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Peer Review

Peer Reviewed

Literature Review

Squamous Cell Carcinoma in the Setting of Hidradenitis Suppurativa: A Retrospective Review of the Literature

December 2023
1943-2704
Wounds. 2023;35(12):E448-E462. doi:10.25270/wnds/23118

Abstract

Background. Marjolin ulcer is an SCC arising from chronic inflammatory tissue. Such ulcers pose a high risk for metastasis; the 5-year survival rate of 40% to 69% suggests that improvement is possible with early diagnosis. Objective. To raise awareness and update education in the medical community regarding this manifestation of SCC. Methods. The authors performed a retrospective literature review specifically for SCC arising in the context of HS. A PubMed search yielded 81 articles reporting SCC in the context of HS from 1958 to November 2022, with a total of 123 cases. The authors’ additional patient, who was treated in practice, is included as Case 1, bringing the total number of patients to 124. Results. Seventy-three percent of patients were male. The mean age at the time of SCC diagnosis was 53 years ± 10.25 standard deviation. The mean interval between HS diagnosis and SCC development was 24.4 years ± 11.33. Thirty-six percent of patients had metastatic disease. Of the 102 cases that included details on life and death, 58 were noted to have died; of those 58, 60% died within the first year following diagnosis. Conclusion. Given the poor prognosis of Marjolin ulcer, with rapid progression after diagnosis, frequent visual examination and biopsies with a high index of suspicion for HS are recommended to identify SCC prior to metastatic transformation and subsequent unresectable disease. If surgical intervention is performed in the management of HS, tissue should always be sent for pathologic examination. 

Abbreviations

HS, hidradenitis suppurativa; SCC, squamous cell carcinoma.

Introduction

Marjolin ulcer is an SCC that arises from chronic inflammatory tissue frequently thought to occur within a scar, with a 30- to 35-year average development time. These ulcers are most often described in patients with burns after grafting or healing by secondary intention; however, they also have been reported in nonhealing wounds such as pressure injuries, venous stasis ulcers, traumatic wounds, osteomyelitis, fistulas, leprosy ulcers, and lacerations.1 Marjolin ulcers pose a high risk for metastasis, with a 5-year survival rate of 40% to 69%.2 HS is a relapsing and remitting inflammatory skin condition of the apocrine glands that often requires systemic, locoregional treatment and surgical operations.

In a comprehensive review published in 2015, Pena et al3 noted that Marjolin ulcer arising from chronic HS had been described in the literature in only 86 patients. Upon review of these 86 cases, the authors of the current study were surprised to find that most patients whose surgical history was described had prior surgical intervention for their HS in the exact area where SCC ultimately developed.3 This is in contradistinction to classic teaching in which malignant transformation was thought to occur owing to chronic turnover from infection and inflammation unassociated with surgical debridement and/or resection. This close examination of prior surgical treatment highlights 2 critical questions. First, if SCC is often diagnosed after it has already progressed to T4 disease, should providers more often send suspicious tissue for biopsy? Second, could surgical intervention for HS wounds, while necessary, be laying the groundwork for the subsequent development of SCC? 

This retrospective review was motivated by a patient well known to the authors’ team who was treated in practice in 2021. The case involved SCC development in the setting of chronic HS, which resulted in death within 1 year of diagnosis. An update and analysis of the literature including all 124 patients with reported SCC arising from chronic HS is provided. 

Methods

Institutional review board approval was obtained for a retrospective institutional patient case review, and review of the literature was performed specifically for SCC arising in the context of HS. A PubMed search included the keywords “hidradenitis suppurativa,” “squamous cell carcinoma,” “cancer,” “Marjolin’s ulcer,” and “Verneuil’s disease” (Figure). The search resulted in 81 articles reporting SCC in the context of HS from 1958 until November 2022, with 123 cases (Table 13-82; see end of Discussion section below). The patient of the authors of the current study, “Case 1,” is included herein, bringing the total number of cases to 124. The current review includes an additional 38 cases compared with the previous comprehensive review by Pena et al3 in 2015, which described 86 cases.4-82

Given the history of Case 1, particular interest was paid to prior surgical history. Keywords were searched in all 81 articles, including “surgical intervention,” “excision,” “incision and drainage,” “deroofing,” and “reconstructive flaps.” If any language to this effect was present in descriptions of each case’s prior HS management, specifically in the region where SCC eventually developed, a “yes” was included in the prior surgical treatment column. “Local wound care,” “radiotherapy,” “debridement,” “laser marsupialization,” and “biopsy” were excluded. All data are reported as mean ± standard deviation. Data analysis was performed using Microsoft Excel.

