Paraneoplastic urticaria in the course of gastric cancer

Introduction

Paraneoplastic syndromes are a group of clinical symptoms associated with malignant tumors which are not a direct consequence of local infiltrative lesions or metastases. They occur in about 5–10% of patients, and their frequency depends on the type of cancer and stage [1]. They are caused by various biologically active substances produced by tumor cells (peptides, amines, cytokines). They can also arise as a result of autoimmunity or immune cross-reactivity between the tumor and normal tissues [2]. Chronic spontaneous urticaria (CSU) is characterized by recurrent skin lesions such as wheals, spots, pruritus, erythema and/or angioedema for more than 6 weeks. Symptoms are most often associated with autoimmune diseases. The etiopathogenesis of paraneoplastic urticaria is not precisely known.

Objective

To present the case of paraneoplastic syndrome in the form of urticaria in the course of gastric cancer.

Case report

A 61-year-old patient presented to his doctor in October 2020 because of chronic urticaria occurring all over the body for a few weeks. The skin lesions regularly appeared in the middle of the night and subsided in the morning (figs. 1, 2). The lesions were accompanied by intractable pruritus, rated by the patient on the Numerical Rating Scale (NRS) at 10 points. The patient denied previous allergic incidents including urticaria and other autoimmune diseases. He had a history of nicotinism, type 2 diabetes mellitus, and more than 40 years of exposure to occupation-related harmful substances (professional locksmith). There were no other medical symptoms suggestive of gastrointestinal cancer, i.e., weight loss, gastrointestinal problems, chronic fatigue, anemia.
There were no abnormalities on routine hematological, biochemical, parasitological and endocrinological tests. When the patient received antihistamines, a temporary reduction of the lesions and pruritus was seen, but there was no complete, permanent remission of symptoms. In addition, it was recommended to implement at least a 3-week diet free of substances that induce mast cell degranulation.
Due to the lack of improvement, diagnosis for malignancy was implemented. In March 2021, an esophagogastroduodenoscopy was performed, which showed an irregular ulceration of about 2 cm with exuberant edges in the lower part of the gastric body. Histopathological examination showed features of poorly cohesive carcinoma. An abdominal computed tomography (CT) scan showed a gastric body lesion along the greater curvature of a homogeneous thickness of up to 20 mm. A TNM classification diagnosis was made: cT3NXM0.
The patient was qualified for perioperative chemotherapy which was started with the FLOT regimen (docetaxel 50 mg/m², oxaliplatin 88 mg/m², leucovorin 200 mg/m² and 5-FU 2600 mg/m² in 24-hour infusion) for 4 cycles from 10 June 2021 to 22 July 2021. Subsequently, subtotal distal gastrectomy (Billroth II) was performed on 11 August 2021. Histopathological postoperative examination identified partially mucinous adenocarcinoma (G3). The tumor infiltrated the mucosa and submucosa, without features of angioinvasion and neuroinvasion. A TNM classification diagnosis was established: yT1b, N0. The surgery was followed by another 4 cycles of postoperative chemotherapy in the FLOT regimen from 13 September 2021 to 15 November 2021. Since then, the patient has been under regular follow-up with the Oncology Outpatient Clinic. After starting chemotherapy, there was a significant reduction in skin symptoms, and after surgery the urticaria resolved completely (fig. 3).

Discussion

The clinical case presented above shows an extremely rare and unusual case of chronic urticaria as a paraneoplastic syndrome in gastric cancer. Chronic urticaria is defined as an inflammatory reaction involving the epidermis and dermis in the nature of wheals (and/or angioedema) that recur most days of the week over a period of at least 6 weeks. Pathognomonic symptoms of urticaria include pruritus, erythema and blisters of less than 24 hours’ duration [3]. A classification of this condition includes chronic spontaneous and induced urticaria (symptomatic dermographism, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory urticaria, cholinergic urticaria, water urticaria) [4]. CSU accounts for about 80% of all cases. The pathogenesis is multifactorial and heterogeneous. It consists of immunological and non-immunological mechanisms, causing mast cell degranulation and release of inflammatory mediators, i.e. histamine, prostaglandins, platelet activating factor (PAF), cytokines or chemokines. These mechanisms lead to stimulation of sensory nerves, vasodilation and increased vascular permeability, escape of plasma and cells into the extravascular space, resulting in urticarial wheals in the dermis or angioedema involving the lower layers of the dermis and subcutaneous tissue [3].
The association between the occurrence of chronic urticaria and malignancy is ambiguous. A study conducted by Chen et al. [5] to examine the relative risk of cancer among patients with chronic urticaria in the Taiwanese population included 12720 patients with CSU, on long-term treatment with antihistamines, with no history of malignancy, autoimmune disease, atopy or allergic disease. Among these patients, 704 were found to have malignancies, as well as an increased risk of malignancies, especially hematologic malignancies. In another study by Larenas-Linnemann et al. [6], there were 26 case reports in which the onset of CSU was associated with malignancy. The development of chronic urticaria preceded the diagnosis of cancer by several months, and resolution of the skin lesions followed chemotherapy and/or surgical treatment of the cancer. With reference to the above studies, the possibility of a correlation between the development of CSU and malignant neoplasm can be inferred.
Urticaria is not specifically categorized as a paraneoplastic dermatosis; however, rare cases have been described suggesting its appearance in association with cancers such as leukemia, lymphoma, ovarian cancer, colorectal cancer, papillary thyroid cancer, brain tumor or mucinous breast cancer [7] whereas the occurrence of urticaria as a paraneoplastic syndrome in gastric cancer has not been documented. Although in descriptions of several clinical situations of the appearance of urticaria correlating with mucinous carcinoma, there are numerous similarities to the case described in this article. The course of cancer was often asymptomatic, and chronic urticaria was the only symptom of the disease. The results of hematological tests, skin or allergy tests were normal, and antihistamine treatment was also ineffective and did not lead to resolution of the skin lesions. Only removal of the malignant tumour as in the above case resulted in resolution of the urticarial wheals and accompanying pruritus.
Cutaneous paraneoplastic syndromes occurring with greater frequency in gastric cancer include acanthosis nigricans, Leser-Trelat sign, dermatomyositis or tripe palms syndrome. The existence of more than 20 different cutaneous paraneoplastic symptoms has been documented, which can be the first symptom of gastric malignancy [8] and, with adequate clinical vigilance, be the basis for implementing oncologic differential diagnosis.

Conclusions

The presented clinical case describes the relationship between chronic urticaria and gastric cancer. A description of an identical clinical case has not been found in the literature. CSU is not classified as a typical example of the paraneoplastic syndrome, although the described case shows a clear correlation between the symptoms presented by the patient and the development of gastric cancer. Dermatoses, including urticaria, can be the early signs of cancer. Oncological vigilance, early implementation of differential diagnosis and causative treatment can improve the prognosis of patients.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References