Persisting Cancer in Black Salve Treated Skin Lesions: Results of a Large 5 Year Retrospective Analysis of Australian Histopathology Specimens

Abstract

Background:

To date there has been minimal research on the use of black salve escharotics. Whether cancer persistence is a frequent finding in treatment areas, the types of lesion being treated by patients, whether rural patients are more likely to use black salve and whether current government prevention initiatives are succeeding are all issues needing investigation.

Methods:

This study was a large national retrospective black salve pathology case series from 2015 to 2019. Five private pathology companies with 1471 collection centers located in 5 of the 8 Australian states and Territories provided de-identified skin pathology report information where black salve treatment had been documented in the pathology request.

Results:

Over the 5-year period 409 patients had treated 475 lesions with black salve. Benign lesions were present at the treatment site in 18% of cases; persisting cancer was found in 34.2% of the remaining black salve treated areas. The majority of treatment areas were located on the head and neck. Black salve caused necrosis of normal tissue when treating benign lesions, refuting claims of cancer specificity. Likelihood of black salve use increased with rurality based on Modified Monash (MM) scores. Black salve use, despite regulatory efforts, appears to be increasing with specimen numbers more than doubling from 2015 to 2019.

Conclusions:

Patients undergoing histopathological assessment of black salve treatment areas have high rates of cancer persistence. Patients are applying black salve to benign lesions and lesions in cosmetically sensitive areas. Rural patients have higher proportional rates of black salve use. The increasing incidence of black salve pathology specimens suggests current Australian black salve public health initiatives are failing.

Introduction

Black salve is a controversial complementary and alternative medicine (CAM) that has been associated with significant adverse outcomes.¹ Despite its importation and sale being prohibited in Australia by the Therapeutic Goods Administration (TGA),² black salve use is advocated by social media groups and it may be easily purchased online.³

Black salve formulations contain 2 core ingredients, the North American herb Sanguinaria canadensis known as bloodroot, which is rich in cytotoxic alkaloids, and zinc chloride, a corrosive chemical.⁴ After learning of the Native American use of bloodroot to treat cancer, an American surgeon, Dr. Fell, was the first to create black salve in the 1850s.⁵ Since then, a procession of health entrepreneurs have promoted black salve as a safe and effective skin cancer therapy.^6,7

Black salve has never been studied in a randomized clinical trial, with only occasional case studies appearing in the medical literature.⁸ The largest case series to date from Western Australia, reported the histopathological features of 16 black salve treatment areas from 11 patients. They found residual cancer in 1 biopsy representing 6.25% of cases.⁹ To better understand the potential threat black salve may pose to patients and assess the potential scale of its public health impact, we conducted a large 5-year national retrospective case series of black salve pathology cases.

Methods

Study Design and Participants

This report represents a 5-year retrospective study of black salve-treated pathology cases received by Australian private pathology laboratories. Fourteen private pathology providers from all states and territories in Australia were approached to participate in January 2020. Five pathology providers agreed to participate and provided data. One pathology company could not participate as they were unable to search for key phrases in pathology request clinical notes, 2 pathology providers were unable to participate due to the increased workload caused by COVID while 6 pathology providers did not reply when contacted. Pathology companies searched their databases using the keyword “black salve” from 1/1/2015 to 31/12/2019. Age, gender, pathology request clinical notes, skin lesion location, histopathology report, and histopathology diagnosis data were extracted.

Remoteness

The Modified Monash Model (MMM) classification system was introduced in 2015 and determines a location’s rurality.¹⁰ Based on remoteness and population size, a location is given a Modified Monash (MM) classification ranging from MM1 to MM7, with MM1 being a major city and areas MM2 to MM7 being rural areas of increasing remoteness. Patient remoteness was classified as metropolitan or large regional town (MM1-MM2), medium regional town (MM3-MM4), small regional town (MM5), or remote location (MM6-MM7).

