actin (alpha SMA). The results were compared to findings in 23 basal cell carcinomas (BCC). Additionally, the influence of TGF beta 1 and EGF on Snail, E-cadherin, vimentin, and alpha SMA expression was analysed in two OSCC cell lines. As a result, Snail-positive cells were mainly found in the stroma of the OSCC invasive front without statistically significant correlation to histological grade or nodal metastasis. Snail was co-localised to alpha SMA but not to E-cadherin or cytokeratin and showed a significant correlation to the loss of membranous E-cadherin. All BCCs were Snail negative. In OSCC culture, the growth-factor-mediated EMT-like phenomenon was accompanied by alpha SMA down-regulation. In summary, Snail expression in OSCC is a stromal phenomenon associated with the myofibroblast phenotype and not related to growth-factor-mediated transdifferentiation of the carcinoma cells themselves. Consequently, Snail immunohistochemistry cannot contribute to the prediction of the metastatic potential. Furthermore, stromal Snail expression is suggested to be the result of mutual paracrine interaction of fibro-/myofibroblasts and dedifferentiated carcinoma cells leading to the generation of a special type of carcinoma-associated fibroblasts.

Ectopic bone formation as a complication of surgical rehabilitation in patients with Moebius' syndrome.

PURPOSE: Treatment of facial paralysis by muscular neurotization resulted in ectopic ossification in 1 of 134 cases in this department. That patient suffering from Moebius syndrome (MS) is presented. Reviewing the literature concerning MS, Hox genes and bone morphogenetic protein dysregulation, a pathogenesis of ossification in MS is suggested. PATIENT: The MS patient exhibited a congenital facial nerve palsy, which was treated by muscular neurotization (Lexer-Rosenthal). Because of postoperative ossification of scarred areas, osteotomy of the processus muscularis and mobilization of the masseter muscle was performed. Nevertheless, further ossification occurred at the interface between the mandible and zygoma and in two masticatory muscles. So, the construction of a neoarthrosis became necessary. Three years later, the iatrogenic bone defect had reossified despite of an active opening therapy. CONCLUSIONS: Ectopic ossification after muscular neurotization seems to be restricted to patients with MS and is triggered by trauma. Molecular pathogenesis: facial malformations in MS are caused by disturbances in embryonic patterning. Failure in the development of the second pharyngeal arch leads to a spatial BMP-4 dysregulation responsible for ossification after wounding of muscle fascia. Therefore, surgical rehabilitation of facial function by muscular neurotization is contra indicated in MS patients.

Mesenchymal cells contribute to the synthesis and deposition of the laminin-5 gamma2 chain in the invasive front of oral squamous cell carcinoma.

Tumour progression in oral squamous cell carcinoma (OSCC) is associated with a reorganisation of extracellular matrix. Laminin-5 (Ln-5) plays an important role for tumour migration and shows an increased expression in areas of direct tumour/stroma interactions. We have previously shown stromal spot like Ln-5/gamma2 chain deposits distant from the basement membrane region. In this study we have analysed which cell type is responsible for Ln-5/gamma2 chain synthesis in situ. Furthermore, we studied its spatial relation to TGF-beta1 as well as the Ln-5 modulating enzymes matrix metalloproteinase (MMP) 2, membrane type-1 (MT1-) MMP and bone morphogenetic protein (BMP-) 1 by different techniques including triple immunofluorescence labelling and in situ hybridisation in OSCC. We found that the stromal spot-like Ln-5 deposits occurred in the invasive front in the vicinity of mesenchymal cells and vessel structures. In particular, not only carcinoma cells but also mesenchymal cells were shown to express the Ln-5/gamma2 chain mRNA. Moreover, stromal Ln-5 deposits showed a spatial association with TGF-beta1 as well as with MT1-MMP and BMP-1. Based on these findings we suggest that mesenchymal cells contribute to the promotion of tumour cell migration as well as vessel formation in OSCC by providing and organising promigratory Ln-5 fragments.

A quantitative co-localization analysis of large unspliced tenascin-C(L) and laminin-5/gamma2-chain in basement membranes of oral squamous cell carcinoma by confocal laser scanning microscopy.

