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МЕДИЦИНСКИ ПРЕГЛЕД, 2023, 59 (5) 5
1Onkoderma – Clinic for Dermatology, Venereology and Dermatologic Surgery
2Department of Dermatology and Venereology, Medical Institute of Ministry of Interior
3Department of Pathology, University of Virginia, Charlottesville, USA
Prof. Georgi Tchernev, MD
Onkoderma – Policlinic for Dermatology,
Venereology and Dermatologic Surgery
26 General Skobelev blvd.
Bg – 1606 Sofia
Phone: 00359885588424
: nitrosamines, skin cancer, metformin, sartan, ranitidine
There is no conflict of interest. No financial disclosure.
Nitrosamine exposure in the form of dust, as well as its
influence on workers in the rubber industry, has been well
studied over the years and according to data in the litera-
ture, it suggests a serious or significant risk in terms of de-
veloping almost all types of cancer, including those of the
esophagus, oral cavity, pharynx, bladder, lungs, stomach,
prostate, pancreas and liver, as well as leukemia, multiple
myeloma, and others [1-3].
Based upon the results of significant epidemiological
studies, there is a direct connection between the intake/in-
halation of nitrosamines and the development of various
forms of cancer, as well as an increased mortality rate in a
significant number of them [1].
Despite the establishment, in 2021, of permissible
levels of nitrosamines in medications on the market (in-
cluding, but not limited to, antihypertensive medications)
[4], the problem with their availability has expanded sig-
nificantly in the last year, as other classes of medications
are also affected, including: oral antidiabetic medications,
such as metformin [5], ACE inhibitors/quinapril [6]/ACE
inhibitors in combination with hydrochlorothiazide [7], an-
giotensin receptor blockers/sartans [8], and smoking cessa-
tion drugs [9].
Even more concerning are the statistically significant
links (published as a meta-analysis in March 2022) between
angiotensin receptor blockers/sartans and the development
of heterogeneous cancers [10]. Unfortunately, the authors
do not weigh in on the possible role of nitrosamines as key
factors in carcinogenesis [10].
According to similar published data, but based upon
the observation of single patients, the dose-dependent time
intervals for the generation of melanomas, after taking sar-
tans that are potentially contaminated with nitrosamines
(as monotherapy), seem to be approximately the same [8,
11] as those for sartans in combination with hydrochloro-
thiazide; i.e., approximately 3 years [12-15].
6 G. Tchernev, S. Kordeva, J. W. Patterson. Nitrosamines and Skin Cancer: Rather Reality than a Myth?
Relatively shorter intervals to the development of
melanomas – e.g., under 3 years – could be associat-
ed with the parallel intake of potentially contaminated
medications with thiazide diuretics [12, 13, 15].
The combined intake of sartans with potentially ni-
trosamine-contaminated metformin could also be of key
importance in terms of exceeding the acceptable daily
intake (ADI) dose, but in this case, related to the intake
of more than one medication. There are also cases in
the scientific literature in which the simultaneous intake
of sartans and metformin has been associated with the
subsequent occurrence of melanoma or atypical fibrox-
anthoma in combination with prostate carcinoma [12,
16]. These reports further suggest that nitrosamines are
capable of causing heterogeneous forms of skin cancer
– not a surprise, since mutagens are practically accepted
as carcinogens [12, 16].
Similar issues arise when there is simultaneous in-
take of ranitidine or ACE inhibitors (with sartans and/
or hydrochlorothiazide), bearing in mind their suspected
(and, actually, repeatedly established) official contami-
nation [6, 17].
The risk of developing neoplasms with the simul-
taneous ingestion of ranitidine and metformin in com-
bination with sartans, sartans/hydrochlorothiazide, or
ACE inhibitors, is apparent. It is a situation that occurs
all too often in clinical practice. And yet, even now, the
problem remains unresolved. Variations in oral intake
of these potentially contaminated drug combinations
from different classes are quite possible and difficult
to control.