Sample Size

The study was based on convenience sampling, which was dependent on (1) the willingness of pathology providers to provide data and (2) the clinical notes of the referring doctor specifically including the use of the term “black salve.” Given the public health priority of this condition, it was determined a priori to report on whatever data was provided.

Data Analysis

Data were provided by pathology providers in Microsoft Excel spreadsheets. Descriptive statistics were undertaken using MS Excel statistical functions. Rurality data was compared to the Australian Census Population Data Australian Bureau of Statistics 2011 standards for rurality. Data were plotted on GraphPad Prism (v9.1.2) using simple linear regression to determine the line of best fit with 95% confidence intervals and to calculate the r² statistic.

Ethics Approval

Ethics committee approval from Southern Cross University Human Research Ethics Committee (SCU HREC), Lismore, Australia was received on 10/12/2019; Approval Number 2019-565. Patient records were de-identified by pathology providers. Additional measures to further protect patient confidentiality included pathology providers recording patient age instead of their date of birth and rurality [based on the Modified Monash Model (MMM) rurality score] instead of postcode.

Results

Five Australian pathology providers with 1471 collection centers located in Queensland, New South Wales, Victoria, South Australia, and the Northern Territory identified 580 lesions potentially treated with black salve. Some cases were excluded from the study: (i) cases where black salve use was inferred by the reporting pathologist without a history of black salve use reported in the clinical notes (n = 11); (ii) pathology date of 2020 falling outside the date range of the study (n = 1); (iii) a double entry of 1 case (n = 1); and (iv) no mention of black salve in the entire pathology report (n = 2). In addition, some patients had pathology specimens (n = 90) taken from multiple lesions, of which some had not specified black salve application. In total, 105 cases were not included in the assessment.

Excluding these cases there were 475 black salve treated lesions from 409 patients. There were 175 male patients and 234 female patients. The average age of male patients was 62.8 years with a range of 23 to 90 years, and the average age of female patients was 57.6 years with a range of 17 to 95 years.

The location of lesions treated with black salve is summarized in Table 1. The majority were located on the head and neck with 31% of total lesions located on the face.

Table 1.

Black Salve Application Areas by Site and Body Region.

Black salve application site	% of cases
Head and neck	40
Face lesions other	15.4
Nose	8
Ear	3.2
Lip	2.3
Eyelid	2.1
Scalp	3.8
Neck	5.3
Trunk	22.3
Chest	8.6
Back	11
Breast/nipple	1.9
Abdomen	0.8
Upper limb	22.3
Hand	2.7
Forearm	9.1
Upper arm	9.1
Arm not specified	1.5
Lower limb	13.9
Lower leg	7
Upper leg	4.6
Buttocks	0.4
Leg not specified	1.9
Site unspecified	1.5

The histopathological analysis of black salve treated areas detected a total of 86 benign lesions located at the treatment site (Table 2). The most common were seborrheic keratoses, actinic keratosis, and a large number of benign naevi. We were unable to determine if these were the original lesion treated by patients or incidental lesions located at the treatment location.

Table 2.

Benign Lesions at Black Salve Treatment Sites.

Benign lesion	Number
Seborrheic keratosis	27
Actinic/lichenoid keratosis	27
Naevi	21
Lentigo	4
Dermatofibroma	2
Large cell acanthoma	1
Epidermal inclusion cyst	1
Epidermoid cyst	1
Chondrodermatitis nodularis helicis	1
Pyogenic granuloma	1
Total	86

Histopathological diagnosis and number of benign lesions located at black salve treatment sites

Of more concern, 137 of the 475 black salve treated lesions (28.8%) showed persisting cancer (Table 3). If the specimens where benign lesions were present (86 cases) represent benign lesions treated by patients where one would not expect to find malignancy at follow up biopsy, the skin cancer treatment failure rate of black salve in this case series would be 35.2% (137 cases of a total 389 cases). The persisting malignancies detected in black salve treatment areas included 74 basal cell and basosquamous carcinomas, 53 squamous cell carcinomas (SCCs), 5 keratoacanthomas, 4 melanomas, and 1 case of cutaneous metastatic renal cancer.

