Paraneoplastic bullous pemphigoid secondary to cutaneous squamous cell carcinoma

Introduction

Squamous cell carcinoma (SCC) is the second most prevalent skin cancer after basal cell carcinoma (BCC). In recent years, the incidence of new SCC cases has been steadily rising. Because SCC has the potential to metastasize both locally and to distant organs, it is regarded as significantly more aggressive and carries a higher risk of mortality than BCC. The most common sites for SCC are the face (particularly the nose and lower lip), the auricles, the frontoparietal region, and the dorsal surfaces of the hands. The group most at risk of developing SCC includes individuals with light skin phototypes, typically over 50 years of age, who have been exposed to carcinogenic substances (such as aromatic hydrocarbons, arsenic, tar derivatives, or chewing tobacco). Cancer can also arise in skin that has been overexposed to UV radiation or affected by chronic inflammation and scarring [1].
Recommendations for therapeutic management are guided by the risk stratification of the primary lesion, with surgical treatment remaining the gold standard [2].
The underlying mechanism of paraneoplastic phenomena remains largely unclear. The association of bullous pemphigoid (BP) with SCC is an exceptionally rare phenomenon [3, 4]. The co-occurrence of these two entities strongly supports a paraneoplastic association.

Objective

The purpose of this paper is to present a case of bullous pemphigoid as a paraneoplastic manifestation of SCC and to review the relevant literature.

Case report

A 62-year-old man with no comorbidities was admitted to the Dermatology Department for non-pruritic erythematous and edematous lesions on the trunk (fig. 1) and the flexural surfaces of the lower limbs, which had been present for approximately 3 weeks. The lesions appeared without any identifiable external causative factor. The mucous membranes were unaffected. Prior to admission, the patient had been treated with potent topical steroids (classified as group III according to the European classification) and systemic steroid therapy (prednisone 30 mg/day), resulting in only partial improvement. During the physical examination, a 10 cm by 7 cm ulceration with bone infiltration in the frontal area was found concealed beneath the headgear (fig. 2). The patient’s medical records indicated that SCC of the intermediate histologic differentiation grade (G2) had been diagnosed at this site approximately a year earlier. The patient reported that electrosurgery procedures had been performed several times at the site.
Based on the clinical characteristics of the skin lesions, Sweet’s syndrome and erythema multiforme were suspected. A microscopic evaluation of a skin biopsy specimen from the erythematous and edematous lesion revealed normal epidermis with a mild lymphocytic inflammatory infiltrate around the intact skin appendages. Laboratory tests showed moderately elevated inflammatory parameters: C-reactive protein (CRP) at 19.6 mg/l and leukocytosis with neutrophilia. A computed tomography (CT) scan of the head found an extensive defect in the cranial bones in the frontal area, primarily on the right side, measuring approximately 45 mm × 37 mm, along with a deep defect in the right frontal squama, accompanied by thickening of the meninges up to 4 mm at the defect site (fig. 3). Imaging results showed no abnormalities in the brain or the intracranial fluid spaces. A chest X-ray and ultrasound of the abdomen and peripheral lymph nodes revealed no significant pathological findings.
A decision was made to gradually taper the dose of prednisone. The patient was promptly referred to a specialized oncology center. The CT scans conducted there showed no evidence of cancer spread. The cancer was clinically staged as cT4N0M0 according to the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (AJCC/TNM) 8^th edition classification. Based on the National Comprehensive Cancer Network (NCCN) classification, the lesion was classified as high-risk for recurrence. Since the primary tumor was surgically unresectable, treatment with intensity-modulated radiation therapy (IMRT) was commenced. During the course of radiation therapy, the disease progressed, metastasizing to the right intraparotid lymph node, with infiltration of surrounding tissues and evidence of central necrosis (fig. 4). Radiation therapy was concluded after delivering 51 Gy of the planned 54 Gy dose. The metastasis to the right intraparotid lymph node led to trismus and necessitated the placement of a gastrostomy tube for nutritional support. The subsequent anticancer therapy involved administering chemotherapy with cisplatin and 5-fluorouracil in 21-day cycles.
During the 4^th cycle of chemotherapy, the evolution of erythematous and edematous skin lesions was observed, manifesting as solitary small tense bullae filled with serous content. Nikolsky’s sign was negative.
Direct immunofluorescence (DIF) revealed microscopically linear deposits of IgG4 and C3 at the dermal-epidermal junction. The diagnosis of BP was confirmed, and topical treatment was initiated on the entire skin surface, except the face, with 0.05% clobetasol propionate cream, at a dose of 40 g/day in two divided doses.
Following the latest NCCN and EADO (European Association of Dermato-Oncology) guidelines, due to the continued progression of SCC, the patient was administered palliative radiotherapy and second-line chemotherapy with paclitaxel (fig. 5). After three cycles of treatment, the patient was lost to follow-up, preventing further monitoring of their clinical progress. Based on the NCCN and EADO guidelines, the preferred treatment for advanced inoperable SCC is cemiplimab, a monoclonal antibody targeting the programmed cell death receptor 1 (PD-1). In Poland, the treatment is covered by public reimbursement through the Drug Program B.125. Unfortunately, following the onset of active autoimmune disease, this treatment could not be implemented, as immunotherapy could aggravate the course of BP.

