Summary
Frostbites can be associated with a number of acute or long-term complications. One of these chronic adversities is neoplastic disorders, arising from frostbite lesions. Because of the sparseness of the available studies in medical literature, in this narrative review, the association between frostbite and cancer was explored with more focus on real-life clinical cases. The results from database searching revealed that only a few studies have evaluated this vicious companionship. According to the studies, frostbite can be a causative factor in the initiation and development of cancerous pathologies. On the other hand, some specific neoplastic disorders have been presented as risk factors for such cold injuries. It can be concluded that thorough evaluation of frostbite cases toward the full healing and considering cancers as a risk factor for cold injuries through the diagnostic procedures can be life and cost-saving for health-care systems.Introduction
Frostbite or freezing cold injury is defined by coldinduced tissue damage through time or vulnerabilitydependent exposure to subzero temperatures (Celsius). Historically, it was a common ailment of soldiers, but the modernization of populations has changed its epidemiology with current dominance among homeless people or those at extremities of age.[1] Obviously, its prevalence can be more worrisome among the nations living in colder climates. For instance, in a study from Finland, the incidence of severe frostbite was reported to be around 10.6% for residents throughout their life. [2] Regardless of the etiology and prevalence, this climate- related pathology can induce several long-term sequelae for the affected patients. Vasomotor, neuropathic and nociceptive complications, and skeletal disfigurations are repetitively reported.[3] Tissue growth abnormalities have been exclusively observed in the affected cases.[4] Regarding the sparse reports in medical literature, cancer is one of the late consequences of this prolonged tissue injury,[5,6] but the lack of straightforward evaluations about this malignant association is alarming among clinical studies.On the other hand, literature shows that frostbite might have some pathologic predisposing factors. Interestingly, a number of these risk factors have neoplastic roots. Again, this matter has not been sufficiently investigated in clinical fields.
The aim of this study is to explore the association of frostbite and cancer, both from causative and associative point of view to build a foundation for more goaldirected clinical trials and observations.
Methods
Our aim in this study was to evaluate the association between frostbite and cancer, regardless of the type of the correlation. In order to find the most relevant data about our topic, an accredited scientific database, PubMed, was explored using this search strategy: ("Frostbite"[Majr]) AND "Neoplasms"[Mesh].Results
PubMed searching with MeSH terms "Frostbite" and "Neoplasms" resulted in only 37 journal articles. Furthermore, some more studies were added from Google Scholar to support the notions of this review in the following sections. Screening the articles showed that cancer and frostbite have a two-way relationship. Only 13 of the articles were about frostbite as a causative factor. The rest presented factors such as hematologic malignancies, metastatic solid tumors, rheumatologic disorders, and iatrogenic cancer therapies to act as precipitating factors for frostbite. In the following part, both issues are discussed in detail, separately.Discussion
For a better understanding of the bilateral association between these two terminologies, the acquired information from the literature is categorized under these subheadings.
PATHOPHYSIOLOGY
Acutely, frostbite develops through vasoconstriction
caused by intense cold. The consequent blood flow decline
prohibits adequate tissue circulation and heating,
which ends in the formation of ice crystals. These crystals
directly cause lipid and protein disruption, shifting the
electrolyte balance, and intracellular dehydration. In addition,
blood flow disturbances and coagulopathy within
the microvasculature cause ischemia.[7] This continues
through an ischemia?reperfusion-inflammation injury
and concludes in tissue necrosis. Free-radical formation
elongates the injury, especially after rewarming for the
survivors. After several days, the remodeling mechanisms
initiate tissue scar formation in bones, skeletal muscles,
and skin. The wound-healing process is accompanied by
circulating factors which are mutual in both scaring and
neoplastic changes.[8] In this way, cancerous pathologies
can be predicted as late adversities of frostbite.
For understanding frostbite as a consequence of underlying diseases, there is no specific mechanistic explanation. However, considering the blood-related etiology of these cases, chronic lack of adequate perfusion to certain skin areas can be suggested.
