Advanced primary fallopian tube cancer was found during chemotherapy for multiple myeloma: a case report and literature.

Background
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells, mainly in bone marrow [1].It accounts for 10%−15% of blood system tumors, and is common in middle-aged and elderly people. Patients are mostly treated for clinical manifestations such as bone pain, repeated or persistent infection, anemia, and renal function damage, and the prognosis is poor. Primary fallopian tube carcinoma is a rare gynecologic malignancy that has various and nonspecific presentations [2].Presenting symptoms and signs included abdominal pain, postmenopausal bleeding, watery vaginal discharge and adnexal mass [3]. Recent histological and molecular genetic evidence suggests that 40%−60% of cancers once classified as ovarian or primary peritoneal cancers may originate in the fallopian tube. Definite diagnosis is usually made postoperatively. We report a 69-year-old woman who developed primary fallopian tube carcinoma with ovarian cancer metastases after five years of chemotherapy for MM. The initial symptoms were abnormal vaginal discharge of yellow, cloudy, thin fluid with no odor and no abdominal pain.

Case presentation
The patient, a 69-year-old woman, menopause 19 years, was admitted to hospital complaining of vaginal drainage for a week. But She had no usual pelvic pain, could not reach a pelvic mass, and did not have vaginal bleeding. Multiple myeloma have been found 5 years ago and chemotherapy was administered. Daretumumab was used as treatment for 13 courses after recurrence 1 year ago and was discontinued 16 days before admission. She had a history of diabetes for 20 years and was treated with insulin. She had a left hip replacement 5 years before, and hypothyroidism was diagnosed in the previous 1 month. One brother had stomach cancer, one brother had prostate cancer, and one sister had breast cancer.
The patient reported that after the discovery of multiple myeloma 5 years ago, a general examination was performed during hospitalization, and no gynecological disease was found. At the time of discharge after chemotherapy, the spirit, diet, and sleep were all well. After this admission, we performed gynecological physical examination and found that the vulva and vagina were normal, the vaginal mucosa was not hyperemic, and the cervix was smooth under the vaginal speculum without bleeding. Bimanual examination showed no cervical lifting pain or rocking pain. The uterine body was posterior, atrophic, medium in texture, smooth on the surface, and nontender. The bilateral adnexal areas were full, with unclear boundaries, nontender, and immobile. Gynecologic ultrasound showed on the left side of the uterus a low-echo mass of about 4.33 × 3.47 × 2.92 cm with irregular shape (Fig. 1 A), and another hypoechoic fluid mass on the left side of the uterus measuring approximately 3.45 × 2.88 × 2.29 cm (Fig. 1B).The right side of the uterus was detected with 3.62 × 5.14 × 3.56 cm hypoecho mass, irregular shape, uneven internal echo, and dark area(Fig. 1C). It is worth noting that the blood flow signals in the hypoechoic mass were abundant(Fig. 1D). Pelvic enhanced computed tomography (CT) showed that there was cystic mass in the right adnexal area, with a size of 3.5 × 6.8 × 4.4 cm, which was not clearly related to the right side of the uterus, considering the possibility of malignant lesions. Multiple soft tissue nodules in the space between the right uterine backup and rectum, with unclear boundaries between the anterior and posterior walls of the rectum, and corresponding thickening of the anterior wall of the rectum, suggested invasion, not excluding malignant lesions; Cystic lesion in the left adnexal region, ature to be determined(Fig. 1E). Colonoscopy showed a huge ulcer in the rectum, with spontaneous bleeding, uneven surface, occupying half of the lumen, brittle quality, and easy bleeding(Fig. 1F). Pathological findings after biopsy showed obvious mucosal inflammation, mucosal muscle hyperplasia, and squeezed cell mass(Fig. 2D). Blood routine examination showed that the three systems were reduced, white blood cells: 1.46 × 109/L, hemoglobin: 89 g/L, platelets: 69 × 109/L. Albumin: 34.3 g/L, total protein: 54.8 g/L. Considering grade III of myelopyrodepression and hypoproteinemia after chemotherapy, human granulocyte stimulating factor was given for two days. Serum calcium: 2.18mmol/L, serum creatinine level: 87.7 umol/L, Durie-Samion stage: Stage II Subtype A, serum β2-microglobulin: 4.04 mg/L, ISS stage: Stage II. CA125:460.40 IU/ml, no abnormality in HE4, no obvious abnormality in other examination results, no obvious surgical contraindications.
The patient underwent laparoscopic exploration. No ascites was observed during the operation. The uterus was normal in size. The posterior wall was adhered to the rectum, and the posterior lacunae was closed. The appearance of the left ovary was normal. There was a 2.5 cm diameter cyst in the left fallopian tube mesofilm with clear boundary and clear fluid inside. The omentum majus was wrapped and adhered to the surface of the right adnexa, and was densely adherent to the peritoneum of the external iliac blood vessel, the posterior peritoneal lobe, the right sacral ligament and the intestinal duct. After adhesiolysis, the right ovary was seen ad atrophied and normal in appearance, and the right fallopian tube was thickened and enlarged with a diameter of about 5 cm, with solid leucobrittle tissue inside, and a large amount of leucobrittle tissue could be seen at the adhesion. There were no visible lesions in pelvic external diaphragm, omentum, intestine, liver and spleen surface and peritoneum. The intraoperative frozen pathology showed malignant tumor of epithelial origin in the right adnexa. According to the intraoperative condition, tumor cell reduction + rectal resection + stomy +/- peritoneal thermal perfusion replacement was recommended. Considering the quality of life, the patient’s family requested only bilateral adnexa resection + peritoneal thermal perfusion replacement. The final pathology revealed malignant tumor cells in peritoneal flushing fluid(Fig. 2A). Paraffin pathology showed high-grade serous carcinoma in the right ovary and fallopian tube, primary carcinoma in fallopian tube(Fig. 2B), chronic inflammation in the left fallopian tube with vesicular appendages(Fig. 2C), and no special findings in the left ovary. Immunohistochemistry: CK7 (+), CKpan (+) and ER (-), Ki − 67 (60%), NapsinA (-) and P16 (+), P504s (-), P53 mutations (type), PAX − 8 (+) and PTEN (-), Vimentin (-), WT (+) − 1, CK20 (-), Villin (-), CAM5.2(+). Finally, according to FIGO staging, the patient was diagnosed with stage IV fallopian tube cancer.
After the operation, the patient was given 3 times intraperitoneal hyperthermic perfusion therapy. Due to the low white blood cells, the patient was given short-acting ascending white therapy for 5 days. The patient’s body surface area was 1.59m2 and the creatinine value was 77.3µmol/L. The weekly regimen of paclitaxel 95 mg + carboplatinc0.3 g was administered. It is intended to continue chemotherapy for 6 courses.

