Secondary amenorrhea as the first presentation of Krukenberg tumor arising from the gastroesophageal junction in a 34-year-old woman: A case report.

B.H.: drafted the article, collected the patient data, and interpreted the findings; L.A: drafted the article; F.H.: chemotherapy treatment and participated in revising the article; A.I.: participated in data acquisition and drafting the article; T.A.: performed the surgical excision and participated in revising the article; Z.A.: the guarantor and supervisor, performed and confirmed the pathological diagnosis and critically revised the article. All authors have read and approved the final manuscript.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval is not required for case reports according to the local institutional review board.

The authors received no financial support from any public, commercial, or non-profit sectors for publication of this case report.

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Dr. Zuheir Alshehabi.

The primary origin of Krukenberg tumor from the esophagus is rare and poses a challenge in terms of proper management and diagnosis. In this article, we aim to advance awareness of possible clinical presentations of this tumor and to add our experience regarding management and outcomes to the available literature. Although esophageal primary is infrequently considered, prompt investigation and diagnosis are crucial to achieve good outcomes. We reported the first case in Syria of Krukenberg tumor originating from the esophagus and presenting as secondary amenorrhea and bilateral adnexal masses.

Krukenberg tumors are rare metastatic tumors at the ovarian level, accounting for up to 1–2 % of ovarian tumors [ 8 ]. In more than 70 % of cases, the primary tumor site is the stomach, but more recent observations have revealed a higher incidence of colorectal origin than gastric origin. These tumors are bilateral in approximately 80 % of cases [ 9 ] and are more common in relatively younger patients, those in their 50s with an average age of 45 [ 2 , 10 ]. Krukenberg tumors may be symptomatic or asymptomatic, symptoms include: pelvic pain, bloating, and changes in the menstrual cycle as the ovarian stroma may be triggered by the presence of cancer cells causing a hormonal imbalance [ 1 ]. The diagnosis of Krukenburg tumors can be done by ultrasound, computed tomography, and magnetic resonance (MRI). Ultrasonographic characteristics of Krukenburg tumor include: solid, mixed solid, and cysts with well-defined margins. Additionally, doppler analysis usually shows randomly distributed tumor vessels with low-impedance flow, other studies also characterize the tumor by prominent vascular signal along the its wall [ 11 ]. Solid components typically show homogeneous enhancement on both contrast-enhanced computed tomography and T1-weighted MRI imaging [ 12 ]. According to current knowledge, three main pathways proposedly explain tumor metastases: lymphatic, hematogenous, and trans-coelomic. Lymphatic and hematogenous metastases indicate metastasizing of the cancer cells via lymphatic channels, and blood vessels respectively. These pathways are especially important in cancer metastasis from primary gastrointestinal cancer to the ovaries. On the other hand, trans-coelomic metastasis resembles the direct seeding of free-floating cancer cells throughout the abdomen. However, Metastases of mixed pathways can occur in most cases, as the original tumor is found at an advanced stage [ 13 ]. Additionally, direct deep invasion has been proposed by several authors as an explanation for KT progression, among other mechanisms [ 14 ]. Immunohistochemical staining plays a key role in differentiating primary and secondary ovarian tumors–A positive cytokeratin 7 (CK7) and negative cytokeratin 20 (CK20) immunophenotype indicate a primary ovarian carcinoma, whereas a negative CK7-and positive CK20 immunophenotype or a positive CK7 and positive CK20- immunophenotype is almost always compatible with a metastatic gastrointestinal carcinoma [ 11 ]. In our case the immunohistochemistry was positive for CK20, CK1, and negative for CK7 indicating a gastrointestinal origin of the tumor. The optimal management strategy for KT has not yet been established [ 1 ]. A wide range of treatments is available, including cytoreductive surgery (CRS), adjuvant chemotherapy, and/or hyperthermic intraperitoneal chemotherapy (HIPEC). These treatments can be used individually or in combination [ 15 ]. A systematic review conducted by Lionetti et al. [ 15 ] that included 1533 KT patients and compared the effectiveness of different treatment protocols showed conflicting results on benefit and overall survival after adjuvant chemotherapy. on the contrary, HIPEC appears to be effective both alone and in combination with CRS, with adverse effect fewer than related to chemotherapy. The benefit of neoadjuvant chemotherapy is also still unclear. Conclusively, the combination of CRS without residuals and HIPEC showed the most efficacy and safety among other therapeutic protocols for KT patients. In our case, both CRS and HIPEC are not available or routinely done locally. However, an adjuvant chemotherapy regimen of oxaliplatin, calcium folinate, and fluorouracil was an effective combination with good outcomes regarding tumor remission. Unfortunately, we were not able to test the long-term effectiveness of this regimen as the patient refused to continue the chemotherapy, which is the main limitation of this case. Previous retrospective studies have suggested that Krukenberg tumors are associated with poor prognosis compared with metastatic disease elsewhere arising from the same primary disease, average survival time is just 14 months [ 14 , 16 ]. A recent retrospective analysis of KT cases over 20 years identified 128 patients with 16 months' median period of survival. The study showed different survival probabilities for different origin sites of the metastatic tumor. In terms of clinical presentation, presence of ascites was found to be associated with greater mortality and reduced patient survival. Synchronous diagnosis, defined as concurrent identification of KT and the primary site of origin or prompt identification of the primary tumor after KT diagnosis, was also associated with poor median survival [ 2 ]. Unfortunately, however, KTs are diagnosed before the primary tumor in up to 65 % of cases [ 17 ].

