Krukenberg Tumor

Etiology

Krukenberg tumor originates in the stomach in about 70% of cases and is most commonly adenocarcinoma of the pylorus. The second most common origin site of Krukenberg tumor is the colon, and this site appears to be increasing in prevalence.[4][6] Gastric and colorectal cancers together account for almost 90% of primary sites of Krukenberg tumor. Less common primary sites are the breast and appendix. Rare sources include the small bowel, gallbladder, ureter, urinary bladder, biliary tract, pancreas, ampulla of Vater, and cervix.[1][2][7][8][9]

Epidemiology

Krukenberg tumors occur in 5% to 10% of women with gastric cancer, many of whom are not diagnosed until their disease is advanced. The incidence is higher in Korea, Japan, and China, where these tumors make up about 20% of all ovarian cancers due to the high prevalence of signet-ring cell gastric cancer in these areas.[10]

The median age of a patient diagnosed with Krukenberg tumor is 48 years, with a range of 27 to 65 years.[4] Patients with primary gastrointestinal tract tumors are the oldest group presenting with Krukenberg, whereas those with breast cancer are the youngest.[1] Ovarian metastases occur in younger women than those who have primary ovarian malignancies; the enhanced ovarian blood supply in younger women may make the ovary more prone to metastatic disease during this time. Additionally, gastric adenocarcinomas in younger women are typically of the signet-ring type, and these have a predilection to metastasize to the ovary.[4][11]

Krukenberg tumors can be synchronous, where the metastasis is discovered within 3 months of the diagnosis of the primary tumor, or metachronous, where the metastasis is found after 3 months, frequently after the completion of initial therapy.[12] Ovarian metastases can occur years after the primary cancer has been treated. Kukenberg tumors are bilateral in 80% of cases and are the most common bilateral metastatic tumor of the ovaries. Compared to primary ovarian cancers, they are less responsive to systemic chemotherapy. The ovarian site of metastatic disease is less responsive than synchronous metastases in different locations. The overall survival remains under 1 year from the time of diagnosis.[10][13][14][15]

Pathophysiology

Malignant tumor spread to the ovary is thought to occur via lymphogenous, hematogenous, and transcoelomic routes.[16][8]  The younger age of a typical patient diagnosed with Krukenberg tumor corresponds to a robust blood supply to the ovaries, supporting a mechanism for hematogenous spread. The short distance from the receptaculum chyli to gastric, hepatic, mesenteric, and pancreatic nodes allows for the ready passage of malignant cells to the urogenital lymph vessel trunks that feed the ovaries. The lesser incidence of peritoneal involvement of Krukenberg tumors suggests the transcoelomic route is not as common.[16]

Lymphogenous spread is thought to be more prevalent from a gastric primary, where there is a short distance from gastric lymph nodes to ovarian lymph conduits. Gastric primary tumors are often found within the mucosa and submucosa, sites of rich lymphatic networks. Studies have correlated the extent of gastric lymph node involvement with the prevalence of ovarian metastasis.[4][17][16][8] In contrast, there appears to be a higher degree of malignant vascular invasion in metastases from a colonic primary.[18][16][19] 

During pregnancy, the hormonal milieu can facilitate cancer spread. Placental growth factor levels are elevated in gastric cancer and are associated with serosal invasion and lymph node metastases. In addition, the state of pregnancy may delay the cancer diagnosis as the enlarging abdomen is attributed to the pregnancy.[12][20][21] 

Histopathology

Histologically, Krukenberg tumor is characterized by mucin-laden signet ring cells with offset, hyperchromatic nuclei. The cytoplasmic mucin within signet ring cells is necessary for diagnosis. The cytoplasm of the signet ring cells may be diffusely granular with eosinophilic bodies, largely vacuolated, or a combination featuring a large vacuole containing a drop of mucin, creating an eosinophilic body. Many patterns of signet ring cell organization are possible even within the same tumor. When arranged in tubules, the tumors are classified as tubular Krukenberg. 