Discussion
MM complicated with primary fallopian tube cancer is extremely rare in clinic. Taking “multiple myeloma”, “primary fallopian tube cancer” and “ovarian cancer” as key words, we systematically searched four electronic databases: PubMed, SCI-Web of Science Citation Index, FMRS Foreign Language Medical Information Retrieval Platform and SciFinder Database, and found no similar case reports. After screening, a total of 21 documents were selected to form this review.
This case history is a stunning demonstration of the coexistence of solid and liquid malignancies. Multiple myeloma combined with fallopian tube carcinoma is very rare in clinical practice. Evaluation of patients with multiple myeloma usually includes serological tests and imaging studies [4]. The determination of serum albumin and β−2 microglobulin in blood is of great value for the staging of diseases [5]. However, the final diagnosis of multiple myeloma requires bone marrow biopsy [6]. As a malignant tumor of the blood system, the treatment of multiple myeloma is constantly developing. In the early 1960 s, Mefaran and prednisone combined therapy became a major treatment method. With the deepening of research, thalidomide, bortezomib and lenalidomide became the main therapeutic drugs [7]. At present, new combination therapy, a new generation of targeted drugs, immunotherapy and autologous stem cell transplantation (ASCT) have been added to its therapeutic methods. In recent years, researchers have found that the development of these therapeutic methods is effective in improving the survival rate of most patients with multiple myeloma, but the survival rate of elderly patients has not been significantly improved [8].
In 2014, the FIGO’s Committee for Gynecologic Oncology put ovarian cancer, fallopian tube cancer and peritoneal cancer into the same system. Because there are few reliable literatures about fallopian tube cancer, the diagnosis method of fallopian tube cancer refers to the relevant literatures about ovarian cancer [9]. The symptoms are not obvious, and most of patients have reached the advanced stage when they are discovered [10]. The diagnostic modalities of early ovarian cancer are mainly the examination of blood tumor markers and ultrasound images [11]. Carbohydrate antigen 125 (CA125) is a commonly used tumor marker, but its sensitivity and specificity are low [9, 10]. Transvaginal ultrasonography is the gold standard imaging method for observing adnexa and uterus [6]. Imaging examination of CT and magnetic resonance imaging (MRI) can help to better understand the degree of disease development of patients [9]. In recent years, it has been found that most high-grade ovarian serous carcinoma (HGSC) originates from serous fallopian tube intraepithelial carcinoma (STIC) lesions at the distal end of the fallopian tube [12, 13].
When pelvic mass is found in patients with multiple myeloma, attention should be paid to the possibility of a second primary tumor in addition to the presentation of multiple myeloma metastasis. Patients may have symptoms associated with both malignancies at the same time, and a definitive diagnosis depends on the final pathological findings. This patient was admitted for systemic examination at the time of initial discovery of multiple myeloma, and no fallopian tube disease was found. During chemotherapy for multiple myeloma and outpatient follow-up, blood routine, white blood cell count, and bone marrow puncture were regularly monitored, and pelvic and abdominal imaging examinations were not regularly reviewed. Gynecological examination was not performed. This case suggests that hematologists should not only regularly review the hematology indicators, but also assess the patient’s general condition, including abdominal and pelvic examination, so as to detect pelvic tumors as soon as possible.
In the present study, we identified a left adnexal mass on ultrasonography, a finding that was not corroborated by subsequent CT imaging or laparoscopic exploration. This discrepancy in imaging results has significant implications for clinical practice and warrants further investigation. Several factors may contribute to this inconsistency. First, masses may be visualized differently across various imaging modalities, and the inherent limitations of these techniques can lead to subjective differences in interpretation by different radiologists. Second, anatomical variations may result in discrepancies between imaging findings and surgical observations. Additionally, dynamic changes in pathological conditions, such as cyst rupture or resorption, may occur between ultrasound and CT scans, further complicating the imaging results. We emphasize the importance of integrating findings from multiple imaging studies and the necessity for careful interpretation in clinical practice. Therefore, when imaging findings are inconclusive, we recommend further evaluation, such as laparoscopic exploration, to clarify the nature of the adnexal mass.
