Analysis of a case of pilomatricoma in an adolescent after receiving recombinant hepatitis B vaccine (CHO cell) in Beijing of China

ABSTRACT

We report and analyze a case of pilomatricoma in an adolescent after receiving recombinant hepatitis B vaccine (CHO cell) in Chaoyang District of Beijing and to evaluate the causality between the disease and vaccination. Based on the professional branch of this case, we organized a seminar and we invited specialists in vaccinology, epidemiology, dermatology, infectiology, and immunology to participate in the conference. Specialists evaluated the relevance and causality between the vaccination and disease. The clinical diagnosis of the adolescent was pilomatricoma after receiving recombinant hepatitis B vaccine (CHO cell) which could not be disregarded as an adverse reaction following immunization. Although rare, there is a possibility of developing pilomatricoma after vaccination. This suggests that the implementation process of vaccination should be standardized and that the injection site after vaccination should be nursed properly.

Introduction

Calcifying epithelioma, also known as pilomatricoma, is a benign skin neoplasm that arises from hair follicle matrix cells. It undergoes a slow, long-term process to form a cutaneous or subcutaneous mass.^1–4 It usually occurs in the head, neck, and upper extremities.⁵ Pilomatricoma occurs predominantly in children and adolescents, with another small peak occurrence in those aged 50–70 years.^5,6 It is more common in women.⁶ Duflo’s study revealed that approximately 20% of cases were accompanied by pain and inflammation.⁷

Recombinant hepatitis B vaccine (CHO cell) is created from hepatitis B virus surface antigen expressed by recombinant CHO cells purified and supplemented with aluminum hydroxide-based adjuvants. The common adverse reactions monitored in clinical application mainly include pain, redness, swelling, and induration at the inoculation site; transient fever after inoculation; and allergic rash. The instructions also mention a rare Arthus reaction and anaphylactic shock, which have not been monitored during clinical application before.

This study aimed to report a case of pilomatricoma in an adolescent after inoculation with recombinant hepatitis B vaccine (CHO cell), which is the first one monitored after vaccination during our clinical application; analyze its occurrence and development process, the possible mechanism of pathogenesis, and the characteristics of vaccination, and then to determine the causal relationship between the case and vaccination.

Materials and methods

Basic information of the case

The female child was 13 years old at the time of vaccination and a first-grade junior high school student. The child’s guardian denied the child’s history of major diseases, allergies, and a family history of hereditary diseases. The child was vaccinated according to the immunization program before, and no adverse reactions were found.

Vaccines and vaccination implementation process

The child was simultaneously vaccinated with one dose of recombinant hepatitis B vaccine (CHO cell) and one dose of the influenza virus split vaccine at 10:04 on September 16, 2022, at a community health center in Chaoyang District, Beijing.

Recombinant hepatitis B vaccine (CHO cell) was manufactured by North China Pharmaceutical Jintan Biotechnology Co., Ltd., the batch number was 202104XC06, and the dose was 0.5 ml containing 10 μg hepatitis B virus surface antigen. Influenza virus split vaccine was manufactured by Beijing Sinovac Biological Products Co., Ltd., the batch number was T202206013, and the dose was 0.5 ml containing 15 μg A/Victoria/4897/2022 (H1N1) pdm09-like virus, 15 μg A/Darwin/9/2021 (H3N2)-like virus, and 15 μg B/Austria/1359417/2021 (B/Victoria lineage)-like virus. The certificate of vaccine approval and issuance was complete, and the vaccine was requested from the Beijing CDC Inventory System and delivered by a logistics company.

The recombinant hepatitis B vaccine (CHO cell) was administered intramuscularly in the deltoid muscle of the right upper arm. The influenza virus split vaccine was administered intramuscularly in the deltoid muscle of the left upper arm. The vaccination process was standardized.

Disease occurrence, diagnosis, and treatment

The child was observed for 30 min after vaccination, and no adverse reactions were detected. The guardian stated that the child’s right upper arm injection site was painful after inoculation, which lasted for several days, and it was also swollen. In March 2023, the child complained of pain again, and the swelling was more obvious. The child was brought to the hospital on April 2 for physical examination: there was a mass at the right upper arm, which was approximately 0.5 cm in size, hard, and painful; Then the mass progressively increased to 2.0 × 1.5 × 1.0 cm, with ulceration on the surface (Figure 1). On May 16, the soft tissue ultrasonography of the right shoulder arm revealed a subcutaneous nodule at the right upper arm, which was filled with contents and localized with calcification, and the surrounding fat was swollen. It was suspected to be a pilomatricoma in the right upper arm.

Figure 1.

A mass on the right upper arm, which was 2.0 × 1.5 × 1.0 cm and hard, with ulceration on the surface.

On July 7, after anesthesia was administered, a longitudinal incision was made over the mass, and the mass was visible subcutaneously, which was 2.0 × 2.0 × 1.0 cm, with an attached membrane. The membrane was thin and hard, and there was a white bean dregs-like material inside. The mass was completely excised, and the skin flaps were sutured intradermally. The child was discharged from the hospital on the same day. Intraoperative pathology was performed, and the pathological diagnosis was: pilomatricoma of the right upper arm.

Results

Organization of expert investigation and diagnosis of adverse events following immunization

According to the request of the guardian of the child, to determine the causal relationship between the pilomatricoma on the right upper arm of the child and vaccination, doctors in Chaoyang CDC verified and investigated the case. According to the professional disciplines to which the case belonged, the experts in vaccinology, epidemiology, dermatology, infectiology, and immunology investigated and diagnosed the case.