The intracytoplasmic mucins of the signet ring are neutral and acidic and stain with Mayer mucicarmine, periodic acid-Schiff-Alcian blue stain with diastase digestion.[8] Krukenberg tumors stain positive for epithelial marker cytokeratin AE1/AE3 and epithelial membrane antigen and negative for inhibin and vimentin.[1][2] One-third of patients will have either a positive cytokeratin 7 or cytokeratin 20; one-quarter will have elevated carcinoembryonic antigen (CEA) or cancer antigen 125 (CA-125).[11] 

Krukenberg tumor induces a sarcomatoid proliferation of ovarian stroma and produces a variable ovarian stromal invasion by poorly differentiated adenocarcinoma. The stroma contains a mixture of spindle-shaped and round cells with minimal atypia. The ovarian stroma impacted by the Krukenberg tumor can be mildly swollen or diffusely edematous to the extent that cellular features are blurred. 

History and Physical

Krukenberg tumor may remain asymptomatic until size or hormonal changes create symptoms. The symptoms related to Krukenberg tumor may be the first clinical signs of a malignancy. The signs and symptoms of  Krukenberg tumor are nonspecific and may include increased abdominal girth, fatigue, abdominal and pelvic pain, abnormal uterine bleeding, hirsutism and virilization, and dyspareunia.[4][11] 

Ascites, typically a late feature of peritoneal metastases, can occur alongside intestinal obstruction and cachexia. When Krukenberg tumor is present and associated with benign ascites and right hydrothorax, it is referred to as Pseudo-Meig syndrome.[17] Ovarian or adnexal torsion can result from tumor burden.[22]  

Evaluation

The discovery of Krukenberg metastasis often precedes the diagnosis of the primary tumor. Nonspecific symptoms may prompt a computed tomography (CT) as the initial imaging modality, but if the lesion is first identified via ultrasound, follow-up via CT or magnetic resonance imaging (MRI) can further define the ovarian process and possibly identify the primary site. It is imperative to differentiate between a primary ovarian versus metastatic malignancy, as prognosis and treatment are markedly different. One recent meta-analysis of Krukenberg tumors found that almost half of Krukenberg tumors were present on the same side as the primary tumor, two-thirds were bilateral, one-third had a diameter >10 cm, and half showed peritoneal involvement, often with ascites.[11]

Ultrasound reveals solid, cystic, or mixed bilateral ovarian masses featuring well-defined margins and a moth-eaten cystic appearance, with a vascular pattern consisting of a main trunk vessel within the central portion of the mass and branching accessory vessels. The sonographic presentation of Krukenberg tumor contrasts with a primary ovarian tumor, which tends to be poorly demarcated with irregular thick septations.[4] 

CT can delineate the extent of metastatic spread, help locate the primary tumor, and identify any intraabdominal adenopathy. When seeking the tissue of origin, particular attention is paid to the stomach, biliary tract, pancreas, colon, and appendix. Krukenberg tumor presented on an MRI features sharply demarcated ovoid tumors with cystic bodies, hypointense T2 solid areas secondary to the stromal reaction, and hyperintense T2 cystic regions due to mucin content.

Biopsies of any suspicious sites identified radiographically are imperative. National Comprehensive Cancer Network (NCCN) guidelines for Krukenberg tumor evaluation include a thorough evaluation of the gastrointestinal tract, including esophagogastroduodenoscopy (EGD), colonoscopy, and evaluation of tissue for tumor markers. Specifically, a negative cytokeratin 7 (CK7) stain and a positive cytokeratin 20 (CK20) stain or concordant CK7 and CK20 positive stains suggest metastatic gastrointestinal cancer. An elevated CEA in an ovarian tumor also suggests a metastatic process. An elevated CA-125 in the setting of Krukenberg tumor can be used as a surrogate to determine completeness of resection, indicate the presence of metachronous metastasis from a known primary, and help determine overall prognosis. One study showed that CA-125 levels >75 U/mL were associated with decreased survival at 5 years.[1][2][23]

