Krukenberg tumor is a metastatic lesion of the ovary, the source of which is a primary cancer focus in other organs (more often – the digestive system). The neoplasm is characterized by rapid progression, may be accompanied by an increase in the abdomen and epigastric discomfort, pelvic pain, menstrual function disorders. Diagnostic methods include gynecological examination and anamnesis collection, ultrasonography, histological verification with immunohistochemical genotype determination. Combined treatment – surgical cytoreductive surgery with chemotherapy.
C79.6 Secondary malignant neoplasm of the ovary
Krukenberg tumor is a secondary ovarian carcinoma characterized by the presence of cricoid cells secreting mucin and growth in the thickness of the ovary. The tumor is named after the German physician Friedrich Ernst Krukenberg, who established its histological structure in 1896. Some authors mean by Krukenberg cancer metastases of carcinoma of any organ, others – exclusively of the digestive tract. Krukenberg cancer is observed mainly in perimenopause, accounting for up to 2% of all ovarian cancers and up to 30% of all ovarian metastatic formations.
Krukenberg metastases are a consequence of the dissemination of cancer that originally arose outside the ovaries. Most often they come from adenocarcinomas, consisting of their ring-shaped (the form of a “signet ring”) cells. The main sources of Krukenberg’s cancer include malignant epithelial neoplasms:
- Stomach. Up to 70% of all Krukenberg carcinomas are due to gastric cancer, and more than 50% of patients have both ovaries affected. The incidence of ovarian metastases in gastric cancer is about 15%. Their occurrence usually involves primary foci localized near the gatekeeper.
- Intestines. Colorectal cancer is accompanied by metastatic ovarian damage in 2-12% of cases. Ovarian metastases arise from the primary node on the colon (mostly sigmoid) 4.5 times more often than the rectum. Secondary neoplasia of the ovaries, originating from the intestine, is often bilateral.
- Breast cancer. Mammary carcinoma leads to metastatic ovarian cancer in 4-10% of cases. 80% of them originate from lobular adenocarcinoma of the breast and often represent Krukenberg metastases. In half of the patients, ovarian lesions are combined with metastases to other distant organs.
Less often, Krukenberg cancer occurs due to the spread of carcinomas of the uterus, gallbladder, bladder, and pancreas. Metastasis does not depend on the volume of the maternal tumor. Sometimes the primary focus is not determined, it can only be suspected due to the presence of Krukenberg tumor.
Microscopically, Krukengberg carcinomas consist of ovarian stroma cells and cricoid cells filled with mucus. Due to their structural similarity, it is difficult to distinguish them from primary cancerous neoplasias of the gonads. Previously, it was believed that Krukenberg’s metastases spread by lymphogenic, hematogenic, implantation pathways (especially from the colon).
According to the modern concept, metastases of this type are characterized by movement with lymph. This is indirectly evidenced by their location not on the surface of the gonads itself, as well as the occurrence of secondary ovarian foci of colorectal cancer only if there are metastatically altered lymph nodes.
There are two theories of the evolution of Krukenberg metastases – linear and parallel. According to the linear model, the “progenitor” cells of metastatic neoplasms first fully form among other cells of the primary node with a single phenotype, “mature”, start up in the body, and adapt to a new place for some time before progression begins. The growth of the “maternal” neoplasm and its distant metastases occurs sequentially.
The parallel model provides for the spread of genetically undeveloped cells at the earliest stages of the primary tumor and their further development among a new environment with mutational adaptation, acquisition of new features. This variant of progression goes in parallel with the development of the “maternal” tumor, gives metastatic cells increased resistance to adverse effects.
The theory of parallel development explains the aggressive nature of metastatic carcinomas, resistance to therapy, and the occurrence of delayed (metachronous) metastases. Unlike synchronous metastases detected simultaneously with primary cancer, delayed metastases may appear much later (after 5 years or more), react poorly to chemotherapy, and significantly worsen the prognosis of the disease.
Krukenberg metastases are characterized by an asymptomatic or low-symptomatic course. In the early stages, there may be an increase in the abdomen due to peritoneal effusion, which occurs in 60-70% of patients, and common signs are weakness, subfebrile temperature, decreased appetite. With the growth of carcinoma, pelvic pain, signs of epigastric discomfort (flatulence, belching and heartburn, nausea) are observed.
With compression of the urinary tract neoplasia, urination becomes difficult. The defeat of the ovarian stroma is accompanied by menstrual disorders (acyclicity, menstrual cramps), hirsutism, masculinization. There may be pain, discomfort during sexual intercourse. A sign of the spread of the process to the fallopian tubes, uterus – bloody discharge from the vagina.
Sometimes there are signs of paraneoplastic syndrome (they may accompany the tumor or precede its development) – swelling due to venous thrombosis, pain and weakness in the legs, impaired coordination of movements. All of these manifestations are not pathognomonic, they often go unnoticed against the background of the symptoms of the development of the main tumor or the consequences of its treatment.
The result of the local spread of Krukenberg tumor can be compression of the intestine with partial or complete obstruction, which often leads to death. The capsule of ovarian neoplasia is easily damaged with the outpouring of mucus, which entails peritonitis, sepsis, shock. The metastatic node spreads cancer cells to other organs – liver, lungs, brain. Violation of the functions of vital organs significantly reduces the quality of life.
