Our cases highlighted the imaging of renal space-occupying lesions and the symptoms related to presence of a renal mass, including painless gross hematuria, lumbago, and anuria. None of these symptoms directly indicate CD and IgG4-RD. However, these symptoms and imaging findings often raise high suspicion of kidney malignancy, and because of the increasing frequency and high risk of kidney malignancies, frequently lead to misdiagnosis (9). The widespread availability of abdominal CT, MRI, and ultrasound has led to an increase in the diagnosis of renal tumors. In 2018, there were more than 400,000 new cases of cancers of the kidney and renal pelvis globally, representing an estimated 2.2% of the global cancer burden, with more than 175,000 deaths due to this disease (10).
The diagnosis and management of kidney cancer have developed rapidly in recent years. The symptoms of kidney cancer include the classic clinical triad of hematuria, flank pain and palpable mass, as well as paraneoplastic syndromes (11, 12). However, over 50% of renal masses are detected coincidentally, with only a few cases presenting with the classical symptoms mentioned above. Furthermore, the presence of these symptoms is often indicative of locally advanced or metastatic kidney cancer (13). Imaging tests and renal biopsy, as well as laboratory tests like urinary cytology, are crucial methods to diagnose kidney malignancy (14). However, imaging evaluation may sometimes lead to misdiagnosis when encountering rare diseases such as CD and IgG4-RD. They can not only pose a diagnostic challenge since these lesions masquerade as kidney malignancy, but also result in unnecessary radical nephrectomy, and delay appropriate treatment (15, 16). Additionally, it is important to recognize that patients managing with nephrectomy, especially radical nephrectomy, have a high chance of developing renal insufficiency (17). Impairment of kidney function after nephrectomy may eventually lead to chronic kidney disease. This is even more likely in patients who show a decline in GFR of the other kidney before the surgery (18). Thus, distinguishing these two diseases from kidney malignancy is urgently required.
CD is an atypical and rare lymphoproliferative disease originally described by Benjamin Castleman in 1956 (19). The incidence rate of CD is roughly 21-25 per million person-years (20). CD can manifest at any age with the peak age of onset between 30 and 50 years, without significant gender differences (21). The role of human herpesvirus-8 (HHV-8) and human immunodeficiency virus (HIV) in the pathogenesis of CD is well documented (22, 23). However, there was no evidence for HHV-8 and HIV infection in our patient. Clinically, CD can be divided into two subtypes: unicentric CD (UCD) and multicentric CD (MCD), based on its involvement in a single lymph node or region of lymph nodes and multiple lymph nodes, respectively. UCD patients are typically diagnosed in those with compressive symptoms or enlarged lymph nodes that are found serendipitously. Most of them are asymptomatic with normal laboratory findings. In contrast, MCD patients often present with lymphadenopathy in more than a single lymph node station accompanied by fever, anemia, emaciation, liver and kidney dysfunction, and other systemic manifestations, including TAFRO syndrome (thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, and organomegaly) (24, 25). Our PET/CT scan of the patient suggested MCD with the median SUVmax between 2.4 and 3.3. Regardless of the type of CD, the median SUVmax is usually approximately 3-8, whereas higher values would be suggestive of malignancy (26). However, in our case, patient mainly presented with hematuria and lower back pain, whereupon preoperative MRI indicated occupying lesion in the renal pelvis. Due to the lack of specificity in imaging findings, it is difficult to distinguish them from kidney malignancy by imaging alone. Furthermore, the postoperative histopathological result of CD is generally different from the preoperative imaging diagnosis (27).
In fact, the diagnosis of CD depends entirely on histopathology. Histologically, CD can be divided into three subtypes, namely, HV, PC an intermediate mixed type. The HV and PC types account for approximately 90% and 10% of CD, respectively, whereas the mixed type is rare (28). The pathology of the HV type is characterized by the proliferation of interfollicular capillaries and small hyaline vascular follicles. In contrast, PC type mainly manifests as the spreading of sheets of mature plasma cells in the interfollicular areas and hyperplastic germinal centers. The mixed type has morphological features of both types (4, 29). Pathologically, the CD patient in our report was finally diagnosed as PC type with no significant systemic symptoms. The interfollicular zone was infiltrated by CD38 (+) and CD138 (+) plasma cells and amorphous eosinophilic deposition was observed in the germinal centers.
Generally, the treatment of UCD primarily based on surgical resection. Complete resection of involved lymphoid tissue is relatively recognized as the gold standard for management and can eliminate clinical symptoms with low recurrence (30). Ten-year overall survival rate in UCD patients is approximately 90% (21). Moreover, radiation therapy can be considered in those unsuitable for surgery(30). Contrastingly, surgery is insufficient for the management of MCD with lower overall survival rate than UCD (21, 31). The management of MCD is mainly based on glucocorticoids, chemotherapy, antiretroviral therapy, and monoclonal antibody therapy targeting IL-6 (30). In case 1, after radical nephroureterectomy performed due to the misdiagnosis of CD as carcinoma of the renal pelvis, the patient underwent combination chemotherapy (R-COP) for the postoperative pathological diagnosis of CD. Fortunately, no recurrence was observed in the follow-up PET/CT after chemotherapy.