In the case of the simultaneous intake of two or
more potentially contaminated, though perhaps other-
wise unrelated, medications, the cumulative daily dose
of a sartan (i.e., to generate cancer) could be lower than
that described by Sipahi I [10] or lower than the recom-
mended ADI dose for nitrosamines from the EMA [4,
10], but the total daily dose of nitrosamine from several
contaminated medications could well be higher, signifi-
cantly exceeding the ADI dose.
The reason that this is such an important issue is
precisely due to the use of multiple medications by poly-
morbid patients that could contain nitrosamines: sartan,
thiazide diuretic, ACE inhibitor, ranitidine, metformin,
and probably many other contaminated, but currently
unidentified and undisclosed medications. This is the
reason that the calculation of the ADI turns out to be
somewhat irrelevant, especially when it concerns the
contamination of only one medication, and not all po-
tentially contaminated preparations taken by a given pa-
tient during the day.
Unfortunately, the association between the use of
sartans and hydrochlorothiazide and the development
of skin cancer – melanoma and keratinocyte cancer –
appears to be non-sporadic, statistically significant,
and established repeatedly based on serious retrospec-
tive studies in the USA and Europe [18-20], but at a
time when there was no data/information in the medi-
cal community about the potential contamination with
One of the most important international retrospec-
tive studies, presented formally as an American Acad-
emy of Dermatology (AAD) poster in Washington, DC,
in 2016, was designed to search for an association be-
tween the development of skin cancer and the use of
various antihypertensive drugs [18]. The results of this
study clearly showed a doubling of the risk of develop-
ing melanoma after administration of angiotensin recep-
tor blockers [18]. A similar constellation was observed
for thiazides (TZ) [18].
Sable at al. also found small risk (about 36%) of
developing BCCs after the use of angiotensin receptor
blockers/sartans [18].
For ACE inhibitors, the risk for developing BCC
was about 30% [18].
Even more indicative is the relationship between the
development of SCC and the intake of angiotensin re-
ceptor blockers (ARB), angiotensin-converting enzyme
inhibitors (ACEIs) and TZ [18].
A few years later Nardone B et al. had similar obser-
vations [19]: in practice, there is a two- to four-fold risk
of developing keratinocyte cancer after administration
of the most common antihypertensive drugs [19].
The risk of developing melanomas after the appli-
cation of the already mentioned medications is the fol-
lowing one: 1) ACEIs (adjusted OR; 1.71; 95% confi-
dence interval (CI): 0.97-3.00), 2) ARBs (adjusted OR;
1.24; 95% confidence interval (CI): 0.54-2.85) and 3)
TZ (adjusted OR; 1.82; 95% confidence interval (CI):
1.01-3.82) [19].
Schmidt SA et al. were the first to demonstrate the
relationship between the risk of skin cancer and the in-
take of various antihypertensive preparations [20].
The question remains open, but without the need for
an answer: “What is the connecting point between the
intake of high blood pressure medications with radically
different mechanisms of action, such as ACEIs, ARBs,
TZs, etc., and the development of all types of skin can-
cer: 1) the availability of up to 3 nitrosamines/carcino-
gens in them, reflected in the currently established of-
ficial position of regulatory bodies and pharmaceutical
companies, or 2) the active substances themselves?”
Even more troubling could be the answer to the
question arising from the results reported by Schmidt
SA et al. [20]: Are nitrosamines also contained in other
medications, such as potassium-sparing agents, non-
МЕДИЦИНСКИ ПРЕГЛЕД, 2023, 59 (5) 7
aldosterone antagonist potassium-sparing agents, low-
ceiling diuretics, and sulfonamides, for which statisti-
cally significant risks for cancer development have been
established as far back as 2015 [20]?
1. Hidajat M, McElvenny DM, Ritchie P, et al. Lifetime exposure to rub-
ber dusts, fumes and N-nitrosamines and cancer mortality in a cohort
of British rubber workers with 49 years follow-up. Occup Environ
Med. 2019 Apr;76(4):250-258. doi: 10.1136/oemed-2018-105181.