Treatment / Management

There are no standardized treatment guidelines for Krukenberg tumors as these malignancies represent a heterogeneity of tumor biology, but the basis for treatment includes systemic chemotherapy and cytoreductive surgery. Krukenberg tumor is thought to be more chemoresistant than metastases in other sites so that metastasectomy may allow for greater efficacy of chemotherapy for the remaining disease burden. Oncologic teams utilize an arsenal of chemotherapy, surgery,  targeted immunotherapy, and radiation, often following protocol from the tissue of origin. Cytoreductive surgery is thought to improve overall survival compared with chemotherapy alone. Chemotherapy may be delivered in a neoadjuvant and/or adjuvant setting or concurrently with surgery in the form of hyperthermia intraperitoneal chemotherapy (HIPEC).[24][5][25](B2)

Differential Diagnosis

Krukenberg tumors must be differentiated from primary ovarian malignancies and other metastatic processes, such as mucinous carcinoids. Carcinoids stain positive for chromogranin and synaptophysin, differentiating them from Krukenberg tumors. Although there can be similarities in gross appearance between primary ovarian and Krukenberg tumors, the malignancies can be distinguished using histologic and immunohistochemical analyses. Accurate identification and classification are important due to the significant differences in treatment and prognoses.

Primary ovarian tumors containing mucin are often unilateral. Primary ovarian tumors contain signet ring cells without mucin, including benign signet-ring stromal tumors, sclerosing stromal cell tumors, and clear cell ovarian adenocarcinoma, which stain negative for periodic acid-Schiff-Alcian blue. Tubular Krukenberg tumors must be distinguished from primary ovarian tumors with an annular or tubular pattern, including Sertoli-Leydig cell tumors, endometrioid carcinoma, and tumors of Wolffian origin. One recent comparative study revealed that primary ovarian cancer is often strongly positive for cytokeratin 7 (CK7) and negative for cytokeratin 20 (CK20), whereas Krukenberg tumor is positive for CK20 or both CK20 and CK7.[1][2] 

Primary ovarian cancer patients are usually diagnosed at 65 years of age versus younger than 50 years of age for Krukenberg patients.[26] The CA-125 tumor marker is usually higher in primary ovarian cancer than in Krukenberg tumors. Median CA-125 levels are 652 u/mL for the former and 43 u/mL for the latter. Both CEA and cancer antigen 19-9 (CA19-9) are, on average, higher in Krukenberg tumors than in primary ovarian malignancies: 5.4 ng/mL (CEA) and 65.9 u/mL (CA19-9) vs 1.4 ng/mL (CEA) and 18.0 u/mL (CA19-9) respectively. 

Surgical Oncology

The mainstay of therapy for Krukenberg tumor remains R0 surgical resection, defined as a microscopically negative margin of resection where no gross or microscopic tumor is found at the surgical site.[27] Prophylactic bilateral oophorectomy is advocated in the setting of unilateral disease. Retrospective analysis showed patients with Krukenberg tumor who underwent palliative surgery, including a unilateral or bilateral salpingo-oophorectomy alone or a total hysterectomy combined with bilateral salpingo-oophorectomy, had a median overall survival of 17 months.[6][8][28][29] Survival is improved in patients with primary gastric or colon cancers and Krukenberg tumors when complete resection of both the primary tumor and the metastatic ovarian tumor is accomplished.[4][13][30][31]

Retrospective studies demonstrate improvement in overall survival for those patients who undergo metastasectomy for Krukenberg tumor compared with systemic chemotherapy alone.[13][31][32] A recent small study examined the efficacy of surgery in patients with gastric cancer and synchronous ovarian metastases. The patients underwent resection of ovarian metastases, either alone or in conjunction with gastric resection and lymph node dissection, either before or following systemic and/or hyperthermic intraperitoneal chemotherapy (HIPEC). Median overall survival was significantly greater in those patients who underwent excision before systemic chemotherapy compared to those who underwent simultaneous gastrectomy and metastasectomy following chemotherapy. Using HIPEC improved overall survival in those patients with peritoneal metastases.[33]