Surgery and chemotherapy are the main methods for the treatment of primary fallopian tube and ovarian cancer. The primary surgery for carcinoma of fallopian tube and ovarian includes total staging surgery and tumor cell reduction. Studies have shown that tumor cell reduction combined with Hyperthermic intraperitoneal chemotherapy (HIPEC) can improve patient survival outcomes [14]. However, most patients still need postoperative supplementary chemotherapy, and some patients develop platinum resistance after multiple chemotherapy, so molecular targeted therapy is also a better approach for this part of patients. PARP (poly-ADP-ribose polymerase) inhibitors and anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies are the two most potent ovarian cancer targeting drugs currently approved [15]. Patients with advanced carcinoma of fallopian tube and ovarian need a comprehensive assessment of their physical condition and a personalized choice of treatment. Some studies have shown that the preoperative status of patients has a certain impact on the risk of postoperative complications of advanced cancer tumor cell reduction [16]. Even if complete resection of the lesion is achieved, the initial disease burden is still an important prognostic indicator [17]. In our medical records, the patient had primary fallopian tube cancer that had metastasized to the ovaries, invaded the rectum, and cytoreductive surgery was the standard surgical procedure. However, due to the patient’s previous history of multiple myeloma, poor physical condition, older age, difficulties in perioperative period, and postoperative quality of life problems, only bilateral appendages were removed.
The perioperative management of MM patients with advanced primary fallopian tube cancer is a great challenge for clinicians. Patients with MM have an increased susceptibility to infection, especially in the elderly and in immunocompromised patients, where infection is a major cause of death [18]. Stage III multiple myeloma with decreased hemoglobin (hemoglobin<90 g/L) and elevated C-reaction protein were independent risk factors for infection, and these factors were significantly associated with poor prognosis [19]. Therefore, the risk of infection should be fully assessed before operation, anemia and leukocyte reduction should be corrected, antibiotics should be prophylactically applied before operation, aseptic operation should be strictly performed during operation, blood routine and C-reaction protein should be actively monitored after operation, and the temperature of the patient should be paid attention to. In addition, kidney function is a key concern in this group of patients, and kidney damage is one of the main features of MM, and kidney damage is associated with decreased overall survival and increased risk of early death in multiple myeloma patients [20]. Therefore, the patient should pay attention to renal function and urine volume after surgery, and adjust the fluid volume in time. At the genetic level, studies have shown that up to 15% of patients with high-grade serous ovarian cancer, tubal cancer or peritoneal cancer have breast cancer susceptibility genes(BRCA), and the lifetime risk of ovarian cancer is 18% to 56% for BRCA 1 mutation carriers and 14% to 27% for BRCA2 carriers [8, 12]. Moreover, the research shows that the disease of MM is closely related to genes [4–6]. A number of studies have confirmed that FA/BRCA pathway plays an important role in the process of DNA damage repair, and the overexpression of FA/BRCA pathway is involved in the process of drug resistance of multiple myeloma. And the down-regulation of FA/BRCA pathway may increase the sensitivity of cells to chemotherapy drugs.In this patient, a relapse of multiple myeloma after 4 years of treatment did not rule out the possibility of a BRCA mutation, but unfortunately, she declined genetic testing.
Therefore, it is recommended that patients and their children have genetic testing, and corresponding preventive measures should be given according to the test results [21]. For women with increased genetic risk, bilateral tubal oophorectomy for risk reduction can be considered [9].

Conclusion
MM combined with primary fallopian tube cancer is rare, and no similar cases have been reported. Managing patients with this type of double malignancy is a great challenge for clinicians. This case suggests that for patients with a history of multiple myeloma, if extramelogenous lesions are found, attention should be paid to the possibility of primary cancer at this site, and detailed imaging examinations should be conducted, including Doppler ultrasound, enhanced CT, MRI, etc. Chemotherapy for fallopian tube and ovarian cancers may interfere with the treatment of multiple myeloma, which requires the collaboration of hematologists and obstetricians and gynecologists to develop a personalized chemotherapy regimen for patients according to their remission. For patients undergoing surgical treatment, perioperative management is also a huge challenge due to their susceptibility to infection. Infection indicators of patients should be closely monitored and infection prevention should be done before and after surgery. Acute renal failure is one of the common causes of death in multiple myeloma, so the selection of postoperative fluid intake and urine volume monitoring are also important parts.

Supplementary Information