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46 МЕДИЦИНСКИ ПРЕГЛЕД, 2025, 61 (4)
S. Kordeva111
1Onkoderma – Clinic for Dermatology, Venereology and Dermatologic Surgery
2Department of Dermatology and Venereology, Medical Institute of Ministry of Interior – Sofia
111
1Онкодерма – Клиника по дерматология, венерология и дерматологична хирургия – София
2Катедра по дерматология и венерология, Медицински институт на МВР – София
Although phototoxicity as a chemical phenomenon is well-researched and under-
stood, its occurrence in certain drug batches remains somewhat elusive. The un-
certainty surrounding why certain drug batches are affected while others are not
extends to the associated risk of photocarcinogenicity, underscoring the need for
focused and comprehensive research. Unfortunately, these occurrences are often
overlooked, with greater emphasis placed on addressing the substantial financial
burden of managing the side effects – phototoxicity and its potential progression to
photocarcinogenicity. The wide range of contamination with nitrosamines creates
prerequisites for easy follow-up in the context of so-called clinicopathological cor-
relations. Assuming that the linking link is the phototoxicity and genotoxicity of these
substances, it could be easily established after the intake of which substances skin
tumors develop. We present two consecutive patients with melanomas who devel-
oped them against the background of taking a potentially/actually nitrosamine-con-
taminated medication: 1) in patient 1, the medications were valsartan, nebivolol, and
hydrochlorothiazide, each of which is available on the FDA list for possible photo/
carcinogen contamination, and 2) in patient 2, the patient developed melanoma on
a background of taking bisoprolol, metformin, and lercanidipine. The possible new
thesis of melanoma pathogenesis, known as photo/nitroso carcinogenesis or onco-
pharmacogenesis, is commented in detail. We live in an era of “cancer pandemic”,
reducing cancer rates must be a shared priority – not only for clinical physicians but
also for the pharmaceutical companies. The first step toward a solution is acknowl-
edging the problem. The current issue is evident and necessitates acknowledgment
through careful observation and analysis of the clinicopathological correlations.
melanoma, nitrosamine contamination, nitrosogenesis, pharmaco-oncogenesis,
phototoxicity, photocarcinogenicity, nebivolol, valsartan/hydrochlorothiazide, ler-
canidipine, bisoprolol, metformin
Address for correspondence: Prof. Georgi Tchernev, MD, e-mail: georgi_tchernev@yahoo.de
Въпреки че фототоксичността като химично явление е добре проучена и раз-
брана, нейната поява в определени партиди лекарства остава донякъде неу-
ловима. Несигурността относно причините, поради които някои партиди лекар-
ства са засегнати, а други не са, се разпростира и върху свързания с тях риск
от фотокарциногенност, като подчертава необходимостта от целенасочени и
всеобхватни изследвания. За съжаление, тези случаи често се пренебрегват,
МЕДИЦИНСКИ ПРЕГЛЕД, 2025, 61 (4) 47
като по-голям акцент се поставя върху преодоляването на значителната фи-
нансова тежест, свързана с управлението на страничните ефекти – фототок-
сичност и потенциалното ѝ преминаване във фотокарциногенност. Широкият
диапазон на контаминация с нитрозамини създава предпоставки за лесно
проследяване в контекста на така наречените клиникопатологични корелации.
Изхождайки от факта, че свързващото звено е фототоксичността и геноток-
сичността на тези субстанции, лесно би могло да се установи след приема на
кои субстанции се развиват тумори на кожата. Представят се поредни двама
пациенти с меланоми, развили ги на фона на приема на потенциално/реално
контаминирана с нитрозамини медикация: 1) при пациент 1 медикаментите са
валсартан, небиволол и хидрохлоротиазид, всеки от които присъства в листата
на FDA за възможна контаминация с фото-/карциногени, и 2) пациент 2 разви-
ва меланом на фона на прием на бисопролол, метформин и лерканидипин.
Коментира се в детайли възможната нова теза за патогенезата на меланомите,
позната като фото-/нитрозокарциногенеза или онкофармакогенеза.