BACKGROUND: A structural interaction of the oncofetal large tenascin-C splice variants (Tn-C(L)) and the gamma2-chain of laminin-5 (Ln-5/gamma2) was recently demonstrated in oral squamous cell carcinoma (OSCC). In situ different patterns of co-localization and co-deposition of both proteins could be detected. Especially the co-localization in re-established basement membrane (BM) structures seemed to be biologically meaningful within the process of tumour progression. METHODS: The amount of Tn-C(L) incorporated in reorganized OSCC BM structures at the tumour margins was investigated by a laser scanning microscopy-based quantitative co-localization analysis. RESULTS: In the BM of normal oral mucosa no Tn-C(L) could be detected. In dysplastic and neoplastic oral mucosa a distinct co-localization of Tn-C(L) and Ln-5/gamma2 in the BM region could be observed. The extent of Tn-C(L) arrangement into reorganized BM structures correlated with malignancy grade. CONCLUSIONS: The results suggest at first, a modulation of carcinomatous BM structures by the inclusion of oncofetal matrix proteins during tumour progression and secondly, the BM incorporation of the adhesion-modulating molecule Tn-C(L) as a pre-invasive structural phenomenon in OSCC.

Comparison of aminolevulinic acid (ALA)-thermogel-PDT with methyl-ALA-thermogel-PDT in basal cell carcinoma.

BACKGROUND: Aminolevulinic acid (ALA) and light irradiation is a treatment option in basal cell carcinomas (BCC). The development of ALA-esters with potential for greater penetration depth promises higher therapeutic success. In a pilot study, we hypothesized that the cytotoxic effect of methyl-ALA (mALA) photodynamic therapy (PDT) leads to a higher success rate compared with ALA-PDT when both are topically applied in a thermogel. METHODS: Twenty-four patients with 112 superficial BCC were treated with either 10% ALA- or mALA-thermogel. After an accumulation time of at least 3h, the lesions were illuminated with a diode laser. The power density was 0.1W/cm(2) and the energy density was 120J/cm(2). After intervals of 12 weeks and 6 months, the therapeutic efficacy was assessed by clinical examination. RESULTS: Sixty percent of the tumors were treated successfully in the first session. All but 3% of the remaining tumors could be treated with a second or third course of therapy. CONCLUSION: Although mALA should have a greater penetration depth, the therapeutic outcome of this preliminary study showed no difference between treatments. The final proof of this preliminary result will require further study.

Complex formation of the laminin-5 gamma2 chain and large unspliced tenascin-C in oral squamous cell carcinoma in vitro and in situ: implications for sequential modulation of extracellular matrix in the invasive tumor front.

Invasion and metastasis in oral squamous cell carcinoma (OSCC) are associated with changes in the extracellular matrix (ECM). We have previously shown an extracellular co-deposition of laminin-5 (Ln-5) and large unspliced tenascin-C (Tn-C(L)) in OSCC. Using a co-culture model of hTERT-BJ1 fibroblasts and the OSCC cell line PE/CA-PJ15, we demonstrate in the present study that Ln-5 and Tn-C(L) are not only co-deposited, but also form a physical complex which can be recovered by co-immunoprecipitation. In agreement with these results, examination of OSCC tissue specimens of different malignancy grade by means of confocal laser scanning microscopy revealed different patterns of Ln-5 and Tn-C(L) co-localization implicating complex formation also in vivo. A ribbon like co-localization was detected in subepithelial basement membranes around well differentiated OSCC parts and tumor clusters. Furthermore, a fibrillar Ln-5 gamma2 chain/Tn-C(L) co-localization occurred in the carcinoma stroma beneath tumor clusters. Additionally, at the site of ruptured basement membranes there were dot or strand like co-deposits of both molecules, but co-localizations were only rarely detectable. These different patterns may reflect a sequential modulation and reorganization of the ECM in the tumor/stroma interface as it occurs in different stages of OSCC invasion.

Analysis of activated EGFR signalling pathways and their relation to laminin-5 gamma2 chain expression in oral squamous cell carcinoma (OSCC).