Table 3.

Persisting Cancer Present After Black Salve Treatment.

Persisting malignancy	Number
Melanoma	4
Squamous cell carcinoma	32
Intra-epidermal carcinoma	21
Keratoacanthoma	5
Basal cell carcinoma NA	37
Basal cell carcinoma Agg	34
Basosquamous carcinoma	3
Cutaneous metastatic renal cancer	1
Total	137

Histopathological diagnosis and number of persisting malignancies found at black salve treatment sites.

Of the remaining 252 cases where a benign lesion or persisting malignancy was not detected, histopathology showed inflamed, ulcerated, or scarred benign tissue. In these cases the original lesion treated by patients may have been benign or malignant. As a best case scenario, assuming all of these cases were malignancies successfully treated by black salve, the treatment success rate would be 65%. This is significantly below the 90% to 99% 5 year recurrence-free rates achieved by conventional skin cancer treatments.^11,12

The number of patients having black salve pathology specimens submitted each year from 2015 to 2019 listed in Table 4 shows increasing patient numbers year on year.

Table 4.

Number of Patients Using Black Salve by Year.

Year	Patients
2015	49
2016	63
2017	83
2018	102
2019	112

Patients using black salve by year of pathology specimen collection.

The influence of remoteness on black salve use is shown in Table 5. Analysis of the effect of rurality on the number of cases was undertaken using simple linear regression. Percentage of cases per 100 000 population were plotted against Modified Monash (MM) category rurality scores and a line of best fit with 95% confidence intervals determined (Figures 1 and 2). When compared to the proportion of patients living in different MM areas, there was an increased likelihood of black salve use by patients living in rural locations (MM3-MM6) compared to those living in metropolitan areas.

Table 5.

Black Salve Treatment by Town Size.

Location	Australian census data (% total population)	Black salve patients
Metro/large regional town	79.8	57.2
Med regional town	10.3	16.8
Small regional town	7.6	20.8
Remote	2.2	5.1

Town size metro/large regional town population >50 000; Medium regional town population 5000 to 50 000; Small regional town population 1000 to 5000. Australian Census Data 2011.

Figure 1.

Linear regression determining the line of best fit (95% confidence intervals) on the percentage of cases per 100 000 people and the Modified Monash Model (MM) Rurality Score.

Figure 2.

Linear regression determining the line of best fit (95% confidence intervals) on the percentage of cases per 100 000 people and the Modified Monash Model (MM) Rurality Score without MM region 7.

Discussion

To date, black salve escharotics as stand-alone cancer treatments have been minimally researched, despite being marketed to and used by cancer patients for over 160 years. This study is the largest histopathological assessment of black salve treatment sites ever reported. Our study of 475 black salve treated lesions from 409 patients adds further evidence of the risks posed by black salve use.

While the discovery of 137 persisting malignancies in 475 black salve treatment sites is concerning, our study as a case series cannot determine the effectiveness of black salve as a skin cancer treatment. A significant selection bias is present in our data with only patients presenting to a clinician and having skin specimens taken of a black salve treatment site being included in the study. An unknown number of patients may have used black salve without cause to seek medical review. Despite this fact, the 28.8% persisting cancer rate found in black salve treatment sites is a concern. It suggests that the use of black salve as a blind chemosurgery, that is without confirming cancer clearance via histological means, is a risky undertaking. Skin cancers with higher metastatic potential including 4 melanomas and 32 squamous cell carcinomas were among the 137 persisting malignancies discovered. Our patient cohort presented for medical review; there are likely a number of individuals using black salve who would not. In such cases, persisting malignancies would place them at considerable risk of metastasis and death, already documented to have occured as a consequence of black salve use.^8,13 As a clinical trial would be unacceptable for ethical reasons based on the potential carcinogenicity of sanguinarine,¹⁴ the warnings against its use by regulators and as effective and safe medical and surgical therapies already exist, large retrospective case series may be the highest level of evidence that can be obtained for assessing the efficacy of black salve.