меланом, замърсяване с нитрозамини, нитрозогенеза, фармакоонкогенеза,
фототоксичност, фотокарциногенност, небиволол, валсартан/хидрохлороти-
азид, лерканидипин, бисопролол, метформин
Aдрес за кореспонденция: Проф. д-р Георги Чернев, e-mail: georgi_tchernev@yahoo.de
The phototoxicity associated with various class-
es of drugs remains poorly understood, with signifi-
cant uncertainty in the medical literature regarding
why certain drug batches induce phototoxicity while
others do not. This uncertainty extends to the subse-
quent risk of photocarcinogenicity, emphasizing the
need for further investigation and focused research
in this area. Unfortunately, the medical community
often overlooks these connections, instead focus-
ing on the substantial financial resources required to
manage the consequences of phototoxicity and its
progression to photocarcinogenicity.
The phototoxicity of nitrosamines has been recog-
nized for decades as one of their nonspecific effects
[1]. In the literature, the term phototoxicity is associat-
ed not only with environmental toxicity [2] but also with
biological toxicity [1], an aspect that deserves particu-
lar attention in the modern medical field. The presence
of nitrosamines in drugs is considered problematic
by regulatory agencies due to their potential carcino-
genicity [3, 4]. The primary concern lies in the fact that
the carcinogenic potency of these substances is not
evaluated based on their phototoxicity. In practice, this
phototoxicity could contribute to the carcinogenic and/
or mutagenic effect and potentially cause skin cancer,
as suggested by several publications in the literature
based on similar conclusions [5-8].
The heterogeneous aspect of poly- and/or
monotherapy with potentially/actually contaminated
drugs with nitrosamines has been associated with
the development of melanomas. A plausible expla-
nation for this phenomenon is the presence of ni-
trosamines, which are known photocarcinogens
with carcinogenic and genotoxic properties. Here,
we present two new, unrelated cases of melanomas
that emerged following polymedication (nebivolol,
valsartan/hydrochlorothiazide; lercanidipine hydro-
chloride, bisoprolol, metformin) potentially or actu-
ally contaminated with nitrosamines.
A 67-year-old male came to the dermatology de-
partment with primary complaints of a tumor formation
located on the right chest region. The patient has a his-
tory of non-insulin dependent diabetes mellitus, with-
out complications, and arterial hypertension. He has
been on systemic therapy for 20 years with nebivolol 5
mg once daily in the morning and valsartan/hydrochlo-
rothiazide 160 mg/12.5 mg once in the morning.
The dermatological examination showed a poly-
poid-like pigmented lesion with irregular borders and
black color located on the right anterior chest area
(Fig. 1a). Enlarged lymph nodes were not palpable.
Routine blood tests revealed mild abnormalities: low
hemoglobin (HGB) 114 g/L (normal range for men
130-180 g/L), low mean corpuscular volume (MCV)
69.5 fl (normal range 82-98 fl), high red cell distribu-
tion width (RDW) 15.5% (normal range 11.5-14.5%),
low platelet distribution width (PDW) 11.1% (nor-
mal range 15.5-30.5%), elevated glucose levels 7.1
48 S. Kordeva, C. S. Henry, J. M. Joseph, G. Tchernev.
Nitrosamine-related phototoxicity/photocarcinogenicity...
mmol/l (normal range 3.3-6.0), and high urea levels
8.62 mmol/l (normal range 1.7-8.3 mmol/l).
CT scans of the head, thorax, abdomen and less-
er pelvis showed no evidence of dissemination in the
examined areas. Findings included bilateral neph-
rolithiasis, kidney cysts, cholelithiasis, hiatal hernia,
and diverticulosis of the colon.
The lesion was suspected to be melanoma, and
surgical excision in two stages according to the AJCC/
EJC guidelines was recommended. The tumor forma-
tion was removed with an elliptical excision under lo-
cal anesthesia using lidocaine. The wound defect was
closed with single interrupted sutures (Fig. 1b). The
histological examination revealed a nodular melano-
ma, staged pT4B Nx Mx R0, Clark level 3, with a Bres-
low thickness of over 4 mm and ulceration. The lesion
exhibited high mitotic activity, scant lymphoid stromal
infiltrate, and no evidence of spontaneous regression.
The resection lines were clear. The second surgical
excision was planned, without the removal of a sen-
tinel lymph node, according to the patient’s wishes. In
the second surgical excision, a 2 cm surgical margin
was achieved (Fig. 2a), and the wound was closed
with single interrupted sutures (Fig. 2b).