Overexpression of epidermal growth factor receptor (EGFR) was shown for the majority of squamous cell carcinomas. The EGFR expression correlates to tumour size, stage and cytoplasmic accumulation of the laminin-5 gamma2 chain (Ln-5/gamma2), which is known as a marker of invading tumour cells. There is only limited knowledge if and how EGFR signalling pathways are important for invasion-associated processes and for the regulation of Ln-5/gamma2. Therefore the distribution of phosphorylated Erk1/2, p38 MAPK and Akt was immunohistochemically defined in oral squamous cell carcinoma (OSCC) of different histological grade and compared to histological criteria of invasion and cytoplasmic Ln-5/gamma2 deposition. With raising histological grade, there is a slight increase in nuclear pErk1/2-stained tumour cells (P=0.398) and a loss of nuclear (P=0.593) and increased cytoplasmic staining (P=0.144) of pAkt mainly in invading OSCC cells. Nuclear pp38 MAPK could only be sporadically detected in few cases. In case of pErk1/2 and pAkt, only a partial co-localisation could be revealed in cases with abundant kinases and Ln-5/gamma2. Among the investigated kinases, only pAkt shows a relation to histological grade and invasion in OSCC. pErk1/2, pp38 MAPK and pAkt do not represent a direct link between EGFR and Ln-5 synthesis. Therefore, enhanced Ln-5/gamma2 may be a secondary phenomenon of EGFR-induced tumour cell proliferation and dissemination.

Cherubism - new hypotheses on pathogenesis and therapeutic consequences.

AIMS: The hereditary occurrence of cherubism indicates a probable genetic aetiology: a correlation with a mutation in the gene SH3BP2 has been demonstrated. A convincing concept of formal pathogenesis is not yet available. The study was aimed at advancing the understanding of the pathogenesis of cherubism by presenting a case study including genetic findings and an evaluation of the literature. RESULTS AND CONCLUSION: Because of its association with the development of the second and third molars, cherubism could be defined as a genetically determined alteration of tooth development. In this context, disturbed PTHrP - PTHrP receptor interaction induced by the mutation in SH3BP2 is discussed. The temporal and spatial determination of the clinical symptoms is explained by an interaction of SH3BP2-dependent signal transduction pathways with jaw morphogenesis (e.g. Hox-gene Msx-1). Because of the disease-induced lack of determination of the cap phase of the second and third molar, a spatial compartmentation, which is necessary for normal dental development, does not take place. This leads to dysregulation of mesenchymal bone building tissue areas, and to the development of giant cell granulomas with high osteoclastic activity. Because of the genetic determination of cherubism and the associated dedifferentiation of the diseased tissue, a surgical removal should be exclusively restricted to specific indications. Therefore an attitude of wait and see is preferred.

Photodynamic therapy of virus-associated epithelial tumours of the face in organ transplant recipients.

PURPOSE: The benefit for organ recipients is still counteracted by the side effects of immunosuppression. Among other effects, there is a 50-250 times increased risk of developing malignant skin tumours. Because these malignomas are known to develop particularly aggressivly, there is a special need for an efficient therapy. Here we demonstrate the treatment response to aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) in these patients. METHODS: Five organ recipients with multiple tumours of the face were multifocally treated with ALA-PDT (32 tumours in all). After topical application of ALA using a thermogel, irradiation was done with a 635 nm diode laser (Ceralas 635, Biolitec, Jena, Germany). After intervals of 2 weeks, 4 weeks, and 12 weeks, therapeutic efficacy was assessed. RESULTS: There was complete remission in 24 tumours (75%). In six tumours (18.8%) a second or third PDT session was necessary for complete clinical remission. In two tumours (5.6%, invasive squamous cell carcinomas) the lesions were refractory to PDT. CONCLUSIONS: ALA-PDT is a valuable therapeutic alternative for the treatment of multifocal skin tumours in organ-transplanted patients. Furthermore, we see a growing role of ALA-PDT also for patients with frequently relapsing tumours of the skin with known genetically determined tumourigenesis (Gorlin-Goltz syndrome).

The therapy of virus-associated epithelial tumors of the face and the lips in organ transplant recipients.

The risk of developing malignant cutaneous neoplasms is increased after organ transplantation. We report three patients with malignant tumors of the epithelium of the facial skin and the lips after kidney and heart transplantation, respectively. They showed an aggressive course of the disease with more than five synchronous or metachronous basal cell and squamous cell carcinomas. Tissue samples were Epstein-Barr virus (EBV) positive by PCR. Using an in situ hybridization technique EBV-encoded RNA (EBER) was detected in tumor-infiltrating lymphocytes. The aggressive course was not alone controllable by surgical or radiological therapy. The systemic and topical application of cidofovir (Vistide) led to remarkable remissions, to a better confinement and operability of the tumors, and to a cessation of tumor pain. The photodynamic therapy represents another opportunity for managing superficial local recurrences and multiple tumors. In conclusion, the results of these case reports demonstrate that combined antiviral, photodynamic and surgical therapy may be used successfully to treat aggressive cutaneous malignancies in patients after organ transplantation.