RB, first reported by Russell[2] in 1890, is an eosinophilic corpuscle formed by the disturbed secretion and accumulation of immunoglobulins (IGs) within the swollen rough endoplasmic reticulum. Plasma cells containing RBs are known as Mott cells. RBG was first described by Tazawa and Tsutsumi[1] in 1998 as microscopic chronic inflammatory changes dominated by massive Mott cell infiltration in the lamina propria of the gastric mucosa. With increased recognition and reporting of this disease, RBs have been found to occur in almost the entire digestive tract. We have presented an overview of RBIDT in this study to understand the phenomenon better.
1.Relevant literature search
The Pubmed database was searched for literature using the search term "Russell body", and case reports of inflammatory lesions in the gastrointestinal tract of RB were used as inclusion criteria, resulting in 51 articles from 1998 to the present, plus 76 cases in this case.
2. Analysis of clinicopathological features
2.1 Prevalent population and site: There were 76 cases of RBIDT, which occurred in middle-aged and elderly males, with a wide range of age (18-88 years) and a mean age of 63 years, 1.71 times more males than females (48/28). 5 of the 76 cases were in the oesophagus, 56 in the stomach, 9 in the duodenum, 1 in the cecum, 2 in the sigmoid colon, 1 in the rectum and 2 in multifocal. (Figure 6)
2.2 Clinical symptoms and endoscopic findings
Patients mostly present with non-specific gastrointestinal symptoms (abdominal pain, dyspepsia and nausea) or may be asymptomatic and found incidentally on physical examination. Endoscopic features are also non-specific, such as mucosal erythema, whitening, oedema, erosions and ulcers, sometimes as raised nodules.
2.3 Russell body Barrett's esophagus (RBBE) (Table 1)
Five cases, all male, with Barrett's esophagus as the underlying disease and one case occurring in Barrett's esophagus and cardia gastric mucosa, so it can be assumed that the disease only occurs in the lamina propria of the overlying columnar epithelium, and that there may be Candida infection in the esophagus, but no HP infection was reported, so it was not considered to be HP-related.
2.4 Russell body duodenitis(RBD) (Table 2)
Nine cases, five men and four women, two with HP infection and three with Mott cells exhibiting a monoclonal immunophenotype. Patients may have chronic enteritis, colonic polyps and immune dysfunctional diseases such as autoimmune diseases, HIV and uroepithelial carcinoma.
2.5 Russell body coloproctitis(RBCR) (Table 3)
Six cases, four males and two females, occurring in the cecum, sigmoid colon, rectum or multiple sites; Mott cell manifestations 2 monoclonal λ-chain immunophenotypes and 1 monoclonal κ-chain immunophenotype, patients with underlying disease similar to RB duodenitis, may have inflammation, polyps and immune dysfunctional disease (diabetes, organ transplantation, NSAID drugs, etc.).
2.6 RBG (Table 4)
RBG is the most common type of RBIDT. A total of 56 cases (male: female = 1.6:1 [34/22]; average age, 62 years) were included in this study; of which, 66% (37) had HP infection. In addition, 13 Mott cells exhibited a monoclonal κ-chain immunophenotype.
In this study, RBG was categorised as HP-positive and HP-negative based on the presence or absence of HP infection.
2.6.1 HP-positive RBG: 37 cases, accounting for 67% of total RBGs, with a male-to-female ratio of 1.5:1 (22/15). Mott cells exhibited a monoclonal κ-chain immunophenotype in only nine cases. At least one-third of the patients with HP-positive RBG reported regression of gastritis after eradication of HP. Therefore, an aetiological association was considered between HP infection and RBG. Specifically, surface antigens of HP stimulate the endoplasmic reticulum of plasma cells to produce excessive amounts of IGs or lead to under-secretion of the Golgi apparatus through certain pathways, resulting in intracellular aggregation of abnormal IGs to form RBs[3]. Umakoshi et al[4] reported a case of multifocal RBG with hepatitis C and HP infection, in which a decreasing number of Mott cells was observed from the mucosa to the submucosa in the ESD specimen. The study attributed this phenomenon to the maturation of plasma cells in the immune system of the gastric mucosa and the IgA secretion features. The overall features included the migration of plasma cell precursors into the lamina propria to mature into plasma cells and the secretion of secretory IgA (S-IgA) into the lumen via the gastric mucosa epithelial cells. Therefore, the formation of RBs may be related to a dysregulation in the IgA secretion mechanism in plasma cells.