Krukenberg tumor (KT) is a metastatic tumor to the ovary that usually arises from the breast or gastrointestinal tract. KTs are named after Friedrich Ernst Krukenberg who first described 5 cases of ovarian tumors associated with ascites and resembled alternating firm and myxomatous areas microscopically, in addition to the characteristic signet-ring cells. This definition was later extended by some authors to include any metastatic tumor to the ovary, and used by others to refer to any metastatic tumor from gastric origin. Wherefore, in 1973, Serov and Scully settled diagnostic criteria that was adapted by the world health organization (WHO) and identifies KTs as the presence of mucus-filled signet-ring cells and stromal proliferation of sarcomatoid type [ 1 , 2 ]. Ovarian metastases are less common than primary ovarian malignancies and represent up to 28 % of all ovarian tumors. Of these metastases, KT is rare and resembles around 9 % of ovarian metastases and only 1.3 % of all ovarian tumors [ 1 , 3 ]. The most common primary site of KT origin is gastric and colorectal cancers in 90 % of cases. Less common primaries include the breast, appendix, and small intestine, among others [ 4 ]. Although KTs of gastroesophageal origin may have different outcomes and prognosis than other primary sites, published data on esophageal primaries remain notably scarce. Additionally, the gastroesophageal origin is rare and not reported in different relatively large-scale cohorts [ 2 , 5 , 6 ]. Herein, we report a case of Krukenberg tumor in a 34-year-old woman originated from the distal esophagus (gastroesophageal junction) and presenting as abdominal pain and amenorrhea. The case is reported in accordance with the SCARE guidelines [ 7 ].