As our study relied on the clinical history provided by clinicians on histopathology forms, we were unable to determine the dose of black salve used and the treatment duration employed by patients. These variables likely impacted patient pathology outcomes and would be essential information to include if a prospective black salve pathology notification system were to be developed. Of the 14 pathology providers approached, the reason 6 pathology providers were not willing or able to participate in the research was not able to be determined, this being a further limitation of our study.

Little is known about the quality control of black salve manufacturing processes. Sanguinarine, the main cytotoxic alkaloid in black salve,¹⁵ had an astounding 12 500 fold variation between manufacturers, the highest sanguinarine concentrations being 900 times greater than that required to kill human epidermal keratinocytes.¹⁶ Our case series further confirmed black salve’s ability to harm normal non-malignant tissue. Where a benign lesion had been treated, the normal skin tissue surrounding these lesions was necrotic/ulcerated or scarred. It cannot therefore be argued that malignancy activated the black salve with subsequent collateral damage to normal skin as no malignancy was present to trigger activation.

Patient de-identification prevented us from determining if patients represented multiple times with the same lesion or if patients presented on multiple occasions continuing their behavior of black salve usage. A strength of our study however, lies in its quantitative nature with solid pathology data that is not open to wide interpretation.

While the majority of patients who used black salve came from metropolitan areas (57%), the disproportionately higher rates of black salve use in patients from rural or remote regions suggest that for some patients a lack of access to health practitioners may be an important factor in deciding to use black salve. Limited health professional access and prolonged wait times in rural Australia have been identified by 35% of patients as barriers to seeking medical skin cancer detection.¹⁷ Increasing rurality has been associated with diagnostic delay and poorer health outcomes for several cancers with rural workforce shortages with diagnostic delay and poorer health outcomes for several cancers with rural workforce shorta travel distance to a general practitioner identified as a contributory factor.¹⁸ While the line of best fit failed to show a correlation with total rurality (Figure 1), removing the most remote location (MM7), where people live in isolation¹⁹ and may have difficulty presenting for skin biopsy, strongly showed that black salve use increases with rurality (r² = .9; Figure 2). With the COVID-19 pandemic altering primary care delivery in Australia, with an increasing number of telehealth consultations in addition to the ongoing development of teledermatology, clinical pathways could be developed to improve dermatology access for rural and remote patients.

Despite TGA warnings against the use of black salve and the criminalization of its sale, the number of black salve treated pathology cases from 2015 to 2019 increased year on year (Table 3). By 2019 the number of cases had more than doubled from 2015 levels. Regulation does not seem to have limited the spread of black salve use suggesting the Australian Government and the TGA may need to change their regulatory approach.

If patient education fails to convince individuals not to use black salve, clinicians should foster a harm minimization approach. Such an approach might include offering to assess lesions to prevent black salve use on benign lesions, offering histological follow up of black salve treated lesions or offering alternate conventional therapies especially in the context of higher risk malignancies such as melanomas and SCCs or those in high risk or cosmetically sensitive locations. Such harm minimization strategies could reduce the risks posed by black salve.

Conclusion

Black salve use continues to increase in Australia and shows no sign of abating despite regulatory efforts. The principal finding of this, the largest ever black salve case series, is that histopathology assessment of black salve treatment areas shows high rates of skin cancer persistence. It demonstrates that individuals choosing to experiment with black salve place themselves at risk of both normal tissue destruction and skin cancer treatment failure. Government policy should focus on increasing the access of rural and remote communities to dermatology services while clinicians should adopt a harm minimization approach with their patients. We recommend black salve pathology reports become a notifiable condition with the establishment of a national black salve registry to better guide public health policy.