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Krukenberg tumor

Krukenberg tumor

Krukenberg tumor is a metastatic mucin-rich signet-ring adenocarcinoma of the ovary caused by the spread of stomach cancer usually arising in the pylorus followed by colorectal, breast, and appendix 1. The stomach has been attributed as the primary site in about 70% of Krukenberg tumor cases 2. Krukenberg tumor is more prevalent in Asian countries, which have a higher prevalence of gastric carcinoma 3. Gastric and colorectal cancers collectively account for almost 90% of the primary site for Krukenberg tumor 4. Other less common primary sites described in the literature are the breast, appendix, small intestine, gallbladder, urinary bladder, biliary tract, pancreas, ampulla of Vater, or uterine cervix 5, 6. Recurrences can occur years after the primary has been treated 7, 8.

Mechanisms of the spread of Krukenberg tumor proposed are retrograde lymphatic dissemination involved in gastric cancer metastases, hematogenous spread most frequent in colorectal cancer, and transperitoneal direct spread 9. Often Krukenberg tumors are bilateral (over 80%), given its metastatic nature. Bilateral involvement of the ovaries appears to be the most helpful finding in differentiating Krukenberg tumor from primary ovarian tumors 10.

Krukenberg tumor is named after Friedrich Ernst Krukenberg (1871-1946), who reported a new type of ovarian malignancy in 1896 11, 2. This was discovered to be metastatic in origin from primary gastrointestinal site 6 years later 12, 13.

The incidence of Krukenberg tumors varies from 1% to 21% all the ovarian tumors diagnosed 14, 15. Of all the ovarian malignancies diagnosed, Krukenburg tumors in Western nations make up less than 4% of these tumors 4. The incidence is higher in Asian countries like Korea, Japan, and China, where Krukenberg tumors make up about 20% of all ovarian cancers 12. The age profile of these patients is relatively younger than patients with other metastatic carcinomas 1. This may be attributed to the higher frequency of gastric signet ring cell carcinoma in younger females in these Asian countries 16, 1. The average age of diagnosis is 35 to 45 years 17. However, it can be seen in all age groups.

Krukenberg tumors are further defined as either “synchronous metastasis,” where the metastasis is discovered within three months of the primary tumor’s diagnosis, or “metachronous metastasis,” where the metastasis is found after three months, frequently after the completion of initial curative therapy 18. The presence of pregnancy, concurrent with a Krukenberg tumor, complicates the diagnosis 19, 20.

Diagnosis of Krukenberg tumor involves careful radiological evaluation of gastrointestinal and other potential sites. With a known primary tumor, CA-125 levels can help with early detection of ovarian metastasis as well assist with prognosis and monitoring of this disease. CA-125 levels are also considered as prognostic; hence, early detection of ovarian metastasis and monitoring serum CA-125 level is helpful for patient’s good outcome. Carcinoembryonic antigen (CEA) levels are not of prognostic value in patients with a colorectal primary, but may serve as an adjunct to imaging for reflecting disease response to chemotherapy.

In all cases, Krukenberg tumor is metastatic disease and the patients are frail and debilitated. The prognostic factors have not been well established; however, the various unfavorable prognostic factors in Krukenberg tumors include peritoneal involvement, synchronous presentation, ascites, and increased serum carcinoembryonic antigen (CEA) levels 21.

When the primary tumor is identified after the metastasis to the ovary is discovered, the prognosis is poor 22.

Currently, no established treatment is available with extremely poor prognosis for the Krukenberg tumor. Aggressive surgery is not recommended as it does not extend life span. There are a few different treatment options available such as cytoreductive surgery (CRS) or debulking surgery, adjuvant chemotherapy (CT), and hyperthermic intraperitoneal chemotherapy (HIPEC). HIPEC employs thermal injury to induce heat-shock protein release from tumor cells and facilitates the cytotoxicity of chemotherapeutic medication 23.

Krukenberg tumors are stage 4 disease and have a poor prognosis and depends on the source of the metastasis with a median survival of 11 months, 21.5 months, 31 months, and 19.5 months for gastric, colorectal, breast, and other origins, respectively 24. Most patients may benefit from hospice care and pain control. The majority of patients are dead within 12-24 months with or without treatment 25.

