A Case Report Of Multiple Primary Squamous Cell Carcinomas Along The Mekong River: Assessing The Impact Of Chronic Arsenic Exposure

The Mekong River is 4300km long with a catchment area of 520,000km². Its alluvial deltas have groundwaters which provide drinking water for many Cambodians via private tube wells since the 1990s. The groundwaters are the people’s lifeblood. Yet, paradoxically, they are polluted by arsenic released by the natural process of reductive dissolution of arsenic-bearing iron phases contained in aquifers. It is estimated that 0.5 to 1 million people in the Mekong delta are at risk of chronic arsenic exposure(1). This can lead to non-cancer conditions such as atherosclerosis, cerebrovascular events, myocardial infarction and peripheral vascular diseases(2) and cancers of the integumentary, respiratory, hepatobiliary and urinary systems(3). Cutaneous lesions are usually the first manifestations of arsenicosis and around 1% of exposed individuals develop squamous cell carcinoma, basal cell carcinoma or other cutaneous malignancies(4).

In this paper, we present a patient treated at the Children’s Surgical Centre in Phnom Penh who developed multiple primary squamous cell carcinomas (SCCs) induced by chronic arsenic exposure. This is one of the very few reports of SCC from arsenic exposure in the Mekong.

A 66-year-old male blacksmith with good past health from Lvea Aem District of Kandal Province in Cambodia first presented with a chief complaint of a chronic ulcer on the volar side of the right thumb in June 2016 (Figure 1a). The lesion had been present for six months and was gradually increasing in size. Suspicious ulcerated lesions were also present on the right middle and 5th fingers. Multiple other skin lesions with hyperkeratosis and hyperpigmentation were found on both hands. The axillary lymph nodes were not palpable. Differential diagnoses included cutaneous malignancies, chronic skin infections and vascular lesions. He underwent excision of the lesions of the right thumb and on the middle and 5th fingers. A rotational flap and split thickness skin graft was used to cover the wound of the thumb (Figure 1b). Histopathological report revealed that the lesions were SCCs.

In January 2022, the patient returned with additional concerning ulcerated lesions which had appeared on both hands over the past two years, namely on the medial side of the right middle finger, the right volar wrist (Figure 2a), the medial side of the left 5th finger and the thenar region of the left palm (Figure 2b). He also had an ulcerated lesion on the plantar surface of the left heel (Figure 3a). He underwent excision of the above-mentioned lesions. Full thickness skin grafts were used to cover the wounds. Histopathological report found that all lesions were moderately to well-differentiated SCCs and margins were clear. In April 2022, the left heel plantar surface was ulcerated, which was suspicious of recurrence. The lesion was excised and a reverse sural flap was performed, however this became necrotic 4 days later and it was removed and replaced by split thickness skin graft from the left anterior thigh. Histopathological analysis showed ulceration and granulation tissue with foreign body giant cell granuloma.

In July 2023, the patient returned with an ulcerated 2x2x1cm lesion at the right scrotum which had been present for two months (Figure 4a). The inguinal lymph nodes were not palpable. High frequency ultrasound showed that the testicles were of normal size, the epididymis had a normal appearance and surrounding lymph nodes were 6-9mm in size. The lesion was excised with 2-3cm margins and removed with the superficial fascia of the scrotum, external spermatic fascia, cremaster muscle and fascia and internal spermatic fascia. The parietal layer of the tunica vaginalis was preserved. Histopathology revealed invasive low-keratinizing moderately differentiated SCC of the right scrotum and the margins were clear. The patient is currently well and will be followed-up intermittently to monitor general health and cancer recurrence. He had no other signs and symptoms of chronic arsenicosis. Patient education was provided by CSC and he was instructed to avoid consuming water from the well. The patient’s household was also examined and at the moment none of them have the same lesions.

Kandal is one of the Cambodian provinces most affected by naturally-produced arsenic pollution of groundwater, with levels in some areas approaching 3500µg/L, well above the Cambodian Standard of 50µg/L(5) and World Health Organization (WHO) standard of 10µg/L. Residents pump groundwater via tube wells for use as drinking water because alternative sources such as surface water or water from shallow dug wells were prone to contamination by pathogenic bacteria(1). However, groundwater is not necessarily the lesser of the two evils. It was estimated that 100,000 people living in Kandal are chronically exposed to levels of arsenic above this standard(5) and a study by Phan et al found that 72% of Kandal residents had scalp hair with arsenic content exceeding the level of toxicity(6). Wells in Lvea Aem, where this patient lives, were installed in 2002 and cases of arsenicosis have been identified in this area(5). This patient had consumed arsenic-containing groundwater from a tube well for more than 20 years.

Cutaneous lesions such as hyperkeratosis, hyperpigmentation and Bowen’s disease (squamous cell carcinoma in situ) are usually the first manifestations of arsenicosis(7). Arsenic is considered a class I carcinogen by the International Agency for Research on Cancer (IARC). The pathophysiology of arsenic-induced carcinogenesis remains unclear, however, processes such as increased reactive oxygen species, chromosomal abnormalities, immune dysfunction and uncontrolled cell proliferation may be involved(8). Although some individuals may be unaffected, cutaneous lesions often present after around 10 to 20 years of chronic arsenic exposure(9); this difference in susceptibility may be attributed to variations in immune regulation(8). In other populations, nutrition and socio-economic status were also found to be factors affecting an individual’s susceptibility to arsenicosis(10, 11). Around 1% of exposed individuals develop squamous cell carcinoma, basal cell carcinoma or other cutaneous malignancies(4).