A 73-year-old male came to the dermatology de-
partment with primary complaints of a tumor forma-
tion located on the left arm region. The patient is on
systemic therapy for diabetes and arterial hyperten-
sion, with lercanidipine hydrochloride 10 mg once
in the evening for 3.5-4 years, bisoprolol fumarate 5
mg twice daily – once in the morning and once in the
evening – for 10 years, and metformin hydrochloride
850 mg twice daily, once in the morning and once in
the evening, for 10 years.
The dermatological examination revealed a poly-
poid-like tumor formation with irregular borders and
black, brown, and red pigmentation located on the left
upper extremity (Fig. 3a). An ultrasound examination
of both axillae was performed, and no lymph nodes
were visualized. Routine blood tests were conducted
resulting without abnormalities. The lesion was sus-
pected for melanoma and the patient was advised
surgery. The lesion was preoperatively marked (Fig.
3b) and subsequently removed with an elliptical exci-
sion under local anesthesia with lidocaine. The wound
defect was closed with single interrupted sutures.
Phototoxicity is a term used in many studies to de-
scribe both environmental and biological toxicity [1, 2].
Photoactivated/phototoxic polycyclic aromatic
hydrocarbons (PAHs) such as anthracene, fluoran-
thene, pyrene, as well as some petrolatum products
containing PAHs, exhibit pronounced phototoxic ef-
fects when exposed to UV radiation in marine envi-
ronments [2]. Phototoxicity of individual PAHs has
been found to be 12 to over 50,000 times greater than
their conventional toxicity, posing a risk for different
marine species [2].
Similarly, the phototoxicity of nitrosamines is pri-
marily attributed to the photodecomposition of the
nitroso group [1]. Nitrosamines demonstrate the abil-
МЕДИЦИНСКИ ПРЕГЛЕД, 2025, 61 (4) 49
ity to induce or inhibit liver microsomal enzymes, re-
sulting in changes to pentobarbital sleeping (PST) in
mice [1]. This phenomenon was considered a more
promising approach for the bioassay of nitrosamines
compared to conventional methods [1]. Carcinogenic
nitrosamines were found to prolong PST, whereas
noncarcinogenic nitrosamines shortened PST [1].
Additionally, some induced an increase in smooth en-
doplasmic reticulum within liver hepatocytes in mice
[1]. These observations, made as early as 1972, sug-
gested that scientists could differentiate carcinogenic
from noncarcinogenic nitrosamines within a short
4-day period, compared to the extended duration re-
quired for conventional bioassay [1].
A more comprehensive analysis of the chemi-
cal mechanisms underlying these photoprocesses
– photooxidation and photodecomposition – is pre-
sented in a paper by Chow et al. [9]. In summary,
under nitrogen conditions, the irradiation of C-nitroso
compounds results in their dissociation into C-nitroso
monomers, which can subsequently undergo photo-
disproportionation, tautomerization, and dimerization
[9]. However, when these reactions occur under spe-
cific conditions, such as in the presence of oxygen,
the primary outcome is the formation of nitrates and
nitro compounds [9]. The study concludes that photo-
dissociation and oxidation contribute to the formation
of both nitrates and nitroso compounds [9].
These findings, combined with the above-men-
tioned articles on nitrosamine and PAHs phototox-
icity, highlight the significant role of photoactiva-
tion in amplifying the toxicological effects of both
nitrosamines and PAHs. Early detection of these
compounds is necessary to reduce or eliminate
their adverse health impacts.
To date, photocarcinogenesis remains one of the
primary and most extensively studied mechanisms
contributing to skin cancer development [10]. In re-
cent years, emerging concepts in skin carcinogenesis
have provided the medical community valuable in-
sights into the pathogenesis of skin cancer. Drug-re-
lated nitrosogenesis and the subsequent pharmaco-
oncogenesis of skin cancer are terms that reflect the
“new reality” of the modern world [5-8]. Unfortunately,
melanoma has been strongly linked to the adverse ef-
fects associated with the intake of potentially/actually
nitrosamine-contaminated polymedication [5-8].
Although still somewhat controversial, inter-
national colleagues have begun associating an-
giotensin II receptor blockers (ARBs, sartans)/
angiotensin converting enzyme inhibitors (ACEi)
therapy with an increased risk of cancer [11]. No-
tably, losartan and lisinopril have been shown to
stimulate MV3 melanoma cell migration and inva-
sion by increasing the expression and secretion of
matrix metalloproteinase-2 (MMP2) [11].
Valsartan, a drug included in our first patient’s
treatment plan, was officially recalled by the FDA due
to nitrosamine impurities [3], turning what was once
considered a “myth” into a substantiated reality [12].