Discussion

Bullous pemphigoid is the most common autoimmune subepidermal blistering disorder affecting the skin and mucous membranes, primarily occurring in elderly individuals. In the pathogenesis of the disease, both cellular and humoral immune responses are involved, targeting two known autoantigens that are components of hemidesmosomes: the BP180 antigen (BPAG2) and the BP230 antigen (BPAG1).
Given the variability in the progression and clinical presentation of the disease, the DIF test remains the gold standard for diagnosis [4–6].
Since the DIF test was positive and the patient’s clinical symptoms were typical, additional immunological serological tests were not considered necessary in this particular case. The DIF technique for evaluating IgG4-associated autoimmunity in the perilesional tissue plays a key role in diagnostic process [7].
Based on the current state of knowledge, the relationship between BP and malignancies is still debated. The few case-control studies conducted to date have not provided definitive answers. A British study by Venning et al. demonstrated a significant rise in the incidence of both hematological and non-hematological malignancies in patients with BP compared to the control group (17% vs. 5.4%; OR = 3.6). However, the authors themselves questioned the results presented, citing the time gap between the diagnoses and the potential effects of the treatment used [8]. Another study conducted in England (between 1999 and 2011) found no increased risk of malignant neoplasm compared to the reference cohort (RR = 1.00, 95% CI: 0.92–1.09). However, it did reveal an elevated risk of bullous pemphigoid in subcohorts of patients with laryngeal cancer, kidney cancer, and lymphoid leukemia [9].
A Swedish study, conducted by Lindelöf et al. also ruled out an elevated risk of malignancies in individuals with BP (RR = 0.84) [10]. Conversely, a study on a German population found no link between bullous pemphigoid and non-hematologic cancers. However, it did reveal a connection with hematologic cancers, specifically Hodgkin’s disease, non-Hodgkin’s lymphomas, and myeloid leukemia [11, 12]. The literature contains only a limited number of case reports documenting the co-occurrence of BP with malignancy. Evidence suggests a link with clear cell renal cell carcinoma, melanoma, and squamous cell carcinomas of the lung, esophagus, and penis [13–17].
In the case reported here, the evolution of skin lesions culminating in the emergence of fully symptomatic BP coincided with the progression of SCC. The diagnosis of radiotherapy-induced BP was ruled out following the development of generalized bullous lesions outside the irradiated area. In their systematic review, Mul et al. documented 27 cases of BP induced by radiotherapy. The majority of cases were in female patients receiving radiation therapy for breast cancer.
A bullous reaction in the treated area developed in 89% of the cases. Most cases of BP were noted 1 year after completing radiotherapy. Four patients developed BP during radiation treatment, and 7 cases were reported immediately after the end of therapy. Only in 14.8% of cases the bullous lesions became generalized [18].
At present, several theories regarding the pathogenetic mechanisms of the paraneoplastic phenomenon associated with BP are under consideration. The prevailing theory suggests that antibodies targeting tumor-specific antigens cross-react with antigens in the basement membrane zone (BMZ), resulting in the formation of bullae [17]. It has also been hypothesized that cancer cells might produce a hormone-like substance that directly damages the BMZ, leading to the secondary production of antibodies that target it [19]. Meanwhile, research is ongoing to identify an external causative agent that has both pro-tumor effects and direct destructive effects on the BMZ [19]. It has recently been shown that the chaperone protein Hsp90 (heat shock protein 90) plays a significant role in the development of both autoimmune blistering diseases and malignant tumors [19]. More research is needed to definitively determine whether BP can be classified as a paraneoplastic dermatosis. Nevertheless, in cases of newly diagnosed BP in younger patients, the presence of warning signs in BP patients, or BP that is refractory to standard therapies, it is crucial to remain vigilant for potential underlying malignancy.

Conclusions

In the presented case, after excluding drug- and radiotherapy-induced BP, and considering the concurrent progression of BP and SCC, a paraneoplastic phenomenon cannot be dismissed.

Funding

No external funding.

Ethical approval

The patient has provided informed authorization for the publication of the photos.

Conflict of interest

The authors declare no conflict of interest.

References