2. Straif K, Weiland SK, Bungers M, et al. Exposure to high concentra-
tions of nitrosamines and cancer mortality among a cohort of rubber
workers. Occup Environ Med. 2000 Mar;57(3):180-7. doi: 10.1136/
3. Nutt A. Rubber work and cancer--past, present and perspectives.
Scand J Work Environ Health. 1983;9 Suppl 2:49-57.
5. Nasr NEH, Metwaly MG, Ahmed EO, et al. Investigating the root
cause of N-nitrosodimethylamine formation in metformin pharma-
ceutical products. Expert Opin Drug Saf. 2022 Feb;21(2):285-287.
doi: 10.1080/14740338.2021.1983312.
8. Tchernev G, Temelkova I. Valsartan Induced Melanoma?! First De-
scription in Medical Literature! Open Access Maced J Med Sci. 2018
Dec 18;6(12):2378-2380. doi: 10.3889/oamjms.2018.517.
10. Sipahi I. Risk of cancer with angiotensin-receptor blockers increas-
es with increasing cumulative exposure: Meta-regression analysis
of randomized trials. PLoS One. 2022 Mar 2;17(3):e0263461. doi:
11. Tchernev G, Temelkova I. Irbesartan Induced Cutaneous Melanoma!
Second Case in the Medical Literature! Open Access Maced J Med
Sci. 2019 Jan 9;7(1):121-123. doi: 10.3889/oamjms.2019.043.
12. Tchernev G, Patterson JW. Telmisartan/hydrochlorothiazide-induced
nevus-associated cutaneous melanoma: first report in the medical lit-
erature. Expert Rev Clin Pharmacol. 2021 Mar;14(3):289-293. doi:
13. Tchernev G, Temelkova I. Valsartan/hydrochlorothiazidе induced
prostatе carcinoma in a patient who subsequently developed melano-
ma. J Biol Regul Homeost Agents. 2019 Jul-Aug;33(4):1125-1127.
14. Tchernev G, Temelkova I. Drug-Induced Melanoma: Irbesartan In-
duced Cutaneous Melanoma! First Description in the World Litera-
ture! Open Access Maced J Med Sci. 2019 Jan 9;7(1):114-116. doi:
15. Tchernev G, Poterov G. Drug induced cancers: Simultaneously de-
velopment of cutaneous melanoma, colon carcinoma and Kaposi
sarcoma under Valsartan/Hydrochlorothiazide. Clin Res Dermatol
Open Access 2020; 7 (5): 1-8.
16. Tchernev G, Oliveira N, Kandathil LJ, et al. Telmisartan (and/or Ni-
trosamine) induced prostate carcinoma and atypical fibroxanthoma:
first report in World literature. Medical Review (Bulgarian) 2022;
18. Sable L, Majewski S, Nardone B, et al. Association of melanoma
and nonmelanoma skin cancer with antihypertensive drugs: A report
form the Research on Adverse Drug Events and Reports Project. J
Am Acad Dermatol 2016; 74(5): AB221.
19. Nardone B, Majewski S, Kim AS, et al. Melanoma and Non-Mela-
noma Skin Cancer Associated with Angiotensin-Converting-Enzyme
Inhibitors, Angiotensin-Receptor Blockers and Thiazides: A Matched
Cohort Study. Drug Saf. 2017 Mar;40(3):249-255. doi: 10.1007/
20. Schmidt SA, Schmidt M, Mehnert F, et al. Use of antihypertensive
drugs and risk of skin cancer. J Eur Acad Dermatol Venereol. 2015
Aug;29(8):1545-54. doi: 10.1111/jdv.12921.
... Nitrosamines in the antihypertensive therapy such as sartans and hydrochlorothiazide (but not limited to them) are perceived as a risk factor for the development of keratinocyte tumors [1]. A number of publications have identified potential contamination with nitrosamines as possibly key to the development of both keratinocytic and melanocytic skin tumors [2]. ...