The median overall survival from Krukenberg tumor surgery is 17 months. The median survival for patients with a colorectal primary compared to all other origins was 15 months and 38 months, respectively. The median overall survival was also shorter for patients younger than 50 years old 24.

Figure 1. Krukenberg tumor signet ring cell

krukenberg tumor signet ring cell

Footnote: Pathology of the gastric tumor showing a poorly differentiated adenocarcinoma and multiple signet ring cells (black arrow) characterized by intracytoplasmic vacuoles that cause peripheral displacement of the nucleus, in comparison with a normal glandular structure (red arrow) (hematoxylin−eosin stain; original magnification ×200).

[Source 26 ]

Krukenberg tumor causes

In most cases, the stomach has been attributed to be the primary site with studies showing this to be in about 70% of cases 4. Gastric and colorectal cancers collectively account for almost 90% of the primary site for Krukenberg tumor. Other less common primary sites described in the literature are breast, appendix, small intestine, gallbladder, urinary bladder, biliary tract, pancreas, ampulla of Vater or uterine cervix 27.

The exact mechanism of tumor spread is still unknown. The tumor is thought to spread via 1 of the 3 mechanisms:

  1. the lymphatic system,
  2. the hematogenous system, or
  3. the transcoelomic pathway.

Hematogenous and lymphatic pathway means the tumor spreads through blood vessels or lymphatic channel respectively. Transcoelomic pathway means the actual cancer cells directly spread through abdominal route to adjacent organs. Given the tumor is diagnosed at an advanced age, it is believed that the tumor metastasizes through mixed pathways. The average age of diagnosis co-relates to increased vascularity of the ovaries which supports the lymphatic and hematogenous spread hypothesis 28.

The lymphatic route is believed to be the most likely route of cancer spread with several supporting evidence 29, 16:

  1. Microscopically, the hilum and cortex have demonstrated lymphatic permeation
  2. Many cases have been reported where primary tumor is confined to mucosa and submucosa, and given the rich lymphatic network in the gastrointestinal mucosa and submucosa, the only logical explanation is that the tumor spread through this pathway
  3. The risk of metastasis is higher with increased number of positive metastatic lymph nodes
  4. Lack of involvement of the peritoneum without any evidence of seedings, adhesion, or tumor infiltrates favors other pathways as opposed to the transcoelomic route.

Krukenberg tumor symptoms

Krukenberg tumors remain asymptomatic until very advanced. In some cases, symptoms are non-specific, like abdominal pain, pelvic pain, weight loss, increasing abdominal girth, bloating, ascites, or dyspareunia (painful intercourse) 1. Krukenberg tumors can become autonomous and produce hormones leading to vaginal bleeding, menstrual cycle irregularities, hirsutism (excessive growth of dark or coarse hair in women) or rarely virilization (a condition in which a female develops characteristics associated with male hormones (androgens) such as excess facial and body hair [hirsutism], baldness, acne, deepening of the voice, increased muscularity, and an increased sex drive) 12.

One recent meta-analysis revealed that almost half of Krukenberg tumors were synchronous with the primary tumor, about two-thirds were bilateral, about forty percent had a diameter greater than 10 cm, and half had peritoneal involvement, often with ascites 30. Ascites, typically a late feature of peritoneal metastases, can occur alongside intestinal obstruction and cachexia and heralds a sharp decline in the patient’s quality of life. Krukenberg tumors with benign ascites and right hydrothorax that contain no malignant cells are known as Pseudo-Meig syndrome 31. These tumors can move about, leading to ovarian torsion and abdominal pain. Patients can manifest pain during sexual intercourse 32.