Paraneoplastic syndrome leads to severe consequences. Against the background of thrombophilia, thrombophlebitis and arterial embolism develop. The threat of myocardial infarction, lung, ischemic stroke is growing. The results of paraneoplastic neuropathy, cerebellar degeneration are impaired motor activity, visual and speech disorders, dementia. These lesions lead to severe disability and often persist after the removal of the tumor.
At the preoperative stage, the diagnosis of Krukenberg tumor is difficult: a biopsy of the formation is not carried out, since damage to the tumor capsule entails the rapid spread of cancer along the peritoneum. It is possible to verify the diagnosis only on the operating table. The main methods of preoperative diagnosis of Krukenberg tumor:
- Clinical examination. During a gynecological examination (rectovaginal bimanual examination), it is possible to determine the volume formation of the ovary, and with palpation of the abdomen on the couch – ascites. Information about the transferred extraovarial cancer makes it possible to suspect Krukenberg tumor.
- Ultrasonography. Abdominal, transvaginal, transrectal ultrasound of the pelvis with the function of color dopplerometry is used. Signs of ovarian metastasis are clear contours and heterogeneous structure of the neoplasm, dense vascular network, the presence of effusion in the abdominal cavity.
- Morphological examination of the punctate. For cytological analysis, fluid is taken from the Douglas space through a puncture of the vaginal arch. The presence of cancer cells in the sample indicates a malignant ovarian tumor. By the type of cells, it is possible to assume Krukenberg tumor.
- Determination of the level of tumor markers. An increase in the level of specific cancer markers (CA125, CA19-9, HE4) in the blood indicates a malignant neoplasm of the gonads. Metastatic tumors increase the concentration of these proteins more intensively than primary ones. The most accurate results are obtained by examining the level of HE4 protein.
- Endoscopic examination. Laparoscopy is an invasive procedure and is used if adequate imaging by ultrasound is not possible (for example, with obesity in a patient, the presence of adhesions) or it is necessary to clarify the nature and spread of neoplasia. This is the most accurate method of preoperative diagnosis.
To verify the diagnosis, the material removed during the operation is subjected to histological and immunohistochemical examination (the latter makes it possible to distinguish primary neoplasia from metastatic). The research is conducted under the guidance of an oncogynecologist with the involvement of an oncologist, an oncologist surgeon. It is necessary to examine all women with gastric, mammary, colorectal carcinomas.
Differential diagnosis is carried out primarily with primary multiple cancer (synchronous and metachronous primary ovarian foci are most often combined with tumors of the breast, colon, pancreas). Like primary ovarian cancer, Krukenberg’s metastasis should be differentiated from benign gonadal formations and neoplasms of other pelvic organs, inflammations (adnexitis, appendicitis), retroperitoneal cysts.
The outcome is largely determined by the success of treatment of the primary focus – the methods depend on its localization and nature (histological type, degree of differentiation). Treatment protocols for Krukenberg tumor have not been clearly developed. The main method of treatment is surgical. Synchronous metastases are removed simultaneously with the primary node. Chemotherapy is prescribed as an adjunct to surgery. Radiation therapy is not used.
Pharmacotherapy is used independently only for the purpose of palliative care, some slowing of the growth of neoplasia, if surgical intervention is not feasible. Krukenberg metastases have increased drug resistance compared to the primary focus. Independent conservative treatment has almost no effect on survival rates. In modern oncogynecology , the following methods are used for the treatment of metastatic gonad cancer:
- Neoadjuvant chemotherapy. The use of anticancer drugs before surgery is indicated for ascites. Antitumor agents are administered intravenously. Polychemotherapy with platinum and taxanes is usually prescribed. This method is often criticized because it weakens the patient, leads to an inoperable condition.
- Adjuvant chemotherapy. Conservative treatment is prescribed after surgery – a combination of surgery and antitumor therapy significantly increases life expectancy. The same drugs are used as in neoadjuvant treatment, they are administered intravenously.
- Intraperitoneal chemotherapy. It gives the best results in the treatment of Krukenberg metastases and is well tolerated by patients. The drugs are delivered to the abdominal cavity immediately after the node is removed. The use of heated solutions (hyperthermic chemotherapy) increases the therapeutic effect. Platinum–based drugs are prescribed – both in mono mode and in combination with mitomycin.
Surgical intervention is recommended for any local spread of Krukenberg tumor. Contraindication is only the unsatisfactory condition of the patient and the unresectability of the primary focus. The possibility of radical surgery significantly increases the chance of a favorable outcome. The optimal volume is considered to be extirpation of the uterus with appendages, omenectomy, pelvic peritonectomy.
If the prevalence of the malignant process does not allow radical intervention, a cytoreductive operation is performed aimed at removing the maximum possible volume of the tumor mass. The success of treatment has an inverse relationship with the size of the residual tumor. After courses of drug antitumor treatment, repeated cytoreductive interventions are possible.
Prognosis and prevention
The overall survival rate in Krukenberg tumor does not exceed 1.5 years. Metastases to distant organs are an unfavorable prognostic factor for any cancer, however, the outcome may vary depending on the localization and resectability of the primary focus, the size of the metastatic node, the presence or absence of extraovarial metastases. The prognosis is more optimistic in patients with synchronous metastasis of breast cancer.
Prevention of Krukenberg metastases consists in early detection of primary carcinomas. After treatment, the patient needs lifelong dispensary supervision – during the first three years, it is necessary to conduct an examination several times a year, then usually once is enough. This makes it possible to detect tumor recurrences and metachronous metastases of Krukenberg in time.