... Clinicians face two main problems when reporting the side effects of potentially nitrosamine-contaminated drugs: 1) the lack of the possibility of a proper review by the regulatory authorities, followed by an official result announcement of whether or not the relevant batches contain a nitrosamine, as well as 2) the inability of calculating the exact total concentration of daily intake of nitrosamines within the multimedication of polymorbid patients [1,2]. ...
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Chronic alcohol use, smoking, poor dental hygiene, absorbed sun radiation over the years, fair skin (Fitzpatrick type 1), light eyes, painful sunburns, congenital or acquired immunosuppression, certain rare syndromes, as well as infections with human papillomaviruses are perceived as risk factors for the development of squamous cell carcinoma of the lips. The new and at the same time modern aspects involving the pathogenesis of keratinocyte tumors in practice prove to be quite problematic for both patients and clinicians. These aspects are involved in the contamination or increased availability of certain nitrosamines in the antihypertensive medications. A serious international study in the last year has linked the intake of potentially contaminated (established availability without data on whether it exceeds the so-called ADI/acceptable daily intake dose) with nitrosamines valsartan with a relatively low, but still present risk of melanoma development. On the other hand, data from 2017 associate individual monotherapy of arterial hypertension with sartans with a significantly increased/statistically significant risk of squamous cell carcinomas development: more than a two-fold increased risk. It should be noted that at that time the problems with nitrosamines were completely unknown to the medical community. At the moment, there are numerous case studies that connect the use of sartans with the development of keratinocyte tumors - either single or multiple. We describe the first case of a patient who took eprosartan at a dose of 600 mg once a day for a total period of about 15 years with intake interruptions of no more than 6 years. Primary complaints in the lower lip area are from about 6 months. The preoperative biopsy showed evidence of squamous cell carcinoma. A multidisciplinary team performed a successful surgical treatment using the Karapandzic method, achieving an optimal aesthetic result. Based on the available literature data, the possible role of nitrosamines as a potential trigger for the development of squamous cell carcinoma is discussed.
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Angiotensin-receptor blockers (ARBs) are a class of drugs approved for the treatment of several common conditions, such as hypertension and heart failure. Recently, regulatory agencies have started to identify possibly carcinogenic nitrosamines and azido compounds in a multitude of formulations of several ARBs, resulting in progressive recalls. Furthermore, data from several randomized controlled trials suggested that there is also a clinically increased risk of cancer and specifically lung cancer with ARBs; whereas other trials suggested no increased risk. The purpose of this analysis was to provide additional insight into the ARB-cancer link by examining whether there is a relationship between degree of cumulative exposure to ARBs and risk of cancer in randomized trials. Trial-level data from ARB Trialists Collaboration including 15 randomized controlled trials was extracted and entered into meta-regression analyses. The two co-primary outcomes were the relationship between cumulative exposure to ARBs and risk of all cancers combined and the relationship between cumulative exposure and risk of lung cancer. A total of 74,021 patients were randomized to an ARB resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent). 61,197 patients were randomized to control. There was a highly significant correlation between the degree of cumulative exposure to ARBs and risk of all cancers combined (slope = 0.07 [95% CI 0.03 to 0.11], p
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Introduction: The treatment of hypertension with certain groups of drugs may be problematic, particularly because certain drugs are capable of potentiating carcinogenesis. The presence of various receptors or components of the renin - angiotensin system in the skin, and particularly in melanocytes, determines the possible influence on this tissue by the so-called angiotensin receptor blockers or sartans. Thiazide diuretics can further influence the processes of carcinogenesis in all forms of skin cancer - melanocytic and non-melanocytic. Areas covered: We present a 67-year-old patient treated for a period of 3 years with a combined preparation containing Telmisartan/hydrochlorothiazide 80 mg/12.5 mg. Within 2 years, the patient observed the rapid development of a nevus that progressed to melanoma and was subsequently identified histopathologically as nevus-associated cutaneous melanoma with a 0.6 mm thickness, Clark IV. Following surgical treatment, no tumor progression has occurred to date. To our knowledge, this is the first reported case of a patient who developed a nevus-associated cutaneous melanoma after combination therapy with generic sartan and hydrochlorothiazide. Expert opinion: We discuss the diverse but mutually potentiating pro-carcinogenic effects of this class of agents, potentially leading to the development of cutaneous melanoma. Keywords: Hydrochlorothiazide; Telmisartan; drug mediated carcinogenesis; melanoma progression; melanoma surgery.