Krukenberg tumor diagnosis

Given the non-specific signs and symptoms, work-up involves obtaining imaging including computed tomography (CT) scan or ultrasound of the abdomen and pelvis. Krukenberg tumors often appear as bilateral ovarian masses and usually appear solid but can also be cystic. Pre-operative level for serum CA-125 can be elevated and decreases after tumor resection 33, 34. These levels can be used for:

  1. Follow-up of patients after surgery to document complete resection as levels will decline
  2. Follow-up of patients to diagnose metastatic spread to ovaries in patients with history of other cancers (e.g., gastrointestinal, breast)
  3. To predict the prognosis of patients with Krukenburg tumors; one study showed that levels greater than 75 U/ml were associated with decreased 5-year survival than patients with lower levels 12, 35.

Krukenberg tumor histopathology

Grossly, the ovaries are asymmetrically enlarged with a bosselated (protuberance-laden) contour 4. They are usually solid, but can occasionally be cystic. The capsular surface is mostly free of any tumor infiltrates, adhesions, implants or deposits which can be deceptive and appear as a primary ovarian tumor 4.

The characteristic finding of Krukenberg tumor is the presence of mucin-laden signet-ring cells, which is present in at least 10% of the cases. The diagnostic criteria of World Health Organization (WHO) based on Serov and Scully description are for making the diagnosis states 36:

  1. The presence of stromal involvement
  2. Ovarian stromal sarcomatoid proliferation
  3. The presence of mucin-producing signet-ring cells

Histochemically, the intracytoplasmic mucins of the signet-ring is neutral and acidic and stains with Mayer mucicarmine, periodic acid-Schiff with diastase digestion, and Alcian blue stain. Immunohistochemically, these tumors stain positive for cytokeratin (AE1/AE3), and epithelial membrane antigen and they stain negative for inhibin and vimentin 12.

Krukenberg tumor differential diagnosis

Krukenberg tumor (i.e., tumors with signet ring cells that lack tubular formation) must be differentiated from ovarian tumors showing signet-ring cells morphology and filled with either mucinous or non-mucinous material 37. Primary mucinous ovarian carcinomas and mucinous carcinoid tumors are the important differential diagnoses for tumors with signet-ring cells filled with mucin 37. Primary mucinous ovarian tumors have a complex papillary pattern and are usually unilateral 38. Immunohistochemical stains also stain positive for chromogranin and synaptophysin help in ruling out mucinous carcinoid 38.

Ovarian tumor with signet ring cell without mucin are divided into signet-ring stromal tumor (benign, unilateral, devoid of epithelial differentiation, stain positive for vimentin and negative for cytokeratin), sclerosing stromal cell tumor (contain lipid with no reactivity to periodic acid-Schiff stain and stain positive for inhibin stain), and clear cell adenocarcinoma of the ovary (contains glycogen that stains with periodic acid-Schiff, papillary and tubulocystic pattern with hobnail cells) 38.

Tubular Krukenberg tumors (i.e., cells arranged in tubules) must be distinguished from ovarian tumors with an annular or tubular pattern including Sertoli-Leydig cell tumor (lack of signet-ring cells, stain positive for inhibin and negative to cytokeratin), endometrioid carcinoma, and tumor of Wolffian origin 12.

One recent comparative study revealed several factors that can be key in helping to differentiate primary ovarian from Krukekenberg tumors 39. Primary ovarian cancer is often strongly positive for cytokeratin 7 (CK7) and negative for cytokeratin 20 (CK20) 27. On the contrary, metastatic gastric cancer is less CK7 positive but is positive for CK20 40. Colorectal cancers are CK7 negative but CK20 positive. Generally speaking, primary ovarian cancer patients are slightly older at 65 years versus 52 years for Krukenmberg patients.

The CA125 level is more pronounced in primary ovarian cancer than the Krukenberg tumor, with median values of 652 u/ml for the former and 43 u/ml for the latter. Both CEA and CA19-9 are greater in Krukenberg patients than in primary ovarian malignancy patients at values of 5.4 ng/ml (CEA)/65.9 u/ml (CA19-9) and 1.4 ng/ml (CEA)/18.0 u/ml (CA19-9) respectively. There was considerable overlap in the value range, however. Krukenberg tumors were likely to manifest peritoneal metastases, while ovarian cancers would, additionally, have tumors at distant sites.