2.6.2 HP-negative RBG:18 patients, accounting for 33% of the total cases, with a male-to-female ratio of 1.4:1 (11/7), Mott cells exhibited a monoclonal κ-chain immunophenotype in four cases. HP-negative RBG was first reported in patients with HIV, hepatitis C and multiple osteomyelitis; therefore, it was considered to be associated with abnormalities in the immune function. With an increase in the number of reported cases, HP-negative RBG has also been identified in patients with intestinal tubular adenoma and chronic gastritis (Figure 7). Given the paucity of the follow-up data, the aetiology and mechanisms of progression of RBG have not yet been described clearly and reliably. Peruhova et al[5] considered RBG an unstable and dynamic morphological finding that progresses in plasma cell-rich chronic gastritis. Factors contributing to RB formation extend beyond HP infection and may include local degenerative and vascular circulatory phenomena. Some patients with HP-negative RBG demonstrate progressive regression of gastritis with PPI therapy, which may be a viable option for the treatment of the condition.
2.7 Immunophenotype
RBIDT was divided into polyclonal (positive for both κ and λ chains) and monoclonal (negative for either κ or λ chains) phenotypes based on the expression of the κ and λ chains in Mott cell IGs. The polyclonal phenotype was predominant, whereas the monoclonal phenotype accounted for 25% of the cases (19/76, 16 and three patients with monoclonal κ and λ chains, respectively). Ten patients with the monoclonal phenotype with HP infection had hepatitis C, SLE, rheumatoid arthritis, chronic gastritis and intestinal tubular adenoma without neoplastic lesions. Two of the monoclonal λ chains occurred in the duodenum and sigmoid colon with intestinal polyps.
Traditionally, the polyclonal expression of IGs by B cells was considered one of the indicators to exclude neoplastic lesions, whereas a monoclonal phenotype implied a malignant lesion. There is now a consensus among most scholars that monoclonal hyperplasia of B cells is not a sufficient condition to diagnose malignancy and does not necessarily imply progression to lymphoma, which is considered a focal and non-progressive lesion. In addition, B cells demonstrate monoclonal hyperplasia in certain chronic inflammatory lesions (lymphocytic thyroiditis, chronic hepatitis C, and HP-infected chronic active gastritis) and sicca syndrome and do not subsequently transform into lymphoma. The IG light chain of Mott cells is expressed restrictively in nearly a quarter of cases of RBIDT. Araki et al[6] stated that it is unreasonable for pathologists to rely solely on the restricted expression of IG light chains in immunohistochemical analysis to diagnose neoplastic lesions. The study reported that the monoclonal hyperplasia of Mott cells in RBG was caused by an inflammatory response, which is consistent with the restricted light chain expression in patients with HP-infected chronic active gastritis. Coyne et al[7] stated that such a restricted expression is associated with abnormal accumulation of IGs in plasma cells. However, Wolkersdörfer et al[8] attributed the phenomenon to a mutation in the gene that expresses IGs. Currently, 11 of the 19 cases of monoclonal hyperplasia are from China, 3 from Japan, 2 from the UK and 1 each from the USA, Australia and Switzerland. Considering that the monoclonal phenotypes were commonly identified in China and Japan, Zhang et al[9] attributed the occurrence to geographical and ethnic differences. In fact, the case in this study is the first Chinese polyclonal phenotype of RBG.
2.8 Aetiology, Pathogenesis and Co-morbidities
The aetiological mechanism of RBIDT remains controversial. Reduction or even regression in the density of RBs has been observed after anti-HP treatment in some patients. In addition, Soltermann et al[10] identified increased production of RBs in the gastric antrum by HP of the vacA m1 genotype (e.g. in the present case, after 1 week of anti-HP treatment, a gastroscopic biopsy revealed significant regression of RBs in the lamina propria of the mucosa). Based on the aforementioned observations, RBs can be considered to be closely associated with HP infection and irritation. According to statistical data, HP infection is chiefly associated with RBG, whereas patients with RB oesophago-enteritis are hardly infected, and one-third of the patients with RBG are not infected with HP. Therefore, considering HP infection as the cause of all cases of RBIDT is one-sided. Approximately half of all the reported cases of RBIDT (Figure 8) are accompanied by chronic gastritis and tubular adenomas of the digestive tract, and some patients suffer from peptic ulcers, hypertension, hyperlipidaemia and diabetes mellitus. The common denominator of these diseases is a local vascular inflammatory response and haemodynamic abnormalities. In this regard, HP infection belongs to the category of inflammatory response. However, some patients may have HIV infection, cirrhosis, malignancies (gastric cancer and gastrointestinal stromal sarcomas), immune system-related diseases (rheumatoid arthritis, SLE, among others) and diabetes or may have undergone organ transplantation. The common denominator in the pathology of these conditions is immune dysregulation. Therefore, the aetiology of RBIDT includes an inflammatory response and haemodynamic abnormalities in the local blood vessels or immune dysfunction. The aetiology of the patient in this study was a local inflammatory response caused by irritable bowel syndrome and HP infection.