CLINICAL PRESENTATIONS
There are cases of bone involvement from the cancerous
invasion of malignant frostbite scar tissue in feet
with more aggressive ulcerations.[16,17]
Besides the causative relationship from frostbite
to malignancies, some cancerous genetic traits are accompanied
by predisposition to frostbites. Therefore,
cancer-associated frostbite (CAF) should be considered
in parallel. As an example, an atypical case of foot
frostbite has been reported in a patient with chronic
lymphocytic leukemia (CML). In this report, CML was
introduced as a sensitizing factor for the development
of frostbite.[18] In addition, cases with vasoactive-secreting
tumors, such as pheochromocytoma patients,
can be accidentally detected with a typical frostbite.[19]
Cold hypersensitivity, namely chilblain and perniosis,
rather than true frostbite, has also been associated
with some hematologic malignancies, specifically
leukemias.[20-23] The association of chilblain lupus
erythematosus and preleukemia has been presented in a
significant number of cases.[24] Pernio, due to the blast
crisis phase of acute B-cell lymphoblastic leukemia has
been observed in a 5-year-old girl. Notably, treatment
of the underlying disease fully suppressed the pernio
symptoms.[25] Along with leukemias, there are case
reports for the co-occurrence of Hodgkin lymphoma
and this rheumatologic malady as well.[26] Even solid
tumors can induce such complications. Contrary to the
majority of case reports in this field, chilblains on feet
have been detected as a metastatic presentation of breast
adenocarcinoma in a 45-year-old female patient.[27]
Iatrogenic frostbite can also occur during the therapeutic
procedures for cancer therapy. For example,
cryoablation of superficial musculoskeletal tumors has
been associated with frostbites.[28] The same report is
available for a patient with mediastinal metastasis of squamous cell carcinoma who had used protective frozen
gloves for the prevention of docetaxel-induced onycholysis
skin toxicity.[29] Similar reactions have been
observed with the utilization of cold caps for chemo-induced
alopecia prevention.[30] Furthermore, in a papilloma
excision procedure on the face, periocular frostbite
as an unusual site was unintentionally provoked
due to the administration of ethyl chloride vapocoolant
spray for local analgesia induction.[31] Chilblain
lupus-like cutaneous reaction as a side effect of pembrolizumab
? therapy for oropharyngeal carcinoma in
Japanese female patients has been reported too.[32]
It is important to know that frostbite scars can be diagnosed
cancerous as long as three decades after the initiating lesion. Commonly, recurrent ulcerations and tenderness
are accompanied by this elongated dormant state.
[9] One of the most susceptible groups for frostbites is
still warzone survivors. Hence, clinical records of cancer
among them are not unexpected.[10] Skin is the first and
most vulnerable tissue to the adverse effects of cold insults.
Accordingly, the number of reports about frostbiteassociated
cancer (FAC) is higher in skin cancer cases.
[11] The scar formation on the dermis provides a cancer-
prone area for such pathologies.[12,13] This fact is
significantly applicable to heel site lesions.[
Conclusion
Cancer should be considered a potential long-term adverse effect of acute frostbites. Continued, recurrent, or incomplete wound healing at the site of frostbites is always the hallmark that gives the clinicians clues for further pathologic authentication of FAC. Skin is the most common tissue for this complication and lesions on lower limbs, especially those on heels, have been more associated with cancerous outcomes.However, the association between frostbite and cancer can be bilateral. There are scientific observations that demonstrate cancer as the initiating factor for frostbite predisposition or symptomatology. Considering the abovementioned facts, three different cancer-induced situations can cause cold-related injury or, in this context CAF. First, the tumor itself can disturb end-organ circulation through secreting vasoactive mediators. A telling sample in this regard is pheochromocytoma. Second, cancer therapies can directly induce frostbite. Both chemotherapeutic agents, such as pembrolizumab and surgical cryoablation techniques, have frostbite in their adverse effect lists. And finally, protective measures that act through decreasing temperature against chemotherapy toxicities can be accompanied by frostbite. To our knowledge, there is no study in the medical literature that examined cancer propensity of CAF lesions.
RECOMMENDATIONS
a. Frostbite is not a life-threatening occasion, according
to the statistics, but the development of cancer
can significantly affect the patient survival and
quality of life. Therefore, meticulous follow-ups and
wound or scar checkups for the affected patients are
mandatory, until full recovery. All efforts have to
be made to treat these wounds through pharmacological or surgical approaches. If complete wound
healing is not expected, considering amputation as
a last resort will be valuable.