Krukenberg tumor treatment

No optimal treatment strategy for Krukenberg tumors has been established 4. Aggressive surgery is not recommended as it does not extend life span. Radiation and chemotherapy offer a small of improvement in the overall prognosis 4. The mainstay of therapy remains surgical reaction with an R0 result. R0 is defined as a microscopically negative margin of resection where no gross or microscopic tumor is found at the surgical site 41. Cytoreductive surgery (CRS) is performed with the goal of complete removal of all macroscopic disease. This is achieved by peritonectomy procedures and en-bloc resection of the viscera where required 42. Hyperthermic intraperitoneal chemotherapy (HIPEC) employs thermal injury to induce heat-shock protein release from tumor cells and facilitates the cytotoxicity of chemotherapeutic medication 23.

Given the metastatic nature of the disease, all surgery can accomplish sometimes is palliation, an improvement in the quality of life. For the patient, this may be a worthy goal. Data from other sources support the assertion that metastasectomy of one or both ovaries increases overall survival 24. Prophylactic bilateral oophorectomy is advocated in the setting of unilateral disease as a countermeasure to the risk of (eventual) contralateral involvement 16.

Metastatectomky is favored over no surgery for its increasing overall survival, especially when an R0 is felt to be an obtainable result 43, 44. A retrospective analysis showed that patients who underwent palliative surgeries including unilateral or bilateral salpingo-oophorectomy alone, or a total hysterectomy combined with bilateral salpingo-oophorectomy, had a median overall survival of 17 months 24.

Krukenberg tumor prognosis

Since Krukenberg tumor is a metastatic disease from the gastrointestinal site or other organs, it is classified as stage 4 cancer. Given the bilateral and metastatic nature of Krukenberg tumor, prognosis remains poor 45. Patients usually die in 2 years, with a median survival of 14 months reported in the literature 4. The median overall survival of patients with Krukenberg tumor is reportedly 11, 21.5, 31, and 19.5 months for gastric, colorectal, breast, and other origins respectively 46, 45. However, metastasectomy (surgical removal of metastases, which are secondary cancerous growths that have spread from cancer originating in another organ in the body), expressive estrogen-receptor beta (ERB), progesterone-receptor (PR), peritoneal carcinomatosis, and signet ring cells were independent predictors of survival 44.

Various studies have been published over the past decade with regards to the prognostic factors and outcomes of surgery for Krukenberg tumors. Metastasectomy, or surgical removal of one or both involved ovaries, has been found to improve overall survival 47, 48, 49. Cytoreductive surgery incorporating Krukenberg tumor removal has also been found to have a beneficial effect, with a 7% overall 5-year survival 50.

Generally, unilateral Krukenberg tumors fared better, as did those with R0 resection 4. R0 is defined as a microscopically negative margin of resection where no gross or microscopic tumor is found at the surgical site 41. Colorectal cancer was better than gastric cancer, particularly when adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) was added to complete resection 51, 32. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment used during surgery in which a heated solution containing anticancer drugs (chemotherapy drugs) is infused directly into the abdominal cavity through a thin tube. After removal of as much tumor tissue as possible with surgery, HIPEC is given to kill any remaining tumor cells. It is most often used to treat cancers that have spread to the peritoneum (the lining of the abdominal cavity). Hyperthermic intraperitoneal chemotherapy (HIPEC) is also called CHPP (continuous hyperthermic peritoneal perfusion, and hyperthermic intraperitoneal chemotherapy).

For gastric cancer subtypes, the presence of estrogen-receptor beta (ERB) and progesterone-receptor (PR) confers a better prognosis in synchronous patients 44.

Krukenberg tumor life expectancy

No optimal treatment strategy for Krukenberg Tumors has been established 4. Patients usually die in 2 years, with a median survival of 14 months reported in the literature 4. The median overall survival of patients with Krukenberg tumor is reportedly 11, 21.5, 31, and 19.5 months for gastric, colorectal, breast, and other origins respectively 46, 45. However, metastasectomy (surgical removal of metastases), expressive estrogen-receptor beta (ERB), progesterone-receptor (PR), peritoneal carcinomatosis, and signet ring cells were independent predictors of survival 44.

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