Recurrence of Non-Hodgkin Lymphoma at the Insulin Injection Site: Case Report

Introduction

Lymphoma is a broad term comprising many can- cers with lymphatic origin. Although the classifica- tion of lymphoma is detailed, it is first divided into non-Hodgkin (NHL) and Hodgkin lymphoma (HL). More than 500,000 cases of NHL are diagnosed every year, making it the most common haematolog- ical cancer worldwide [1]. It constitutes 90% of all lymphomas, with the remaining 10% being HL [2]. Moreover, NHL has many histological varieties, the most common being diffuse large B cell (DLBCL), which accounts for 30% of NHL. In addition to that, variation is also seen among clinical presentations. Patients typically present with a fast-growing pain- less mass of cervical, mediastinal, or abdominal lymph nodes, thus usually presenting in advanced stages. On the other hand, one-third of patients are symptomatic for B symptoms (fever, night sweats, and weight loss) [3]. Frequently presenting in men, with an average age at presentation of 53.56 ± 17.95 years [4], DLBCL is an aggressive tu- mour that is fatal within months if left untreated; however, two-thirds of patients are curable with proper and timely treatment [5]. Over 50% of pa- tients can be cured using multi-agent chemotherapy, radiotherapy, and/or immunotherapeutic drugs, combined with or without autologous stem cell transplant. Unfortunately, despite appropriate treat- ment, relapse is fairly common, presenting in 30- 40% of patients, making it the leading cause of mor- bidity and mortality [6]. Lymphomas, or neoplasms generally, can arise from the dysregulation of the in- sulin/insulin-like growth factor (IGF) signalling pathways, and studies have shown a relationship be- tween insulin receptors and tumour development [7]. Moreover, insulin receptors and IGF-1R (recep-

tors of IGF) have a very similar sequence and struc- ture; thus the increase of both insulin and IGF have been significantly associated with the development of neoplasm [8].

Case Presentation

Our patient is a 64-year-old male, previously diag- nosed with diffuse large B-cell non-Hodgkin lym- phoma (DLBCL). He presented with pain in his up- per left arm. His medical history includes coronary bypass surgery, cholecystectomy, cataract surgery, and insulin-treated diabetes mellitus. He is an ex- smoker with a history of 53 pack-years and used to consume alcohol.

B: High proliferative index infiltration under the epithelium in the tonsil biopsy sample, MIB-1 immunohisto-

The patient was initially diagnosed with stage IIA large B-cell lymphoma in 2012, confirmed by an ex- cisional biopsy of the tongue root. Immunohisto- chemical and histomorphological findings were con- sistent with DLBCL (Figure 1). He underwent chemotherapy (R-CHOP) and adjuvant radiotherapy (IFRT—involved-field radiotherapy) in 2012 and 2013. The chemotherapy regimen included MabThera (rituximab) at 375 mg/m2, Endoxan (cy- clophosphamide) at 750 mg/m2, doxorubicin at 50 mg/m2, Oncovin (vincristine) at 1.4 mg/m2, and Mesna (uromitexan) at 750 mg/m2. After four cycles of R-CHOP, the patient achieved complete remis- sion and continued with four additional cycles of MabThera.

chemistry, DAB chromogen, magnification x200.

verse View

magnification x200.

