CSH is a rare disease, which is characterized by a large number of histiocytes and the aggregation of immunoglobulin crystals in the cytoplasm. The name CSH is descriptive and sounds innocuous, but up to 90% of cases are associated with an underlying lymphoproliferative or plasma cell diseases, such as multiple myeloma, lymphoplasmacytic lymphoma or monoclonal gammaglobulinemia of unknown significance (1, 3, 4). In other words, CSH is an under-recognized paraneoplastic phenomenon and knowledge of CSH may help to detect hidden malignancies. If CSH is so subtle, it can be ignored, while extensive CSH can mask the accompanying lymphoma.
One hundred seventy cases of CSH were identified through a PubMed search of the literature to date. CSH in the stomach is extremely rare. To date, 17 cases of gastric CSH (including the present case) have been described in English literature (4–13). The detailed clinical and pathological findings of these patients are summarized in Table 1. The 17 patients reported included 10 men and 7 women with a mean age 56 years at the time of diagnosis (range, 35 to 86 years). There were two generalized (11.8%) and 15 localized (88.2%) forms. Among them, 9 patients (52.9%) were associated with or secondary to lymphoplasmacytoma: 4 MALT lymphoma with kappa restriction, 1 mantle cell lymphoma with lambda restriction, 2 diffuse large B cell lymphoma with kappa restriction, 1 multiple myeloma with lambda restriction and 1 metachronous thymic lymphoma. Five patients (31.2%) had no related diseases other than Helicobacter pylori infection. During the follow-up, only four patients with Helicobacter pylori infection had no other gastric lesions or symptoms (7–9). Compared with other organs, gastric CSH is mainly localized, and about half of the cases have nothing to do with clonal lymphoproliferative diseases. On the contrary, they are often associated with Helicobacter pylori-associated gastritis. However, in the process of reading the literature, I found that one report involved three cases (7), and their morphology was indeed very similar to that of CSH. However, one case of IHC showed CD68 negative, while CD20 and CD79a were all positive. Moreover, the patients were all positive for HP, only had anti-inflammatory treatment, and there were no other diseases in the follow-up. We just only speculate that the exact diagnosis of this case may be Russell body gastritis, but need further discussion.
Table 1
Clinical and pathological findings of previously published cases of gastric crystal-storing histiocytosis in the English literature.
| Year | Study | Sex/Age (yr) | Endoscopic finding | Helicobacter polori infection | Associated neoplasm | Ig light chain | Follow up |
| 1999 | Jones et al.(5) | F/35 | NS | NS | Thymic lymphoma | Polyclonal | Persist |
| 2006 | Stewart et al.(7) | M/82 | Gastritis | Yes | No | Lambda | Died of unrelated cause |
| 2006 | Stewart et al. (7) | M/81 | Gastritis | Yes | No | Insufficient | No symptoms or lesion |
| 2006 | Stewart et al.(7) | F/52 | Erosion | Yes | No | Lambda | No symptoms or lesion |
| 2007 | Joo et al.(8) | F/56 | Polyps | Yes | No | Polyclonal | No residual lesion |
| 2013 | Yano et al.(9) | F/55 | Discoloration with granularity | Yes | No | Polyclonal | Alive without disease |
| 2014 | Vaid et al.(10) | M/NS | Discolored patch | NS | No | Kappa | No |
| 2016 | Kanagal-Shamanna et al.(4) | M/43 | Nodule | NS | MALT lymphoma | Kappa | Alive without disease |
| 2016 | Kanagal-Shamanna et al.(4) | M/51 | NS | NS | Multiple myeloma | Lambda | No |
| 2018 | Arnold et al.(6) | NSa | Discoloration with granularity | Yes | MALT lymphoma | Kappa | Persist |
| 2018 | Arnold et al.(6) | NSa | Discoloration with granularity | Yes | MALT lymphoma | Kappa | Persist |
| 2018 | Arnold et al.(6) | NSa | Malignant-appearing mass | No | Mantle cell lymphoma | Lambda | Died of lymphoma |
| 2018 | Arnold et al.(6) | NSa | Malignant-appearing mass | No | DLBCL | Kappa | Died of lymphoma |
| 2018 | Fujita et al.(12) | 72/F | diffuse granular mucosa | No | No | Kappa | Alive without disease |
| 2020 | Jooet al.(11) | M/79 | Ulcer, flat nodularity | No | MALT lymphoma | Kappa | No |
| 2021 | Bansal et al.(13) | M/86 | Forrest IIB gastric ulcer | Yes | DLBCL | Lambda | Persist |
| 2022 | Present case | M/69 | irregular whitish focus | No | No | Kappa | No symptoms or lesion |
| F, female; NS, not stated; M, male; MALT, mucosa-associated lymphoid tissue; DLBCL, diffuse large B cell lymphoma. aIncluding 2 females and 2 males with age range from 56 to 82. |
