This case report describes a female iRPF patient who was later diagnosed with endometrial cancer. At the time of admission, the patient has a 13-year history of iRPF. RPF is clinically rare with an age-standardized incidence of 0.1 cases/100,000 persons per year . Around 70% of RPF cases are idiopathic with no clear etiology. While the remainder are secondary to certain medications, such as inflammatory disorders, malignant diseases, radiotherapy and abdominal surgery etc. . RPF commonly occurs in adults between the ages of 40 and 60 years old, especially in men (incidents occurring nearly two to three-fold more than female) [2, 8]. It is characterized by a fibroinflammatory tissue surrounding the abdominal aorta and compressing the retroperitoneal organs especially the ureters. Urologic manifestations included obstruction of the ureter, hypertension secondary to renal artery stenosis, renal insufficiency or failure, and non-functioning kidneys are common in cases of ureteral involvement [1, 2]. Laboratory findings of elevated inflammatory markers of ESR and CRP, and reduced Hb often herald the active state of RPF. Studies reported that 10–20% of RPF cases were ANA-positive, and a higher frequency of ANA positivity (30–40%) was observed in iRPF [9, 10]. Recent studies have proposed that iRPF belonged to IgG4-related diseases (IgG4-RD) which manifests as significantly elevated serum IgG4 level and mass-like lesions which could easily be misdiagnosed as tumors . However, the specificity of serum IgG4 level is limited. Liao and colleagues compared the differences between IgG4-RPF and iRPF in a Chinese population which found elevated serum IgE concentration and tissue eosinophilia in the IgG4-RPF subgroup . For this patient, her total IgG was 27.4 g/L, with elevations in IgG1 and IgG2, while IgG3 and IgG4 were normal (Table 1). Her serum IgE was also in a normal level of 25.8 IU/ml. Additionally, IHC of her biopsied fibrotic retroperitoneum showed no IgG4-related pathologic features. Therefore, this case was most likely not IgG4 related-RPF.
Imaging examinations played vital roles in the diagnosis and follow-up of RPF. This mainly included ultrasound, CT, MRI, and PET, and in which this disease often manifested as a homogeneous, well-defined plaque wrapping retroperitoneal organs. Differential diagnosis should be made between iRPF and other diseases like malignant tumors, infectious diseases, systemic issues and etc. CT is typically the modality of choice to visualize the location and the extent of fibrosis and the possible etiology. Bakir et al. evaluated the role of MRI in RPF which found apparent diffusion coefficient of inactive RPF was higher than that of active RPF or malignant RPF, and diffusion-weighted imaging could contribute to the differentiation of inactive RPF from malignant neoplasms . Moroni et al. reported that 18F-FDG PET/CT could accurately discriminate active from inactive disease (93.9%) . Notably, aseptic inflammatory processes, infections and malignancies could also increase 18F-FDG uptake. Fernando et al.’s study showed that 18F-FDG PET seemed to be able to distinguish cancer from noncancerous RPF . However, in the present case, multiple enlarged lymph nodes, which were considered as lymph node metastasis through preoperative imaging methods including CT, MRI and PET/CT, were pathologically confirmed as fibrosis. Therefore, imaging methods to distinguish RPF and malignancies still need further assessment and investigation. The most definitive diagnostic test for RPF is retroperitoneal biopsy which can be performed under imaging guidance in cases with clinical symptoms and the presentation of retroperitoneal mass. The pathological features of iRPF are fibrosis and chronic inflammatory infiltration which consist of a large number of lymphocytes, plasma cells and the formation of lymphoid follicles.