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The side effects of antihypertensive drugs are often the subject of discussions, publications and presentations, but not in cases where they include in their “palette” or “repertoire” concepts such as generating / promoting or potentiating various types of cancer, as well as metastasis of already existing one. Unfortunately, progress within the real, clinical medicine often does not start with the desired results (from those expected within clinical observations or experimental data after administration of a particular substance or drug). Breakthroughs in medicine and progress start with the careful registration and analysis of unwanted and unexpected, unplanned results. Again, unfortunately, the analysis of it is often swept under the table, without thinking that the negative results should be the generator of progress. When the observations of certain clinical or experimental data remain insufficiently analyzed, neglected or deliberately hidden - the result is often alarming or fatal - similar to the scandals (from 2018) with Sartans and the generation of hundreds of cutaneous melanomas, as well as heterogeneous species and other cancerous forms. However, if we all focus together on the problems through the prism of the possibilities to solve them, there is a real chance to achieve a drastic decrease in the incidence of a number of tumor diseases, due to the possibility of rethinking their pathogenesis. The article is a kind of analysis and directing clinicians in the right direction in relation to an urgent need to clarify issues related to the procarcinogenic effect of drugs from the so-called group of Sartans and Thiazide diuretics. In the first mentioned drugs, the carcinogenic effect could be due to: 1) the action of the main substance of the Sartans themselves (proven in experimental conditions, but also in in vivo data) and 2) the additive, undesirable ingredients or the so-called nitrosamines arising as additional contamination within the production process. The combination of Sartans and Thiazide diuretics (plus Nitrosamines, the presence of which is not adequately tested) could in all likelihood have a fatal, mutually potentiating procarcinogenic effect, leading to the manifestation of 3 or even more cancers simultaneously. This publication presents for the first time in the world literature a patient who developed three cancers at the same time (Kaposi’s sarcoma, skin melanoma and colon cancer) after starting therapy with Valsartan and hydrochlorothiazide.Our critical analysis is focused on the regulatory authorities in the face of the FDA, EMA, but also on the National Agency for Drug Control. Attention is also paid to the non-traditional and illegal from the point of view of all ethical norms ways of influencing the pharmaceutical industry, in order to protect its positions in the framework of the daily emerging world scandals.
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Objectives: To quantitatively evaluate exposure-response associations between occupational exposures to rubber dust, fumes and N-nitrosamines and cancer mortality in the UK rubber industry. Methods: Competing risk survival analyses were used to examine cancer mortality risk in a cohort of 36 441 males aged 35+ years employed in the British rubber industry in 1967, followed up to 2015 (94% mortality). Exposure measurements are based on a population-specific quantitative job-exposure matrix for rubber dust, rubber fumes and N-nitrosamines from the EU-EXASRUB project. Results: Exposure (lifetime cumulative (LCE))-response associations were found for N-nitrosomorphiline and all cancers (subdistribution HR (SHR) 1.48, 95% CI 1.39 to 1.57) and cancers of the bladder, stomach, multiple myeloma, oesophagus, prostate and pancreas, as well as for N-nitrosodimethylamine and all cancers (SHR 2.08, 95% CI 1.96 to 2.21) and cancers of the bladder, stomach, leukaemia, multiple myeloma, prostate and liver. LCE to the N-nitrosamines sum were associated with increased risks from all cancers (SHR 1.89, 95% CI 1.78 to 2.01) and cancers of the lung, non-Hodgkin's lymphoma and brain. LCE to rubber dust and fumes are associated with increased mortality from all cancers (rubber dust SHR 1.67, 95% CI 1.58 to 1.78; rubber fumes SHR 1.91, 95% CI 1.80 to 2.03) and cancers of the bladder, lung, stomach, leukaemia, multiple myeloma, non-Hodgkin's lymphoma, oesophagus, prostate, pancreas and liver. Conclusions: Consistent with previous studies, N-nitrosamines exposures are associated with mortality from cancers of the bladder, lung, stomach, leukaemia, multiple myeloma, oesophagus, prostate, pancreas and liver. The long follow-up with nearly complete mortality enabled estimations of lifetime cancer mortality risk from occupational exposures in the rubber industry.