verse View

In 2015, a F-18 PET-CT scan revealed two soft tis- sue lesions with high metabolic activity in both up- per extremities: one larger lesion on the left (22 mm, SUV max: 4.58) and a smaller lesion on the right (13 mm, SUV max: 3.57). In response, he received an- other four cycles of R-CHOP followed by two cy- cles of MabThera. In 2016, the patient reported pain in his upper left arm, leading to further investigation. An MRI of the humerus with IV contrast revealed a nodular lesion (7 mm) in the subcutaneous fatty tissue adjacent to the deltoid muscle, along with a larger irregular le- sion (34 x 26 x 17 mm) causing contour lobulation in the deltoid. Both lesions showed T1 hypo-inten- sity and significant post-contrast uptake, raising sus- picion for metastasis given the patient's history of lymphoma (Figures 2, 3, 4 and 5). A tru-cut biopsy of the left upper extremity confirmed lymphoma in- filtration consistent with DLBCL (Figure 6). In response to this recurrence, he underwent chemo- therapy and adjuvant radiotherapy (IFRT) again in 2016. The chemotherapy regimen consisted of cis- platin at 100 mg/m2 and Cytarabine (cytosine arabi- noside) at 750 mg/m2 for three cycles. Later the same year (2016), a follow-up MRI with IV contrast revealed a 3 mm-diameter nodular lesion in the subcutaneous fatty tissue adjacent to the del- toid muscle of the proximal left upper extremity. Additionally, a posterior irregularly contoured le- sion measuring 19 x 4 mm was observed in the same region. Both lesions continued to exhibit T1 hypo- intensity, with similar post-contrast findings indicat- ing potential metastatic involvement. However, compared with the MRI results from earlier that year, a marked regressive decrease was observed in the sizes of the lesions, as shown in Figures 7 and 8. Furthermore, no malignancy was detected on the right upper extremity.

Discussion

Insulin resistance, hyperglycaemia, and hyperin- sulinaemia are important components of type 2

diabetes mellitus (T2DM) that aid the development of neoplasms. Insulin/IGF signalling regulates cel- lular viability; thereby dysregulation induces neo- plasia. Insulin and insulin-like growth factor (IGF) are responsible for multiple cellular functions, in- cluding glucose metabolism, proliferation, differen- tiation, and survival. Both activate the same path- ways comprising phosphoinositide 3-kinase (PI3K) and AKT, or RAS, and MAP kinase, which conduct diverse cellular stimulations. The insulin and IGF mechanism is a complex system consisting of lig- ands, receptors, and signalling pathways. Our study emphasises the importance of considering the possi- bility of tumour progression when prescribing insu- lin or insulin-associated therapies; most importantly, the progression of lymphoma. We deduce the need to screen diabetic patients, particularly those who are prescribed insulin injections, for tumour growth, and especially lymphoma, at the injection sites. Re- cent studies have identified a connection between cancer growth and T2DM. It was ascertained that type 2 diabetes is a growing global epidemic associ- ated with an increased risk of cancer and increased cancer-related mortality [9]. Studies using diabetic non-obese mice demonstrated the link between dia- betes and the development and metastasis of tu- mours dependent on insulin and insulin growth fac- tor-1 (IGF-1) [10-11]. Moreover, T2DM predis- poses individuals to tumour growth; adding to this the use of insulin increases the risk of lymphoma, as seen in the case of our patient. Investigations into insulin receptors (IRs) have substantiated a relation- ship between IRs and tumour development, where IGF-1R is also involved in neoplasm genesis. Ele- vated IR expression was established in human breast cancer compared with normal breast tissue [12], and different studies have demonstrated that IRs are ex- aggerated in thyroid, colon, and ovarian malignan- cies [13-15]. Investigations into these kinds of hu- man adenocarcinoma showed raised numbers of IRs on the endothelial cells, establishing an association between surplus IR and angiogenesis. Furthermore,

in-vitro angiogenesis experiments that tested spe- cific commercially valid insulin products demon- strated that insulin has the potential to enhance the capillary-like tube manufacture of human microvas- cular endothelial cells; thus, IR overexpression is as- sociated with angiogenesis and may be the main driving factor for the development of tumours in cer- tain types of adenocarcinoma where IR was also concurrently increased. It is important to clarify that, while previous studies have indicated that metastatic disease or tumour growth can arise from mecha- nisms such as chronic inflammation due to repetitive administration of subcutaneous injections at a spe- cific site [16], we hypothesise that the similarity be- tween insulin and IGF pathways may also play a role. Specifically, this similarity could contribute to the upregulation of IRs and enhanced angiogenesis in the cells of the upper extremities, where our pa- tient administered insulin. This interaction may have facilitated the development of lymphoma in these re- gions. Through this case report, we wish to highlight the importance of screening for diabetes mellitus pa- tients, particularly those undergoing insulin therapy, due to the potential risk of developing tumours such as lymphoma. Furthermore, existing literature sug- gests that insulin resistance is a significant risk fac- tor for poor prognosis in patients with DLBCL.