The most important thing about CSH of the stomach is that it needs to be differentiated from Russell body gastritis (RBG), which can also observe similar pathological changes. RBG is another rare entity characterized by abnormal immunoglobulin deposition in the stomach, which is closely related to Helicobacter pylori infection (67%) (14). RBG is composed of plasma cells, in which there are small concentrated spherical immunoglobulins, surrounded by endoplasmic reticulum membrane (called Mott cells) (15), which is different from CSH consisting of predominantly histiocytes with crystallized immunoglobulin in the lysosome. RBG cases also have similar characteristics, such as frequent kappa light chain restriction of accumulated immunoglobulin (43%) (14). There were two cases of RBG associated with lymphoplasmacytic neoplasm: one with MALT lymphoma and the other with metachronous multiple myeloma three years after RBG diagnosis (16, 17). However, up to now, RBG has been considered as a unique inflammatory reaction, rather than a paraneoplastic phenomenon. Therefore, gastric CSH seems to be more significant than RBG in its association with lymphoproliferative diseases. In addition, the differential diagnosis of CSH may include a variety of diseases characterized by aggregation of large eosinophilic tumor cells (adult rhabdomyoma, granular cell tumor, and oncocytic neoplasms) or histiocytic aggregation (Langerhans cell histiocytosis, fibrous histiocytoma, xanthogranuloma, Gaucher’s disease, and mycobacterial or fungal infection) (1, 3, 4, 6). CSH is rare, so it is not widely known and may be easily confused. On the low-power image, CSH is characterized by polygonal or spindle-shaped tissue cells, which contain abundant eosinophilic cytoplasm. On the high-power image, the refracted needle-like crystal substance fills the cytoplasm. Immunohistochemical analysis is helpful for differential diagnosis. In our case, immunohistochemical staining of CD68 confirmed that the large pink cells were histiocytes. Electron microscopic examination showed that a large number of high electron density particles were found in the cytoplasm of cells, with crystal structure, different sizes and shapes, such as needle, rectangle, polygon and diamond. S100 protein immunohistochemical staining ruled out the possibility of granular cell tumor and Langerhans cell histiocytosis. Congo red excluded amyloidosis, and desmin, MSA and myogenin were performed to exclude adult rhabdomyoma. CK ruled out the possibility of metastatic cancer. The definitive diagnosis was CSH.
At present, the pathogenesis of CSH is unclear, which may involve many factors, including overproduction of immunoglobulin, abnormal secretion and impaired excretion. Immunoblotting, amino acid sequencing, mass spectrometry and gene mutation showed that the variable region of Ig kappa light chain was replaced by abnormal amino acids, and the sequence change led to the change of the three-dimensional structure of immunoglobulin, which promoted the formation of protein crystals and resisted the degradation of lysosomes in tissue cells, resulting in crystal accumulation. Hereditary or acquired tissue cell processing defects (processing defects), damage of enzyme degradation of tissue cells, resulting in the formation of Ig crystals (4, 18, 19). Among the 17 cases of gastric CSH, there were 8 cases of Kappa Ig light chain (47.1%), 5 cases of lambda (29.4%), 3 cases of polyclonal (17.6%), and one case of unknown (5.9%).
The shape, size and staining characteristics of the crystals are relatively constant in an individual case, but vary widely between cases. They can be small (2–4 µm) or large (> 40 µm long); they can be rectangular, hexagonal, rhomboid or square, elliptical, curved or semilunar, and can resemble intact or broken needles, rods, spindles, prisms, pyramids or double pyramids (20). The crystal formation may be related to the special structure of secreted immunoglobulin. Observation of crystal structural characteristics by the electron microscope is the most effective method to accurately diagnose the disease at present. In our case, a large number of high electron density particles were observed by electron microscope in the cytoplasm of cells, showing crystal structure with different sizes and shapes, such as the needle, rectangle, polygon and diamond.
In conclusion, we reported a case of gastric CSH, and summarized the clinical and pathological features of gastric CSH reported in English literature in recent years. This case highlights how immunohistochemistry and electron microscopy can help with differential diagnosis and classification. CSH is so subtle that it is easily overlooked and misdiagnosed. Understanding CSH may help to find hidden malignant tumors. Extensive CSH will obscure the potential tumors, which may cover up the accompanying malignant tumors of lymphohematopoietic system, making it difficult to identify the tumors. Therefore, pathologists should know the detailed histological features of CSH to avoid misdiagnosis, and at the same time, they should be highly suspicious of the existence of associated lymphoproliferative diseases. Once the pathological diagnosis of CSH is made clear, it is necessary to follow up the patients with potential lymphoproliferative diseases, including detailed clinical history, serum and urine protein examination, imaging examination and bone marrow biopsy and so on. The treatment and prognosis of patients with CSH varies significantly depending on the associated disease.