This patient’s case demonstrates the elevated risk of development of cutaneous lesions due to chronic arsenic exposure and emphasizes the importance of close monitoring, early detection and treatment. At present, there is no known effective treatment for established arsenicosis. For early SCCs, excision can be curative(12). Fortunately, this patient had sought treatment early enough such that the SCCs could be excised with clear margins and there was no evidence of metastasis. The sural flap necrosis was likely due to venous congestion as the flap was vital for the first two days and became necrotic 48 hours later. A treatment option for flap necrosis was leech therapy, however it was noticed too late in this case. In certain cases, a delayed reverse sural flap could also have been considered. To date, the lesions excised in 2016 and 2022 exhibited no local recurrence. Ideally, the patient should have further evaluation with magnetic resonance imaging or computed tomography. However, CSC does not have such facilities and it would cost around USD130 to 180 for patients to have these imaging done privately, which most of them, including this patient, could not afford. Late presentation of arsenic-induced cutaneous cancers can lead to devastating consequences such as the amputation of an affected limb, as reported in a previous case series, resulting in significant morbidity(13). In a high-risk region such as Kandal province, the average cancer risk index was estimated to be 5 in 1000 exposure (0.5%) (6), which is triple the incidence rate of cancers in Cambodia at 133.3 per 100000 (0.13%)(14). There remains a dearth of data on the incidence of arsenicosis in Cambodia. 12 patients with suspected arsenicosis have been treated by CSC since 2008. Since symptoms manifest years after chronic arsenic exposure and given the statistics of the at-risk population, it is expected that there are many more existing cases, or similar cases which will emerge in the future.

The provision of safe drinking water in Cambodia has been a gradual work in progress. The decision to switch to alternative sources of drinking water or implement measures to treat the groundwater in these regions was previously hindered by lack of education and access to information, as well as financial ability(5). A successful example of a community-led programme to reduce arsenic exposure among private well users was demonstrated in American Indian communities. Known as the Strong Heart Water Study (SHWS), a cluster randomized controlled trial was conducted to compare between the installation of a point-of-use arsenic filter and a mobile health programme including three phone calls to a more intensive intervention, which included the above measures and three home visits. There was no significant difference in urinary arsenic levels between the two treatment arms at the final follow-up visit at two years, and a 47% reduction in urinary arsenic was observed when both study arms were combined(15). This study demonstrated the importance of multilevel community involvement in reducing arsenic exposure. In Cambodia, community leaders can also capitalize on mobile phone access and social media to promote arsenic mitigation and public health education.

Several limitations exist regarding the link between this patient’s SCCs and arsenic exposure through the Mekong River. Details about the patient’s family history and other SCC risk factors (e.g., smoking, HPV, radiation) are unknown (6). While the patient reported drinking groundwater from the arsenic-contaminated Mekong River delta, arsenic levels in biological samples (urine, blood, or hair) were not measured, preventing confirmation of arsenicosis. The lack of specific data on arsenicosis and SCC in the Kandal region limits our ability to assess the Mekong River’s role in predisposing patients to SCC and underscores the absence of screening guidelines for arsenic-induced SCC (1). Despite these limitations, the patient’s prolonged arsenic exposure and the known long latency period for SCC development support the hypothesis of arsenic-induced SCC (1,4). Previous literature has called for better coordination between government bodies, NGOs and donor agencies to address this problem.

In 2019, the Ministry of Rural Development of Cambodia prepared a national action plan for rural water supply, sanitation and hygiene. It aimed to provide everyone in rural communities with sustained access to safe water supply by year 2025(16). Plans by the Phnom Penh Water Supply Authority under the Ministry of Industry, Science, Technology and Innovation to build new water treatment plants are underway to meet the increase in demand for pipe water. The success of this measure in preventing arsenicosis will also be contingent on the willingness and ability of the people in rural communities to pay for treated water. While it is hopeful that these efforts will bring an increase in equitable access to clean drinking water, given the large population already chronically exposed to arsenic, there remains a need for public health education to raise awareness and encourage early medical treatment to prevent morbidity and loss of lives, and regular screening of these residents for signs of arsenicosis.

We presented a patient who developed multiple primary SCCs induced by chronic exposure to arsenic. Given the large population presently and chronically exposed to arsenic through consumption of contaminated groundwater from the alluvial deltas of the Mekong River, it is imperative that multidisciplinary efforts involving healthcare providers, policymakers and communities prioritize the creation of solutions to increase equitable access to safe drinking water. In the meantime, the incidence of arsenicosis should be ascertained through screening and high-risk populations educated on the importance of seeking early medical treatment when signs and symptoms of arsenicosis arise.

Consent

Informed consent had been obtained from the patient for the release of photographs and details of the case management for this case report.