Pertinent Studies and Ongoing Trials

Studies on Krukenberg tumors have examined how treatment approaches impact progression-free and overall survival. Other research focuses on improving diagnostic capability, and still other studies focus on identifying promising targets for directed therapy. Several small studies compared combination chemotherapy regimens in conjunction with cytoreductive surgery with the addition of radiotherapy on occasion. The overall trend is toward prolonged progression-free and overall survival in those patients who undergo more aggressive therapy.[5] In 2018, Haiyan et al examined programmed death-ligand 1 expression in Krukenberg tumors as a potential therapy target.[34]

Huang et al examined the distribution and type of tumor-associated macrophages within primary and metastatic sites in patients with Krukenberg tumor from a gastric primary as an indicator of responsiveness to chemotherapy. Results suggest that Krukenberg tumors are relatively insensitive to chemotherapy and that metastasectomy before chemotherapy improves survival.[9] 

In a recent case study, a 34-year-old woman with Krukenberg of colorectal origin was treated with cytoreductive surgery and postoperative chemotherapy, consisting of capecitabine and oxaliplatin, with disease-free survival noted in a 3-year follow-up.[35] A 76-year-old woman with Krukenberg from a colorectal primary was deemed unresectable. Failing a second line of systemic chemotherapy, she received a high fractional dose radiation with subsequent 4-year survival, 2 of which were progression-free.[13]

Xie et al proposed an algorithm based on neural network modeling, an artificial intelligence (AI) paradigm, to improve the discrimination of Krukenberg from primary ovarian cancer. In this model, biochemical and clinical features are added to a preexisting radiographic algorithm to improve the diagnostic accuracy of AI modeling for Krukenberg tumors.[26]

Medical Oncology

Chemotherapy regimens are based on the tissue of origin, and national and international guidelines specific to the primary cancer should be referred to. Regimens often include 5-fluorouracil (5-FU), either as a monotherapy or in combination with taxanes and a platinum. When molecular data from the tumor reveal a mutation for which a drug has been synthesized, such as overexpression of human epidermal growth factor receptor 2 (HER2), targeted therapy such as trastuzumab (Herceptin) is used. 

Cytoreductive surgery is thought to increase the responsiveness of chemotherapy in patients with Krukenberg tumors. Chemotherapy alone has less impact on overall survival than metastasectomy. Adjuvant systemic chemotherapy confers a survival benefit in those patients with Krukenberg able to first undergo surgery, and HIPEC has been shown to prolong disease-free survival in those with peritoneal metastases.[24][36][37]

Staging

Krukenberg tumor is, by definition, classified as stage IV disease.

Prognosis

Patients with Krukenberg tumors frequently do not survive beyond 2 years.[23] The median overall survival is reported to be 14 months, and the median survival by tissue of origin is reportedly 11, 21.5, 31, and 19.5 months for gastric, colorectal, breast, and other sites, respectively.[38][23] Patients with unilateral Krukenberg tumors fare better, as do those who undergo successful R0 resection. Colorectal cancer has better survival data than gastric cancer, particularly when HIPEC is added to R0 resection.[22][24][39]

Metastasectomy, expressive estrogen receptor beta, progesterone receptor, and signet-ring cells are independent predictors of survival.[29] For gastric cancer subtypes, the presence of the tyrosine kinase receptor Erb and progesterone receptor confers a better prognosis in patients with synchronous tumors. Factors related to a worse prognosis include synchronous presentation of tumors, ascites burden, high CEA and programmed cell death ligand 1 (PD-L1) levels, peritoneal involvement, and lymphovascular invasion.[29]

Tumor markers are helpful in gauging response to therapy.[8] CA-125 levels fall following tumor resection and may be followed as an indicator of recurrence. Rising levels in the preoperative period may signify a metastatic process. Also, the preoperative absolute value of CA-125 may be a prognostic indicator.  

Complications

Complications of Krukenberg tumors may include ovarian torsion and small bowel obstruction.