Introduction

Systemic treatments with sartans, and in particular telmisartan, are generally associated with a more frequent association with all forms of human cancer¹. According to other scientific works, this risk is determined by the total cumulative intake of sartans over a certain period of time².

Literature data has linked both keratinocytic and melanocytic cancers to the use of sartans³.

The simultaneous occurrence of basal cell carcinomas (BCC) and dysplastic nevi after taking sartans or sartans in combination with hydrochlorothiazide could be consideredas extremely important, eventually confirmatory, regarding the thesis that potential contamination with nitrosamines is able to generate multiple forms of cancer or skin cancer and/or its precursors⁴,⁵. Contamination with mutagenic nitrosamine remains the link between the intake of sartans and the development of skin cancer. The recently confirmed presence of nitrosamines in hydrochlorothiazide (within monomedication or in combination), could reinforce the mentioned assumptions⁶.

Case report

A 69-year-old female came to the dermatology department with a 5-year-old tumor formation on the scalp in close proximity to the frontal region, that had been growing for about five years prior to the consultation. Physical examination showed a giant tumor, 5-7 cm in diameter, covered with hemorrhagic crusts, with undefined borders (Fig. 1A). A biopsy taken preoperatively confirmed the histophatological diagnosis of basal cell carcinoma.

Figure 1 A-C: giant tumor formation of the scalp, 5/7 cm in size, covered with hemorrhagic crusts, with undefined borders (a). Outpatient follow-up with primarly healing wound and good aesthetic outcome (b,c).Due to comorbidities (arterial hypertension known for 13 years, hypertriglyceridemia, hypercholesterolemia and sinus tachycardia) the patient was under systemic therapy with Telmisartan 80 mg/Amlodipine 5 mg once daily for 9 years, Hydroxyzine 25 mg once daily in the evening and Chlorthalidone 25 mg once daily for 2 years. Glucose level was 7.15 mmol/L (normal range 3.9-5.6 mmol/L), but other blood tests were normal. A Computerized Tomography of the head showed a normal brain image without deviations or changes in the bone structure of the frontal bone. 

After consultation with a cardiologist, the medication was switched to moxonidine 0.2 mg twice daily, Nebivolol 2.5 mg once daily, and clonidine when needed.

The tumor was excised under general anesthesia followed by reconstruction with an advancement rotation flap. Histopathology showed a stage 2 (T2N0M0) nodular type of basal cell carcinoma without evidence of metastases. There was a good cosmetic result, and outpatient follow-up showed no tumor recurrence (Fig. 1B,C).

Discussion

Nitrosamines are well-known mutagens, carcinogens that without any doubt are causing in vivo different types of carcinomas such as: cancers of the bladder, lung, stomach, leukaemia, multiple myeloma, oesophagus, prostate, pancreas and liver⁷. Their pathogenetic role in the development of almost all forms of cancer remains undeniable and well-defined¹,²,⁷, either after inhalation⁸ or oral intake should. Their procarcinogenic effect remains statistically significant after taking sartans potentially contaminated with nitrosamines, especially for keratinocyte cancer, confirmed in serious retrospective analyses: unadjusted OR (95% CI) for BCC: 2.16 (1.85-2.82), as well as adjusted OR (95% CI) for BCC: 2.86 (2.13-3.83)⁸.

A two-fold increased expression of the Angiotensinogen gene in tumor cells of patients with BCC has been shown⁹. Although the role of the reninangiotensin system in the skin physiology is undeniable¹⁰, it remains unclear whether this expression is a result or a cause for the development of BCC.

A number of publications have established a link between sartans administration and the increased risk for melanoma progression in the experimental environment¹¹,¹². An interesting recent publication indicated that valsartan contaminated with nitrosamines was associated with a 10% higher risk of developing melanomas¹³. Regarding BCC, such observations are completely absent, but the present case will perhaps be accompanied by other reports in the future. Currently, sartan use is associated with a significantly increased risk of actinic keratoses development, which are perceived as preforms of keratinocyte cancer¹⁴.

According to expert conclusions of specialised collectives, which are focused on monitoring the possible side effects of nitrosamines, their potential availability in sartans, ACE inhibitors, thiazide diuretics, metformin, and ranitidine, could lead to skin cancer development¹⁵.

The potential role of nitrosamines is mentioned within the perspective of large-scaled retrospective analyses⁸. According to them, both sartans and thiazide diuretics, but also ACE inhibitors, are associated with an over two-fold to nearly three-fold increased risk of developing BCC⁸. Batches of all these three classes of medications have been withdrawn from distribution in recent years due to the elevated concentrations of nitrosamines, many times exceeding the so-called ADIs (Acceptable daily intake doses).

Following statistical results and analyses⁸, it remains unlikely that the link between the three types of skin cancers (BCCs, Squamous cell carcinomas and melanomas) and different classes of antihypertensive medication with distinct pharmacologic activities is sporadic, but very probably related to common nitrosamine contamination of all these classes of drugs⁸.

In this case report, the absence of painful sunburns in the patient's history, as well as the long-term use of telmisartan (potentially contaminated with nitrosamines), reinforce this pathogenetic relationship.