b. The target population of patients for on-time diagnosis should be kept in mind among all medical practitioners. Enough attention should be paid to specific populations which have been or will be at high risk for such pathologies, such as warzone veterans or the refugees who are mobilized from harsh climates such as Ukraine, especially during the cold seasons. Furthermore, those who attend winter sports and are affected by frostbite are a growing population that should be screened more efficiently.[33]
c. Coexistence of frostbite and certain lymphoproliferative or neoplastic disorder is announced to bear poor prognostic outcomes for the affected patients. [34] Considering the high frequency of reports about cancer or leukemia-associated frostbite, chilblain, or pernio,[35] some authors have proposed that this co-pathology might be induced through blood hyperviscosity and stasis due to interference of malignant cells and gamma globulins in such morbid situations.[36] Furthermore, many diseases affecting skin microvasculature, including Kaposi sarcoma, can mimic the common presentations of rheumatologic chilblain, and this fact has to be considered in differential diagnosis steps.[37] All these facts need to be assessed through well-designed clinical studies because the results might be lifesaving for the affected patients. In addition, any suspicious case with low threshold cold injury must be appropriately examined for the coexistence of common cancers in this specific field.
d. In a study from Kazakhstan, where generally a cold climate is predominant, frostbite has been presented as the causative element in basal cell carcinoma and squamous cell carcinoma of the skin. [38] Because these types of cutaneous pathologies are generally ultraviolet induced, taking the cold climate into account as a risk factor within specific geographic locations with a high prevalence of skin cancers will be constructive in establishing preventive practice guidelines besides sun protective strategies for nationwide populations.
Acknowledgment: The article is dedicated with respect to survivors of Türkiye-Syria earthquack, winter 2023.
Peer-review: Externally peer-reviewed.
Conflict of Interest: I have no conflict of interest.
Financial Support: None declared.
References
1) Basit H, Wallen TJ, Dudley C. Frostbite. StatPearls.
Treasure Island (FL): StatPearls Publishing LLC; 2022.
Available at: https://www.ncbi.nlm.nih.gov/books/
NBK536914/. Accessed Apr 25, 2023.
2) Mäkinen TM, Jokelainen J, Näyhä S, Laatikainen T,
Jousilahti P, Hassi J. Occurrence of frostbite in the general
population--work-related and individual factors.
Scand J Work Environ Health 2009;35(5):384-93.
3) Regli IB, Strapazzon G, Falla M, Oberhammer R,
Brugger H. Long-term sequelae of frostbite-a scoping
review. Int J Environ Res Public Health 2021;18(18).
4) Crouch C, Smith WL. Long term sequelae of frostbite.
Pediatr Radiol. 1990;20(5):365-6.
5) Koch H. Frostbite lesions and neoplasm etiology from
the viewpoint of expert testimony. Zentralbl Chir
1970;95(5):146-52.
6) DiPirro E, Conway H. Carcinoma after frostbite: a case
report. Plast Reconstr Surg 1966;38(6):541-3.
7) McIntosh SE, Freer L, Grissom CK, Auerbach PS,
Rodway GW, Cochran A, et al. Wilderness Medical
Society clinical practice guidelines for the prevention
and treatment of frostbite: 2019 Update. Wilderness
Environ Med 2019;30(4s):S19-S32.
8) Cangkrama M, Wietecha M, Werner S. Wound repair,
scar formation, and cancer: converging on activin.
Trends Mol Med 2020;26(12):1107-17.
9) Katsas A, Agnantis J, Smyrnis S, Kakavoulis T. Carcinoma
on old frostbites. Am J Surg 1977;133(3):377-8.
10) Kunze P. Carcinogenesis caused by war injuries. Arch
Geschwulstforsch 1965;25(2):97-117.
11) ZIu I. Primary multiple cancer of the skin of both
feet originating on frostbite scars. Vopr Onkol
1959;5(1):122-3.
12) Kramchaninov NF. Cancer of the skin on scars after
frostbite. Sov Med 1967;30(9):137-8.
13) Eun HC, Kim JA, Lee YS. Squamous cell carcinoma in a
frost-bite scar. Clin Exp Dermatol 1986;11(5):517-20.
14) Rossis CG, Yiacoumettis AM, Elemenoglou J. Squamous
cell carcinoma of the heel developing at site of
previous frostbite. J R Soc Med 1982;75(9):715-8.
15) Uysal A, Koçer U, Sungur N, Cöloğlu H, Kankaya Y,
Ulusoy MG, et al. Marjolin's ulcer on frostbite. Burns
2005;31(6):792-4.
16) Baux S, Martinaud A, Roland J. Case of cancer on
frosbite with invasion of the calcaneus. Ann Chir Plast
1969;14(4):359-62.