Figure

Table 2

Results

Demographic data are presented in Table 1. Not all studies reported sex; however, 73% of patients in those studies that did were male. The mean age at the time of SCC diagnosis was 53 years ± 10.25. The mean interval between HS diagnosis and SCC development was 24.4 years ± 11.33. Thirty-six percent of patients had metastatic disease. Details on life and death were noted for 102 patients. Of the 58 patients who were noted to have died, 60% died within the first year following diagnosis. Tumor location was categorized as posterior (buttock, perineum, perianal, gluteal), anterior (groin, thigh, scrotal, vulva), or both depending on where the SCC was discovered on initial diagnosis. Tumor frequency by location was as follows: 82% posterior, 10% anterior, 5% both, and 3% unknown. Of note, SCC in the setting of HS has yet to be described in the axilla; this likely represents a gap in the literature on the subject matter. Twenty-five percent of patients are known not to have attempted excision following SCC diagnosis. Table 2 lists qualitative details concerning the decisions to forgo excision. 

Of the 124 patients reviewed, only 49 had descriptions of prior surgical treatment for their HS. Of the 49 patients whose prior surgical management for chronic HS was described, 67% had prior surgical intervention in the region where their SCC was ultimately discovered. 

Case 1 had confirmed pathology of SCC in the setting of chronic HS. She was 54 years of age at the time of diagnosis and had developed HS in her early 30s. Multiple medical treatments had been attempted previously (eg, bleach baths, doxycycline, infliximab), with minimal improvement. She refused all surgical intervention. SCC diagnosis was made on biopsy of the right perianal region after the patient presented to the clinic for worsening drainage and pain caused by HS lesions in that region. Computed tomography was significant for locally advanced disease and nodal metastasis. The patient died 4 months after diagnosis. 

Table 1

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Discussion

Marjolin ulcer is a type of SCC that develops in the setting of chronic nonhealing wounds. Such ulcers are most often reported in association with burns (76.5% of all Marjolin ulcers reported); however, they have also been described in association with pressure injuries, venous stasis ulcers, traumatic wounds, osteomyelitis, fistulas, leprosy ulcers, and lacerations.1 To date, no consensus has been reached on the exact mechanism that leads to this malignant transformation of chronic wounds.83 However, a so-called multiple hit phenomenon is suggested by recurrent injury in the pathogenesis. The authors of the current review hypothesize that frequent cellular turnover owing to inflammation and chronic infection may predispose to mutagenesis similar to a large thermal injury with subsequent operation with a long time to malignant transformation. In fact, thermally injured patients are advised to wear sunscreen on prior burns to prevent further UV damage, which may contribute to the progression to Marjolin ulcer; repeated injuries which parallel the cycles of infection and inflammation in HS. Marjolin ulcers have a metastatic rate of 20% to 30% and a 5-year survival rate of 40% to 69%, which suggests that improvement in patient outcomes is possible with early diagnosis.2,84 Multiple factors account for the advanced disease state often encountered at diagnosis, including a variety of presentations that are difficult to diagnose without pathological confirmation, a predilection for economically and socially disadvantaged patients, lack of adequate early wound care along with the late presentation, and a prolonged latency period from the time of injury to malignant transformation.1,2,85,86 

Less commonly, Marjolin ulcer has been described in the setting of HS, in areas with and without prior surgical intervention, which contradicts current teaching and suggests that current medical education must be updated. As stated previously, HS is a relapsing and remitting inflammatory skin condition of the apocrine glands that often requires systemic immunosuppression, locoregional treatment, and surgical operations. The worldwide prevalence is estimated to be 1% to 4%, and no universal consensus for definitive treatment has been reached.87 HS affects females 3 times as often as males; however, perianal lesions, which have a higher propensity for malignant transformation, are more common in males.88 HS flares often present with pain, drainage, and skin changes, making it difficult to distinguish malignant growths. In 2009, Lavogiez et al4 highlighted a 4.6% prevalence of SCC in HS in their study of 217 patients with HS. In the current review, the authors hope to emphasize the importance of frequent examination and biopsy and high clinical suspicion for Marjolin ulcers in patients with HS. As stated in the Methods section, SCC has been described in all classic areas of HS development except the axilla. Therefore, HS arising anywhere in the body outside of the axillary region should be viewed as a premalignant condition.45

This review of Marjolin ulcer in the setting of HS, as detailed in Table 1, highlights the late presentation of this disease often encountered upon diagnosis. In 2015, Pena et al3 reported that 42.9% of the patients they specifically studied died; in contrast, a 2007 review reported that 48% of patients died within 2 years of diagnosis. The current review found that death occurred within 1 year of diagnosis in 60% of patients in which mortality was known; this finding may be an underrepresentation.