3 . Differential Diagnosis
Diseases that should be differentiated from RBIDT include SRC of the digestive tract, lymphohaematopoietic tumours accompanied by plasma cell differentiation and extramedullary plasmacytomas.
At low magnification, Mott cells appear similar to mimics signet ring cells, which is associated with a high possibility of misdiagnosis as SRC. However, the nuclei of Mott cells are not allotypic or pathologically divided under high magnification, and the cytoplasm is generally eosinophilic. Bozhkova et al[11] reported that most AB-PAS are positive in RBs, which is beneficial in their identification. However, PAS is also expressed in SRC; therefore, identifying the two is not helpful. Notably, SRC CK positivity can differentiate between the two conditions. Lymphohaematopoietic tumours accompanied by plasma cell differentiation are identified based on medical history, laboratory examination, histomorphology and specific immunophenotype. Extramedullary plasmacytomas are the most difficult to differentiate from monoclonal hyperplastic RBIDT owing to the lack of early evidence of bone marrow and serological involvement and Bence-Jones albuminuria, which may be accompanied by RB formation. Considering that some chronic inflammatory conditions can demonstrate monoclonal hyperplasia but do not transform into lymphoma at a later stage (including monoclonal expression in one-fourth of the cases of RBIDT), the restricted expression of B-cell IGs is of little significance in the differentiation between the two conditions. Consequently, gastroscopy findings, nuclear atypia and mitotic activity of the pathological cells and biological behaviour should be considered for a comprehensive assessment. Close follow-up is recommended in cases where the nature of the disease cannot be determined.
In the present case, the cytoplasm of the mimics signet ring cells demonstrated mucus-like basophilic rather than eosinophilic nature, which was different from that reported in previous studies. Initially, this phenomenon was hypothesised to be a pseudo-basophilic result of abnormal fixation and handling of the biopsy tissue. However, microscopic observation of the section revealed that the fibrous connective tissue adjacent to the mimics signet ring cells and the red blood cells in the lumen of the microvasculature were eosinophilic, thereby negating this hypothesis. In the present case, PAS and D-PAS special staining were performed to stain the mucogenic granules in the cytoplasm of the surface mucus of the normal mucosal epithelium to a purplish red colour. In this case, the non-staining of mimics signet ring cells indicated the absence of glycogen and neutral mucus in the cytoplasm. In addition, this phenomenon confirmed the basophilic nature of the cytoplasm of the mimics signet ring cells in this case rather than the commonly observed eosinophilic nature in most RBs, which led to the initial misdiagnosis of SRC. However, gastroscopy only revealed white mucosa and mild erosion, and the clinical symptoms were mild, neither of which supported the possibility of malignancy. Therefore, immunohistochemical analysis was performed. Overall, negative CK excluded the possibility of SRC, strong positivity for CD79a and CD138 suggested a plasma cell origin, negative CEA, CK20, ALk and cyclin D1 indicated the absence of other malignancies and Ki-67 (approximately 1% +) suggested a low proliferation index. Three lymphoid follicular dendritic networks were observed around the CD21 mimics signet ring cells, comprising cell clusters with high positive rates of Ki-67, CD10 and Bc1-6 (approximately 30%–60%, 10%–30% and 40%–70%, respectively), indicating the presence of germinal centres and good biological behaviour. Furthermore, there was no restrictive expression of κ or λ, and molecular investigations revealed polyclonal rearrangement of B cells. Malignant lesions such as MALT lymphoma and plasmacytoma accompanied by plasma cell differentiation could be excluded, given that no abnormalities were detected on serology or bone marrow examination. After 1 week of anti-HP treatment, endoscopy performed during the follow-up revealed regression of Mott cells. The patient was followed up closely for 10 months without recurrence. Therefore, this patient was diagnosed with RBG accompanied by polyclonal plasma cell hyperplasia and basophilic RBs.
4. Treatment and Prognosis
Despite the reported association of autoimmune diseases and EBV-associated gastric cancer with RBIDT, HP infects approximately two-thirds of the patients with RBG, and at least one-third of the patients with HP-positive RBG demonstrate regression of gastritis after eradication of HP. In addition, gastritis has been reported to resolve gradually after PPI treatment in patients with HP-negative RBG. Therefore, it is reasonable to consider it an incidental benign finding. In other words, eradication of the bacteria is essential in patients with HP infection. Moreover, symptomatic treatment with PPI is sufficient for patients without HP infection, and there is no requirement for overtreatment. However, appropriate follow-up and subsequent gastroscopy are essential.