A 34-year-old middle-eastern female with no previous medical history presented to the obstetrics and gynecology clinic with a compliant of amenorrhea and mild abdominal pain of short duration. She had no history of contraception. Physical examination was remarkable for palpable pelvic masses extending to the umbilicus that were also visualized on ultrasonography (US). US showed bilateral heterogenous adnexal masses located in contiguity with the posterolateral walls of the uterus, containing hyper- as well as hypoechoic foci. An evidence of blood supply was also noted on duplex color sonography. The right mass dimensionally measures (93 × 98 × 127 mm) and the left one (74 × 92 × 105 mm) on US. Blood tests were normal and cancer antigen 125 (CA 125) measured 20.5 U/ml. Two weeks later, the patient underwent a laparotomy upon initial clinical suspicion of uterine or ovarian fibroids. Subsequently, two left and right ovarian masses measuring 15 and 12 cm respectively were observed with no concomitant ascites ( Fig. 1 ). Total hysterectomy with complete adnexal resection were performed. The ovaries were not adherent to the surrounding structures or the peritoneum and therefore were readily resected. Accordingly, pathologic evaluation of the resected ovaries revealed numerous signet-ring like cells characteristic of Krukenberg tumor and the patient was therefore scheduled for gastrointestinal endoscopy to work out any primary foci of malignancy. Fig. 1 Surgical view of the ovaries with Krukenberg tumor. (A) and (B) show asymmetrically enlarged ovaries with bosselated ovarian surface characteristic of Krukenberg tumor. Fig. 1 Surgical view of the ovaries with Krukenberg tumor. (A) and (B) show asymmetrically enlarged ovaries with bosselated ovarian surface characteristic of Krukenberg tumor. The upper GI endoscopy showed ulcerated, edematous mucosal fold that is irregular in shape and measures 3 cm located at the inferior portion of the esophagus and extending to the cardia, in addition to erythematous petechial gastric mucosa ( Fig. 2 ). Fig. 2 Upper gastrointestinal endoscopy of the primary lesions in the GI tract (A) Esophageal mass with ulceration located at the lower esophagus and extending to the gastroesophageal junction. (B) Mild petechial congestion in gastric mucosa of the body and fundus. Fig. 2 Upper gastrointestinal endoscopy of the primary lesions in the GI tract (A) Esophageal mass with ulceration located at the lower esophagus and extending to the gastroesophageal junction. (B) Mild petechial congestion in gastric mucosa of the body and fundus. Biopsies were taken from the esophagus, gastroesophageal junction and gastric mucosa for pathologic evaluation. Microscopically, the esophageal and gastroesophageal biopsies revealed invasive proliferation of the lamina propria by atypical neoplastic cells occurring in sheets and small groups, and irregular and hyperchromatic nuclei pushed by cytoplasmic mucin to the side, forming signet-ring cells ( Fig. 3 ). Gastric biopsies revealed chronic active gastritis with reactive lymphoid follicles. The pathologic features were consistent with signet-cell carcinoma of the esophageal lesion and chronic gastritis. Fig. 3 Microscopic examination of the ovaries with metastatic adenocarcinoma (Krukenberg tumor). (A) Metastatic adenocarcinoma: proliferation of cells in glandular formation (H&E × 100). (B) Higher magnification of the metastatic adenocarcinoma shows cells filled with mucin and pushing the nuclei peripherally (signet-ring cells) (H&E × 400). Fig. 3 Microscopic examination of the ovaries with metastatic adenocarcinoma (Krukenberg tumor). (A) Metastatic adenocarcinoma: proliferation of cells in glandular formation (H&E × 100). (B) Higher magnification of the metastatic adenocarcinoma shows cells filled with mucin and pushing the nuclei peripherally (signet-ring cells) (H&E × 400). Lower endoscopy was also performed but no abnormal features were found. A computed tomography (CT) scan of the thorax, abdomen and pelvis was also performed to detect other malignant foci but was negative. Immunohistochemistry of the ovarian biopsy prior to chemotherapy was positive for HER2-Neu oncogene (positive score + 3 in ∼50 % of tumor cells). It was also positive for general cytokeratin CK1 and CK20 and negative for CK7 (CK7-, CK1+, and CK20+) ( Fig. 4 ). Fig. 4 Immunohistochemistry of the metastatic ovarian adenocarcinoma. (A) The neoplastic cells are negative for CK7 staining. (B) neoplastic cells positivity for general keratin CK1 staining. (C) The neoplastic cells are positive for CK20. Fig. 4 Immunohistochemistry of the metastatic ovarian adenocarcinoma. (A) The neoplastic cells are negative for CK7 staining. (B) neoplastic cells positivity for general keratin CK1 staining. (C) The neoplastic cells are positive for CK20. Carcinoembryonic Antigen (CEA) and Cancer Antigen 19–9 (CA 19–9) were normal and measured 1.4 ng/ml and 0.7 U/ml respectively. Six weeks after ovarian resection, the patient was started on adjuvant chemotherapy regimen that included oxaliplatin, calcium folinate, and fluorouracil. She was also referred for thoracic surgery to resect the primary tumor in the gastroesophageal junction but refused to undergo the surgery. During 3 months of chemotherapy, she received 5 cycles resulting in a complete remission evidenced by positron emission tomography (PET) scan. The patient experienced relieve of symptoms and was reluctant to continue the chemotherapy. She died 5 months after discontinuation and was rendered cause of death diagnosis of myocardial infarction (MI). Despite absence of any chemotherapy complications, the specific cause of MI in this patient remains obscure; however, her stressful background of family problems may have had a role in triggering the infarction.

KT Krukenberg Tumor US Ultrasonography CA 125 Cancer Antigen 125 CEA Carcinoembryonic Antigen CA 19–9 Cancer Antigen 19–9 CT Computed Tomography PET Positron Emission Tomography MI Myocardial Infarction MRI Magnetic Resonance Imaging CK Cytokeratin CRS Cytoreductive Surgery HIPEC Hyperthermic Intraperitoneal Chemotherapy Krukenberg Tumor Ultrasonography Cancer Antigen 125 Carcinoembryonic Antigen Cancer Antigen 19–9 Computed Tomography Positron Emission Tomography Myocardial Infarction Magnetic Resonance Imaging Cytokeratin Cytoreductive Surgery Hyperthermic Intraperitoneal Chemotherapy

The authors declare that they have no competing interests.