Despite the growing evidence, the list of drugs poten-
tially/actually contaminated with nitrosamine impurities
is still categorized as “hypothetical” in the FDA’s official
release, which includes over 300 medications [4]. This
list outlines recommended acceptable intake (AI) limits
for certain hypothetical nitrosamine drug-substance-
related impurities (NDSRIs) and other identified nitros-
amine impurities based on the predicted carcinogenic
potency [4]. According to this list, N-nitroso-hydrochlo-
rothiazide, an impurity found in the drug hydrochloro-
thiazide, is classified under potency category 4 (on a
scale where 1 is the lowest and 5 is the highest), with a
recommended AI limit of 1500 ng/day [4].
The pharmaceutical company Pfizer also initiated
a recall for INDERAL LA (propranolol hydrochloride)
due to the presence of N-nitroso-propranolol impurity
[13]. This raises concerns about the potential for im-
purity contamination in other beta blockers. Accord-
ing to the FDA’s official release, N-nitroso-nebivolol,
an impurity found in the beta blocker nebivolol, has
been classified in potency category 4 with a recom-
mended AI limit of 1500 ng/day [4].
Nebivolol, valsartan and hydrochlorothiazide
were all part of the patient’s combined therapy regi-
men. This raises several important questions regard-
ing their potential cumulative effects. Specifically: 1)
There is no official data on the potency category of
valsartan on the FDA’s site despite its recalls, 2) val-
sartan was used in combination with hydrochlorothi-
azide (160 mg/12.5 mg per day), and 3) both nebivo-
lol and hydrochlorothiazide are listed under potency
category 4. The question arises whether the potency
category remains unchanged when these drugs are
combined in a therapeutic regimen or if there is a cu-
mulative effect. Given the 20 years of consistent use
of these medications, it seems reasonable to consid-
er the possibility of a cumulative effect. The constant,
daily intake of impurities could potentially lead to can-
cer formation over time, as we have observed in both
patients. This appears to be the most logical clinico-
pathological correlation in these cases, and not only.
Since these are not the first cases in the literature
of melanoma following the use of potentially or ac-
tually contaminated nebivolol, valsartan, and hydro-
chlorothiazide, existing scientific works have already
raised similar “hypothesis” [7, 14]. With this “another
50 S. Kordeva, C. S. Henry, J. M. Joseph, G. Tchernev.
Nitrosamine-related phototoxicity/photocarcinogenicity...
case”, we aim to emphasize the importance of con-
sistently reminding the medical community that this
“side effect” is not only possible but occurring. This
highlights the need for further insights into the poten-
tial and actual implications of long-term exposure to
such impurities in the context of polymedication.
Although N-nitroso lercanidipine exists [15], it is
not currently included in the FDA’s official database.
As a result, there is no available information regard-
ing its safety or potential potency category. N-nitroso-
bisoprolol, an impurity identified in the drug bisoprolol,
is classified under potency category 4, with recom-
mended AI limit of 1500 ng/day [4]. In 2020, the FDA
officially announced the contamination of metformin
with NDMA [16]. In the context of melanoma induc-
tion, metformin has been described in combination
with amiodarone, hydrochlorothiazide and telmisar-
tan [17]; as well as with antihypertensive therapy and
ranitidine [18]. Although metformin was not identified
at the time of the article’s publication as a potential or
actual inducer of skin carcinogenesis, the paper now
offers valuable insights, particularly given the clear
clinicopathological correlation between the period of
drug intake and the onset of the lesion [17].
Given that 1) lercanidipine is not currently listed
on the FDA’s list for potential contamination, nor is
there available data regarding its possible carcino-
genic effect, and the patient’s 3.5-4 years of intake
may not have been “sufficient” for skin carcinogen-
esis; 2) bisoprolol is classified under potency cat-
egory 4 and has been administered twice daily for
10 years; 3) metformin, a drug known to have impu-
rities, has been administered at 850 mg twice daily
for 10 years; and 4) the patient’s lesions began to
appear several years after the initiation of systemic
drug therapy, we cannot definitively state whether
each of these medications is solely responsible for
the carcinogenic phenomenon. However, we can
certainly assert that there is a visible link, and this
connection is evident to us all.
In an era marked by a “cancer pandemic”, it is
essential to work towards reducing cancer rates. The
patient’s health must always be a priority.
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Постъпила за печат на 26 март 2025 г.