Early identification before metastatic transformation continues to prove difficult, given the lack of standardized monitoring guidelines and the evolving nature of HS. Given that HS flares often present with pain, drainage, and skin changes, it is challenging to differentiate and identify a Marjolin ulcer in the setting of HS. Especially for patients who are familiar to the health care provider and are seen frequently, the tendency among providers toward complacency must be challenged. Comprehensive progress reports, monthly measurement and photographic documentation of wounds, frequent biopsies with routine pathology of all debridement specimens, and monitoring for any new constitutional symptoms may be lifesaving. The authors of the current review emphasize early intervention and consistently erring on the side of caution. As noted in the literature, if clinical suspicion remains high following a negative biopsy, it is suggested that the entire lesion be excised.88 In 2020, Ward et al89 described a patient with a 20-year history of HS who underwent at least 5 negative biopsies over 3 years until the last was positive for hyperkeratosis and condyloma acuminatum, both known precursors of SCC. This patient survived because of early detection and action.

Surgical intervention for HS prior to Marjolin ulcer formation has not been a focus in the literature prior to this review. Including Case 1 above, only 39.5% of cases describe whether the patients underwent surgical intervention of any kind for management of HS. Of these 49 cases, 67.3% underwent prior surgical procedures for HS in the region where SCC ultimately developed. This association could point to areas of focus in future research. First, the resulting inflammatory response following the surgical intervention for HS may contribute to Marjolin ulcer formation or may cause more rapid formation of the SCC. Continued inflammation often results in scarring and fibrosis, with SCC a known complication of both.88 Second, the question is whether physicians are less likely to biopsy regions that have previously been operated on. Thermal injury is not a standard part of all surgical residencies, and knowledge of Marjolin ulcer in the surgical community is variable. Patient refusal owing to sensitivity/pain sensitivity and/or pain, or a false sense of self-reassurance on the part of the physician both may contribute to progression of HS to Marjolin ulcer. This false sense of self-reassurance goes hand in hand with confirmation bias, which is known to be a prevalent issue for surgeons. In a review of approximately 1.5 million surgical procedures, confirmation bias was cited as the most common contributing factor to surgeon error when analyzing so-called never events.90 Thus, surgeons operating on patients with HS lesions may be biased to believe those regions have minimal malignant potential following successful surgical intervention.

Regardless, surgical intervention for HS should be considered a risk factor for the malignant transformation of HS. If any surgery is performed for management of HS, tissue should be sent to pathology, along with orientation. For the authors of the current review, it has become standard practice to visualize all HS wounds regularly, even if patients initially balk owing to dressing concerns, and to send all debridement and excision specimens marked for pathology. Simple interventions such as these may lead to lifesaving diagnoses early enough for curative treatment. It is also important to note that 32% of patients included in this review developed SCC despite no prior surgical intervention, including in Case 1. Malignant transformation of HS is a varied process, and an individualized approach for each unique patient and diligent monitoring are essential. 

Limitations

This report and literature review are not without limitations. The review highlights outcomes and prior surgical interventions related to HS, with the understanding that malignant transformation of chronic wounds is a multifactorial process. For example, previous studies have investigated the correlation of smoking and human papillomavirus infection with Marjolin ulcer formation.4,70,73 Additional research evaluating contributing factors to Marjolin ulcer formation is encouraged. Furthermore, the authors recognize that not all conclusions about SCC formation in the context of HS can be extended to describe non-HS chronic wounds. Thus, studying these variations of Marjolin ulcer formation together is beneficial, but overgeneralization should be avoided. Finally, it is not enough to advocate for early biopsy and pathology. Standardized monitoring guidelines are necessary to catch and truly halt the progression of these conditions prior to metastatic disease. Further research is required on this condition. 

Conclusion

Marjolin ulcer is a dangerous SCC that should be considered a lethal complication in patients with chronic wounds. Frequent visual examination and biopsies are recommended to diagnose Marjolin ulcer prior to metastatic transformation and subsequent unresectable disease. If surgical intervention is performed in the management of HS, tissue should always be sent for pathology. The authors encourage that instances of SCC in the setting of HS be reported in the literature to aid in the actualization of universal monitoring guidelines in the near future. 

Acknowledgments

Authors: Austin Dixon, DO1; Fae Kayarian, BS2; and Thea Price, MD3

Affiliations: 1Department of Surgery, Sinai Hospital, Baltimore, MD; 2Rush Medical College of Rush University Medical Center, Chicago, IL; 3Department of Surgery, Rush University Medical Center, Chicago, IL

ORCID: Dixon, 0000-0003-1059-4423; Kayarian, 0000-0003-0434-6060

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Austin Dixon, DO; 2401 W. Belvedere Avenue, Baltimore, MD 21215; austin.dixon5@gmail.com

Manuscript Accepted: November 20, 2023

How Do I Cite This?

Dixon A, Kayarian F, Price T. Squamous cell carcinoma in the setting of hidradenitis suppurativa: a retrospective review of the literature. Wounds. 2023;35(12):E448-E462. doi:10.25270/wnds/23118

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