IgG4-RD is a newly recognized chronic and progressive autoimmune disorder of unclear etiology, involving multiple organs and tissues. The disease responds well to glucocorticoids. It is characterized by elevated serum IgG4 concentrations and tumefactive lesions in the affected organs, caused by abundant infiltration of IgG4-positive plasma cells and lymphocytes with fibrosis (3, 32). The epidemiology of the disease remains poorly reported due to lack of recognition. However, Japan has estimated that the incidence of this disease would be 0.28-1.08/100,000 population per year with the mean age of affected patients being 60 to 70 years (6). IgG4-RD exhibits a is more common in males with a male-to-female ratio of 2 to 1 (33). Clinical symptoms of IgG4-RD vary depending on the involved organs, but most patients have relatively mild symptoms with a long disease course. Furthermore, IgG4-RD is likely to go undiagnosed or misdiagnosed because it is treated in different specialties depending on organ involvement (34). In case 2, our patient was sent to the urology department for anuria. Unlike other autoimmune diseases, systemic symptoms such as fever, malaise, swelling, and pain in joints are uncommon (35). Hypergammaglobulinemia is frequently observed in laboratory testing of patients with IgG4-RD. Serology often reveals elevation in IgG, IgE, and eosinophil count (36). Serum IgG4 >135 mg/dl (1.35 g/l) is the suggested cutoff value or diagnosis of IgG4-RD, with a sensitivity and specificity of 97.0% and 79.6%, respectively (37). However, we did not consider IgG4-RD as a diagnosis before surgery, and consequently, serum IgG4 concentration was not evaluated preoperatively. We then considered the mass lesions as lymphoma in CTU. Imaging of IgG4-RD patients usually reveals enlargement or compression of the different organs involved. Contrast-enhanced CT scans of IgG4-RD with kidney involvement often presents multiple well demarcated low-density lesions in the kidney or thickening of the renal pelvis wall (34). CTU in case 2 revealed large soft tissue lesions, but with mild-to-moderate homogeneous enhancement and smooth renal pelvis surface, which is a noteworthy imaging feature for urologists to identify kidney malignancy.
The diagnosis of IgG4-RD is primarily based on histopathological examination. Specific features include dense lymphoplasmacytic infiltrates in affected tissues or organs, obliterative phlebitis and storiform fibrosis (38). Additionally, to diagnose IgG4-RD, the ratio of IgG4-positive plasma cells to IgG-positive plasma cells should be greater than 40% in the affected tissue, with a sensitivity of 94.4% and a specificity of 85.7% (37). However, increased IgG4-positive plasma cells is not a specific feature of IgG4-RD and can exhibited in various chronic inflammatory diseases like inflammatory bowel disease, vasculitis, and lymphoma, which do not exhibit histological features of storiform-type fibrosis and obliterative phlebitis (33). In case 2, CD was diagnosed by intraoperative frozen section examination, but paraffin-embedded pathology and immunohistochemistry after surgery confirmed IgG4-RD. MCD is often difficult to distinguish from IgG4-RD since they have overlapping clinical and/or histological features (39). In 2011, the comprehensive clinical diagnostic criteria for diagnosis of IgG4-RD were established in Boston (40), which include (1) clinical manifestations of characteristic diffuse/localized enlargement or mass formation in single or multiple organs, (2) Serological tests, presenting elevated serum IgG4 levels ≥ 135 mg/dl, and (3) histopathological features, showing dense infiltration of lymphocytes and plasma cells with fibrosis, and the ratio of IgG4-positive plasma cell / IgG-positive plasma cell >40% and >10 IgG4-positive plasma cells per HPF. Only when all three criteria are met can a definitive diagnosis be made. A probable diagnosis can be made if conditions 1 and 3 are met, and 1 and 2 can make a possible diagnosis. In case 2, we made a definitive diagnosis of IgG4-RD based on all three criteria above after surgery.
Once we confirm the diagnosis of IgG4-RD, glucocorticoids, a well-recognized therapy, can be considered for patients. Patients treated with glucocorticoids have an overall response rate and complete response rate of 93% and 66%, respectively (33). Combined use of immunosuppressants such as cyclophosphamide, mycophenolate mofetil, and azathioprine may be effective in the maintenance of remission, allowing for the reduction of steroids while helping prevent recurrence. In patients exhibiting glucocorticoid resistance or relapsing disease, rituximab is a better alternative (33, 41). Moreover, urgent surgical intervention is needed to reduce the severity of obstruction symptoms and improve organ functions rapidly (41). Our patient in case 2 responded well to glucocorticoids and cyclophosphamide after partial excision of the mass lesion. The follow-up imaging tests showed that drug therapy caused continued reduction in the size of the mass, indicating that the surgical excision may be unnecessary. Hence, we need to consider whether surgery for IgG4-RD can be avoided to reduce surgical risk and financial costs associated with overtreatment of benign conditions.
In conclusion, we reported two cases of two rare diseases, CD and IgG4-RD, presenting with renal space-occupying lesions and masquerading as kidney malignancy. The prominent feature in our cases is that preoperative diagnosis was difficult since CD and IgG4-RD can exhibit nonspecific clinical manifestations and imaging findings, and our diagnosis was eventually based on postoperative pathology. Our cases highlight how CD and IgG4-RD can affect the kidney, manifest as mass lesion, and mimic malignancy. Although rare, we recommend that clinicians should take CD and IgG4-RD into consideration while diagnosing patients with renal masses to avoid unnecessary surgical treatment of the kidney.