The treatments of RPF include surgery to relieve compression symptoms and medication to prevent further progression of the inflammation. Drug therapy is suitable for RPF patients with early mild symptoms or in late stages of inoperability, or as prevention of postoperative recurrence. Glucocorticoid is currently considered to be one of the most effective drugs for the treatment of RPF. It is rapidly effective and can fully inhibit the early inflammatory response of RPF. However, long-term use of glucocorticoids has many adverse systemic effects and increases the risk of cardiovascular events. Tamoxifen (TMX) was reported to be a suitable alternative to glucocorticoid with no or mild side effects for RPF, especially to those patients who may not be able to tolerate steroids-related toxicity or have contraindications to glucocorticoid [4, 5, 16]. TMX is a non-steroidal anti-estrogen drug which has potential anti-angiogenesis and anti-fibrotic properties . Vaglio and fellow researchers found that receiving TMX for 8 months was significantly less effective in prevention of relapse than 8-month treatment with prednisone in iRPF patients through performing a randomized controlled trial . In addition, TMX has a weak estrogen-like effect, long-term use (especially for more than 5 years) may increase the risk of endometrial hyperplasia or even endometrial cancer. Studies had demonstrated that the risk of endometrial cancer was increased following TMX therapy for women with breast cancer (36/6101 vs. 15/6131), predominantly in women over the age of 50 years. However, existing research has not reported any RPF patients that suffered from an increased risk of endometrial cancer when taking TMX [4, 5, 16]. It may in part be explained by the small number of female RPF patients included and limited follow-up period recorded in these studies. Interestingly, the patient mentioned in this study had endometrial cancer after her TMX treatment for iRPF, but the causal link was unknown. Therefore, the risk–benefit ratio and long-term safety of TMX treatment in female RPF patients should be carefully assessed in future studies. A close follow-up including inflammatory markers (ESR and CRP), creatinine, and imaging (ultrasound, CT, MRI or PET) should be advised to monitor the therapeutic response and allow early detection of relapse in RPF patients. Researchers had reported that the relapse rates of RPF varied from 22 to 69% [3, 8, 17]. Therefore, long-term monitoring and remission maintenance strategies must be considered.
For this case, there are some key points that could be taken away. The diagnosis of RPF remains challenging due to the nonspecific clinical symptoms and the lack of standardized diagnostic criteria. Imaging helped to make diagnosis but there were many limitations when it came to differentiating between iRPF and other malignancies. Considering this, biopsy may be the best way to obtain a reliable diagnosis. This patient was diagnosed with iRPF after a splenectomy. Long-term use of tamoxifen might have been a high-risk factor of endometrial cancer. Accurate diagnosis benefited from the careful history taking and thorough physical examination. Organ involvements were evaluated before surgery. Her right kidney almost lost all function from long-lasting obstructive uropathy, but the left kidney compensated so she had almost normal renal function, and this was enough so she could tolerate surgery. Imaging examinations including CT, MRI and PET/CT all showed enlarged lymph nodes and increased FDG uptake in PET/CT. Clinicians believed that it was lymph node metastasis based on patients’ history and imaging findings. However, these enlarged lymph nodes were surgically proven to have no cancer involvement. This case report stressed the difficulty to distinguish between lymph node metastasis and inflammatory hyperplasia by imaging methods. Here, lymph node assessment with biopsy seemed to be particularly important. For early-stage endometrial cancer, studies had shown that systematic lymphadenectomy did not benefit in overall survival but improved surgical staging [18, 19]. Thus, the clinical benefit of routine lymphadenectomy should be further investigated to avoid additional surgical complications and over-treatment. Criteria of < 50% myometrial invasion, tumor size < 2 cm, and G1-2 differentiated endometrioid histology were suggested as indication of low-risk for nodal metastases with endometrioid uterine cancer . Further large data studies aiming to see if multiple biopsies or molecular markers may be useful to differentiate lymph node inflammatory hyperplasia from tumor metastasis in RPF patients. However, for those patients with clinically enlarged or suspicious lymph nodes in cancer patients, lymph nodes should still be resected to rule out metastatic disease. Additionally, long-term use of TMX may increase the risk of endometrial cancer. Therefore, TMX should be carefully considered especially in postmenopausal females, and close monitoring should be performed regularly to aid early detection of gynecological diseases.