17) Mittelmeier H, Schmitt O. Carcinoma in scar tissue
after frost inquiry to the foot (author's transl). Arch
Orthop Trauma Surg 1978;92(1):47-52.
18) Shelley WB, Shelley ED. Frostbite desquamation of
the soles as the presenting sign of leukemia. Cutis
1986;38(4):259-60.
19) Dreno B, Gandon P, Bureau B, Milpied N, Barrière
H. Skin lesions from hypersensitivity to cold during
chronic myelomonocytic leukaemia. Br J Dermatol
1986;115(5):607-9.
20) Nishiyama J, Yoshizawa N, Ohshima S, Takeuchi A,
Kubota T, Kondoh S, et al. A case of extra-adrenal
pheochromocytoma with frostbite in extremities. Nihon
Jinzo Gakkai Shi 1992;34(8):951-7.
21) Kelly JW, Dowling JP. Pernio. A possible association
with chronic myelomonocytic leukemia. Arch Dermatol
1985;121(8):1048-52.
22) Al-Niaimi F, Chadha M, Cox N. Leukaemia cutis presenting
as digital and chilblain-like perniosis. Eur J
Dermatol 2010;20(6):836-7.
23) Klobassa DS, Dworzak MN, Lanz S, Skrabl-Baumgartner
A, Beham-Schmid C, Cerroni L, et al. Chilblain
lupus and steroid-responsive pancytopenia precede
monosomy 7-linked AML as manifestation of rasopathy.
Pediatr Blood Cancer 2017;64(12).
24) Marks R, Lim CC, Borrie PF. A perniotic syndrome
with monocytosis and neutropenia--a possible association
with a preleukaemic state. Br J Dermatol
1969;81(5):327-32.
25) Park KK, Tayebi B, Uihlein L, Speiser J, Mir A, Gerami
P, et al. Pernio as the presenting sign of blast crisis
in acute lymphoblastic leukemia. Pediatr Dermatol
2018;35(1):e74-e5.
26) Passarini B, Pileri A, Neri I, Piraccini BM, Reggiani C,
Patrizi A. Chilblain lupus erythematosus in a patient
affected by Hodgkin lymphoma. Australas J Dermatol
2013;54(1):74-5.
27) Tan BB, Lear JT, English JS. Metastasis from carcinoma
of breast masquerading as chilblains. J R Soc
Med 1997;90(3):162.
28) Maybody M, Tang PQ, Moskowitz CS, Hsu M, Yarmohammadi
H, Boas FE. Pneumodissection for skin protection
in image-guided cryoablation of superficial musculoskeletal
tumours. Eur Radiol 2017;27(3):1202-10.
29) Begon E, Blum L, Fraboulet G, Assouad S, Bachmeyer
C. Frostbite as a complication of frozen gloves in the
prevention of docetaxel-induced onycholysis. Eur J
Dermatol 2011;21(4):628-9.
30) Belum VR, de Barros Silva G, Laloni MT, Ciccolini
K, Goldfarb SB, Norton L, et al. Cold thermal injury
from cold caps used for the prevention of chemotherapy-
induced alopecia. Breast Cancer Res Treat
2016;157(2):395-400.
31) Rodriguez NA, Ascaso FJ. Ocular surface frostbite
secondary to ethyl chloride spray. Cutan Ocul Toxicol
2012;31(1):77-80.
32) Takeda K, Nakano K, Udagawa S, Fukuda N, Nishizawa
A, Ono M, et al. Chilblain lupus-like cutaneous reaction
associated with systemic lupus erythematosus
induced by immune checkpoint inhibitor. Rheumatology
(Oxford) 2021;61(1):e13-e4.
33) Claes G, Henry F, Letawe C, Piérard GE. The skin, cold
and winter sports. Rev Med Liege 2001;56(4):257-60.
34) Lorenzo-Villalba N, Andres E, Guerrero-Niño J,
Nasco E, Cattelan J, Jannot X, et al. Frostbite and cold
agglutinin disease: coexistence of two entities leading
to poor clinical outcomes. Medicina (Kaunas)
2021;57(6).
35) Tran C, McEwen G, Fraga GR. Chilblain-like
leukaemia cutis. BMJ Case Rep 2016;2016:10.1136/
bcr-2016-214838.
36) Nazzaro G, Genovese G, Marzano AV. Idiopathic
chilblains in myelomonocytic leukemia: not a simple
association. Int J Dermatol 2018;57(5):596-8.