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BACKGROUND Drug-induced melanoma is a topic, concept or “reality” becoming more and more popular as the list of drugs considered as potential inducers of cutaneous melanoma is constantly growing. Interesting and current at the moment is the question/dilemma of “Irbesartan induced melanomas” and “Valsartan induced melanomas”! The following questions are without answers: 1) the general risk which angiotensin receptor blockers contain for potentiating the carcinogenesis and cancer development (as a whole); 2) available officialized data for withdrawal from the market of products with valsartan and irbesartan due to detected potential carcinogens-NDMA/NDEA, and 3) the missing official information on the most likely forms of cancer potentiated by these drugs. That is precisely why many questions remain open, and the inevitable assumption arises for the key, although according to some conspiratorial role of so-called “pharmaceutical giants” in the concept of drug-induced malignancies. CASE REPORT We present a 72-year-old man with arterial hypertension in connection with which he is taking Irbesartan 300 mg (1-0-0), Amlodipine 5 mg (0-0-1) and Moxonidine 0.2 mg (0-0-1). The patient reported the presence of pigment lesion in the head area, which dates from many years and 3 years ago it was at the size of the nail plate on the index finger. Irbesartan therapy dates from 1.5-2 years, and according to the patient 1.5-2 years after the start of irbesartan therapy, the lesion grew sixfold, accompanied by sensitivity and discomfort in the area. Clinically and dermatoscopically the lesion had data on superficial spreading cutaneous melanoma. Tumour thickness ≤ 1 mm was measured preoperatively by ultrasound. The so-called one-step melanoma surgery (OSMS) was performed, and the lesion was removed by elliptical excision with an operative surgical margin of 1 cm in all directions within one operative session. The subsequent histological study (and screening staging) found that it was a superficial spreading melanoma stage IA (T1bN0M0). CONCLUSION Possible, but unlikely, in our opinion, is that the intake of angiotensin receptor blockers (in particular irbesartan), and the progression of benign precursor lesions to malignant do not have a direct relationship. The growing number of data in the literature for drug-induced melanoma and massive withdrawal of products with valsartan and irbesartan due to the content of probable carcinogens speaks, however in favour of the opposite, namely that it is more likely to speak about established dependence than of a sporadic association. Drug-induced melanoma-rather a reality than a myth.
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BACKGROUND Melanoma appears to be a malignant disease, whose development can be potentiated by different drug groups. More and more data are in favour of the claim that commonly used antihypertensive drugs also contain the risk of developing melanoma. The most evidence is that angiotensin receptor blockers may be carcinogenic. Two representatives from this group, valsartan and irbesartan, produced by certain pharmaceutical companies are being withdrawn from the market due to finding content of NDMA and NDEA, which are believed to be potent carcinogens. Another representative of this group, losartan, according to in vitro data, potentiates cell adhesion and invasion of human melanoma cells. CASE REPORT We present a 45-year-old man with arterial hypertension. For year and a half/two years, the patient is on systemic therapy with Aspirin and Irbesartan/Hydrochlorothiazide. The patient also reported about the presence of a pigmented lesion in the abdominal area, which occurred 5-6 years ago, before the onset of cardiac therapy. According to him, there was a change in the colour and size of the lesion within the framework of cardiac therapy (from 1.5-2 years). Innovative one step melanoma surgery was performed, and the lesion was radically removed with a 1 cm operational safety margin in all directions within one operative session. The subsequent histological verification found the presence of thin melanoma. CONCLUSION Drug-induced melanoma turned out to be a problem of significant importance. The group of angiotensin receptor blockers should be investigated more thoroughly and in detail on the probability of potentiating carcinogenesis. We describe an interesting case showing the progression of pigment lesion to melanoma as a possible result of irbesartan therapy, i.e. we share a theory that differs from that of drug-induced de novo melanomas. It should not be overlooked the fact that another widely used drug-Aspirin, is also likely to potentiate the development of melanoma. Furthermore, the case is indicative of the use of one step melanoma surgery in a melanoma patient with a thickness less than 1 mm.
