A case of multiple basal cell carcinomas in an immunocompromised skin district: The aetiopathogenetic role of congenital lymphqedema

The immunocompromised skin district (ICD) refers to a cutaneous region that is considered more vulnerable than other regions due to local congenital or acquired alterations of the immune system, thus causing a major risk of developing tumours, infections and dysimmune reactions.1 Chronic lymphoedema of a particular district could be one of the causes of ICD, making it an immunologically vulnerable area because of inadequate lymphatic drainage.2 Lymphoedema consists of an interstitial proteinrich fluid overload due to lymph drainage failure that leads to an interstitial fluid volume increase.3 It typically affects lower or upper extremities.3 According to lymphoedema classification, primary lymphoedema includes congenital abnormalities affecting the lymphatic system, while secondary lymphoedema could develop after lymphadenectomy, radiotherapy, chronic lower extremity venous insufficiency, trauma, lymphatic filariasis or lymphatic obstruction by cancer cells.3 Herein, we report the case of a 48yearold female patient affected by congenital primary lymphoedema of the left thigh, caused by local hypoplasia of the lymphatic system confirmed by lymphoscintigraphy. The patient presented to our observation with three lesions of the same thigh affected by lymphoedema (Figure 1). The medical history showed no risk factors, such as chronic photoexposure or radiation therapy, related to the occurrence of the lesions, and there was no evidence of family history of skin cancer. The largest one had appeared two years ago, while the other two in the last year. At clinical examination, lesions presented as eczematouslike plaques, in particular, the largest one, with a diameter of 3 cm, was located on the lateral face of the thigh (Figure 1b), whereas the other two were located on the posterior face and had a diameter of 1.5 cm and 0.6 cm, respectively (Figure 1c). Dermoscopic examination of the three lesions showed the presence of shiny white lines, microulcerations, branched vessels and peripheral blue– grey globules. Three excisional biopsies were performed with histologic examination confirming basal cell carcinomas. To date, this is the first case reporting basal cell carcinomas developing in the same ICD. Local immunodepression occurs in an ICD, making these areas more subjected to the process of carcinogenesis.1,2 Numerous cutaneous malignancies have been described in lymphoedematous areas in literature, such as basal cell carcinoma, squamous cell carcinoma, melanoma, Kaposi sarcoma, Merkel cell carcinoma and several cutaneous lymphomas.4– 6 There are two main hypotheses about the promotion of skin cancer by lymphoedema.4,5 The first one is the impaired lymphatic circulation causing chronic inflammation and altering Langerhans cells (LC) function and migration. These alterations cause a decrease in LC expression of MHC class II molecules, thus antigen presentation in association with these molecules is impaired.5,7 Furthermore, chronic lymphoedema has been shown to cause proangiogenic factors increase, in particular vascular endothelial growth factor (VEGF), which promotes skin carcinogenesis by altering cell growth and proliferation.4,5 In literature, cases of basal cell carcinomas in immunocompromised districts caused by secondary lymphoedema have already been described5,8,9; however, this would be the first reported case of three basal cell carcinomas arising from an ICD after a primary lymphoedema simultaneously. Finally, it is important to periodically monitor ICDs and perform biopsies in case of suspicious lesions. This will allow earlier diagnosis and easier surgical treatments. We believe it is important to emphasize that our hypotheses should be confirmed in the future with new studies on the topic, which to date is characterized by a paucity of data.


A case of multiple basal cell carcinomas in an immunocompromised skin district: The aetiopathogenetic role of congenital lymphqedema
The immunocompromised skin district (ICD) refers to a cutaneous region that is considered more vulnerable than other regions due to local congenital or acquired alterations of the immune system, thus causing a major risk of developing tumours, infections and dysimmune reactions. 1 Chronic lymphoedema of a particular district could be one of the causes of ICD, making it an immunologically vulnerable area because of inadequate lymphatic drainage. 2 Lymphoedema consists of an interstitial protein-rich fluid overload due to lymph drainage failure that leads to an interstitial fluid volume increase. 3 It typically affects lower or upper extremities. 3 According to lymphoedema classification, primary lymphoedema includes congenital abnormalities affecting the lymphatic system, while secondary lymphoedema could develop after lymphadenectomy, radiotherapy, chronic lower extremity venous insufficiency, trauma, lymphatic filariasis or lymphatic obstruction by cancer cells. 3 Herein, we report the case of a 48-year-old female patient affected by congenital primary lymphoedema of the left thigh, caused by local hypoplasia of the lymphatic system confirmed by lymphoscintigraphy. The patient presented to our observation with three lesions of the same thigh affected by lymphoedema ( Figure 1). The medical history showed no risk factors, such as chronic photoexposure or radiation therapy, related to the occurrence of the lesions, and there was no evidence of family history of skin cancer. The largest one had appeared two years ago, while the other two in the last year. At clinical examination, lesions presented as eczematous-like plaques, in particular, the largest one, with a diameter of 3 cm, was located on the lateral face of the thigh (Figure 1b), whereas the other two were located on the posterior face and had a diameter of 1.5 cm and 0.6 cm, respectively (Figure 1c). Dermoscopic examination of the three lesions showed the presence of shiny white lines, micro-ulcerations, branched vessels and peripheral blue-grey globules. Three excisional biopsies were performed with histologic examination confirming basal cell carcinomas.
To date, this is the first case reporting basal cell carcinomas developing in the same ICD. Local immunodepression occurs in an ICD, making these areas more subjected to the process of carcinogenesis. 1,2 Numerous cutaneous malignancies have been described in lymphoedematous areas in literature, such as basal cell carcinoma, squamous cell carcinoma, melanoma, Kaposi sarcoma, Merkel cell carcinoma and several cutaneous lymphomas. [4][5][6] There are two main hypotheses about the promotion of skin cancer by lymphoedema. 4,5 The first one is the impaired lymphatic circulation causing chronic inflammation and altering Langerhans cells (LC) function and migration. These alterations cause a decrease in LC expression of MHC class II molecules, thus antigen presentation in association with these molecules is impaired. 5,7 Furthermore, chronic lymphoedema has been shown to cause proangiogenic factors increase, in particular vascular endothelial growth factor (VEGF), which promotes skin carcinogenesis by altering cell growth and proliferation. 4,5 In literature, cases of basal cell carcinomas in immunocompromised districts caused by secondary lymphoedema have already been described 5,8,9 ; however, this would be the first reported case of three basal cell carcinomas arising from an ICD after a primary lymphoedema simultaneously.
Finally, it is important to periodically monitor ICDs and perform biopsies in case of suspicious lesions. This will allow earlier diagnosis and easier surgical treatments. We believe it is important to emphasize that our hypotheses should be confirmed in the future with new studies on the topic, which to date is characterized by a paucity of data.

AUTHOR CONTRIBUTIONS
All the authors equally contributed to this work.

ACKNO WLE DGE MENTS
None to declare.

FUNDING INFORMATION
None to declare.

CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflicts of interest.

ETHICS STATEMENT
Not required.

PATIENT CONSENT
The authors have obtained the consent of the patient for clinical images.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.