On December 20, 2023, doctors in Chaoyang CDC organized the investigation and diagnostic meeting. According to the “Vaccine Administration Law of the People’s Republic of China,” administrative regulations, technical specifications, and evidence-based medicine, combined with the clinical manifestations of the case (pathogenetic process, diagnosis, and treatment), the results of the medical examination/test, and the characteristics of the vaccine, experts reached a consensus after comprehensive evaluation, analysis, and full discussion.

Diagnostic conclusion

The clinical diagnosis of the disease following vaccination with recombinant hepatitis B vaccine (CHO cell) in the right upper arm of the child was pilomatricoma. In addition, the relationship between the pilomatricoma and vaccination could not be disregarded.

Discussion

Pilomatricoma can develop alone or may be associated with other conditions such as Steinert disease, Gardner syndrome, Turner syndrome, Sotos syndrome, 21 Rubinstein-Taybi syndrome, medullary thyroid carcinoma, and nodular disease.⁸

The exact etiology of pilomatricoma is unknown.

Genetic factors and gene mutations have been reported to be associated with the development of pilomatricoma.^9,10 Mutation in beta-catenin protein (CTNNB1 genes), a downstream effector of the Wnt signaling pathway that influences multiple cellular processes, including hair follicle differentiation, exists in 26%–100% of pilomatricoma cases.^9,10 In addition, the presence of high expression of B-cell lymphoma 2 proto-oncogene is associated with the activation of neoplastic cell proliferation.²

Infection and persistent inflammation can also be associated with the development of pilomatricoma.⁹ Pirouzmanesh’s research indicated that microscopic examination revealed that inflammation exists in 40.8% of pilomatricoma cases.⁹

Mechanical injuries such as trauma, insect bites, or surgery have also been found to be important influences in the development of pilomatricoma, which are present in 3.9% of pilomatricoma cases.^6,8,11–13 Mechanical injury can potentially disrupt dermal integrity and the vascular microenvironment, which can lead to pilomatricoma.¹²

It has been reported that pilomatricoma found at inoculation scars may be caused by trauma, persistent inflammation, or inoculation biologics.^3,5,14,15 On the one hand, needle injury may cause pilomatricoma by preventing apoptosis of damaged follicular epithelial cells.^11,15 On the other hand, the foreign body reactions induced by needles during vaccination may lead to local immune disorder and the formation of immunocompromised areas, which may cause tumor occurrence when immune surveillance ability is low.¹⁶ The case reported in this article exhibited inflammatory reactions such as pain and swelling during the initial period after vaccination; then, the inflammation gradually subsided, the pain and swelling diminished, and a hard nodule gradually formed. In addition, there was a clear diagnosis of infection during the medical procedure. These all support the role of inflammation as a facilitator in the development of pilomatricoma. This is also consistent with the findings of three other studies.^3,4,16

Studies have found that some adjuvants in vaccines can induce inflammatory responses.³ The case reported in this article received one dose of influenza virus split vaccine and one dose of recombinant hepatitis B vaccine (CHO cell) simultaneously in the left and right arms. Then, pilomatricoma occurred at the injection site in the right arm, but not in the left arm, which may be related to the aluminum hydroxide-based adjuvants in the recombinant hepatitis B vaccine (CHO cell). In addition, adjuvants in vaccines (as foreign bodies, like needles during vaccination) may cause local immune dysregulation, which in some cases can lead to the development of tumors.¹⁷

In addition to the external factors analyzed previously, it is considered that this case may also be caused by individual factors of the recipient, such as mutation of CTNNB1 genes and/or high expression of B-cell lymphoma 2 proto-oncogene mentioned earlier. However, it is not yet possible to clarify the genetic background of this case as no genetic testing was performed during the medical procedure.

Based on the analysis of this case, it is recommended that in future vaccination, the skin disinfection of the injection site should be improved, the site and depth of vaccination should be strictly recognized, and adequate pressure should be applied to stop bleeding after vaccination. After vaccination, recipients should take good care of the injection site and minimize scratching to avoid mechanical damage. For cases with varying degrees of inflammation (such as redness, swelling, pain, and ulceration at the injection site just after vaccination) that then turned into chronic lesions, they should be suspected of suffering from the disease. In addition, timely medical treatment should be sought when discomfort occurs.

The case suggests that while promoting vaccination and protecting public health, monitoring, analysis, research, and early warning of post-vaccination adverse reactions should be further strengthened. Comparison and assessment of trends in the level of common adverse reactions over the years and detection and identification of rare adverse reactions facilitate early detection and timely treatment of post-vaccination adverse reactions, enhance public confidence in vaccination, and create a favorable social environment for vaccination.

Conclusions

Although rare, there is a possibility of developing pilomatricoma after vaccination.

Biographies

Shuping Li, Master of Public Health, is the Chief Physician of Preventive Medicine. Li has been engaged in the prevention and control of infectious diseases and has developed programs on immunization for more than 30 years. Li’s main research fields are the clinical evaluation of vaccines and management of adverse reactions to vaccines. Li has presided over and participated in more than 10 clinical trials of vaccines; has published nearly 20 papers, one of which won the Third Prize in the academic paper of Chaoyang District Science and Technology Association; and has educated eight master and undergraduate students.

Li Li, Jingyi Xu, Jianlin Cai and Zhen Li have been committed to the evaluation of vaccines for more than 10 years, and have carried out nearly 50 clinical trials of vaccines phased I-IV.

Dongkun Zhang and Xiaohui Zhang have been engaged in children’s preventive vaccination for more than 20 years.

Funding Statement

The author(s) reported that there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

All authors were involved in the analysis of the case, subsequently assisted in the writing and review, and approved the final version of the manuscript.

Abbreviations

CHO

chinese hamster ovary