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BACKGROUND Drug-induced carcinogenesis is a matter of huge popularity and the subject of in-depth research over the last few years. According to the literature, dopamine agonists and acetylsalicylic acid fall into the list of drugs likely to potentiate the development of cutaneous melanoma. However, according to recent data, widely used angiotensin receptor blockers (ARBs) for the treatment of arterial hypertension, also carry a risk of malignancy development. The content of probable carcinogens, such as NDMA or NDEA in the drug valsartan (ARBs), causes the product to be withdrawn from the market. Recent experimental data suggest that another angiotensin receptor blocker-losartan also stimulates cell adhesion and melanoma cell invasion. CASE REPORT We present a 70-year-old patient who has been on systemic therapy with a combined drug of amlodipine and valsartan since 2008 and only valsartan from 2015. Three years after the first intake of valsartan (2011), the patient developed a pigment lesion on the right arm. Approximately 2.5 years after doubling the dose of valsartan, the patient observed a progression in the size of the lesion, which was the cause of the dermatological examination and hospitalisation for surgical removal. The melanocytic lesion was removed by radical excision and a surgical field of 0.5 cm in all directions, followed by histological verification, which found the presence of cutaneous melanoma with a tumour thickness of 3 mm. A re-excision was planned with an additional surgical field of 1.5 cm in all directions combined with parallel removal of a draining lymph node. CONCLUSION The case is indicative of two things: 1) the possible triggering of melanoma within the systemic treatment with valsartan; and 2) the necessity for optimization of melanoma surgery within the one-step melanoma surgery, which in this case would result in a single surgical excision of the primary lesion, with an operational security field of 2 cm in all directions, along with the removal of a draining lymph node.
IntroductionControversy exists about an association between angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), and thiazides (TZs) and the risk of malignant melanoma (MM), and non-melanoma skin cancer—basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Objective The aim of this study was to determine if an association exists for ACEI, ARB, or TZ exposure and skin cancers. Methods This was a matched cohort study using a large electronic medical records repository, the Northwestern Medicine Enterprise Data Warehouse (NMEDW). The exposed population consisted of patients with a documented order for an ACEI, ARB, or TZ with no prior history of skin cancer. The control population consisted of matched patients without documented exposure to ACEI, ARB, or TZ and no previous skin cancer. Incident MM, BCC, or SCC diagnosis by ICD-9 codes was recorded. Odds ratios (ORs) were obtained by using logistic regression analyses. ResultsAmong the 27,134 patients exposed to an ACEI, 87 MM, 533 BCC, and 182 SCC were detected. Among the 13,818 patients exposed to an ARB, 96 MM, 283 BCC, and 106 SCC were detected. Among the 15,166 patients exposed to a TZ, 99 MM, 262 BCC, and 130 SCC were detected. Significant associations using ORs from logistic regression were found for MM and TZs (OR 1.82; 95% confidence interval [CI] 1.01–3.82); BCC and ARBs (OR 2.86; 95% CI 2.13–3.83), ACEIs (OR 2.23; 95% CI 1.78–2.81) and TZs (OR 2.11; 95% CI 1.60–2.79); SCC and ARBs (OR 2.22; 95% CI 1.37–3.61), ACEIs (OR 1.94; 95% CI 1.37–2.76), and TZs (OR 4.11; 95% CI 2.66–6.35). ConclusionsA safety signal for ACEIs, ARBs, and TZs and BCC and SCC, as well as for TZs and MM, was detected. An increased awareness and education, especially for those who are at high risk for skin cancer, are warranted for patients and healthcare providers. Further exploration of such associations for these commonly used drug classes is warranted.