Continuing Education Activity

Krukenburg tumor is a metastatic malignancy of the ovary characterized by mucin-rich signet-ring adenocarcinoma that primarily arises from a gastrointestinal site in most cases and less commonly from other sites. Often these tumors are bilateral (over 80%), given their metastatic nature. This activity reviews the pathophysiology of Kruckenberg tumors and highlights the role of the interprofessional team in their diagnosis and management.

Objectives:

• Describe the pathophysiology of the Kruckenberg tumor.
• Review the presentation of the Krukenberg tumor.
• Summarize the treatment options for the Krukenberg tumor.
• Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by the Kruckenberg tumor.

Introduction

Krukenburg tumor is a metastatic malignancy of the ovary characterized by mucin-rich signet-ring adenocarcinoma that primarily arises from a gastrointestinal site in most cases and less commonly from other sites. Often these tumors are bilateral (over 80%), given their metastatic nature. This tumor is named after Friedrich Ernst Krukenberg (1871-1946), who reported a new type of ovarian malignancy in 1896. Six years later, this malignancy was discovered to be metastatic in origin from the primary gastrointestinal site.[1][2][3]

Etiology

In most cases, the stomach has been attributed to be the primary site, with studies showing this in about 70% of cases. Recent sources note an increasing prevalence of colorectal tumors.[4] Gastric and colorectal cancers collectively account for almost 90% of the primary site for this tumor. 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.[1][2][5] Recurrences can occur years after the primary has been treated.[6][7] 

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.[8] The presence of pregnancy, concurrent with a Krukenberg tumor, complicates the diagnosis.[8][9][10] 

As the tumor increases in size, it compounds an already increasing abdominal girth from the uterus. Sex hormones can augment gastric cancer dissemination. Placental growth factor levels are elevated in gastric cancer and associated with serosal invasion and lymph node metastases. Surgery appears to be the only treatment advocated for this situation - the role of the other modalities is questionable. 

Epidemiology

The average age of diagnosis is 35 to 45 years. However, it can be seen in all age groups. Of all the ovarian malignancies diagnosed, Krukenburg tumors in Western nations make up less than 4% of these tumors. The incidence is higher in Asian countries like Korea, Japan, and China, where these tumors make up about 20% of all ovarian cancers.[1] It is felt that the high prevalence of gastric cancer in these areas accounts for its predominance.[11]

Pathophysiology

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

1. The lymphatic system
2. The hematogenous system
3. The transcoelomic pathway

Hematogenous and lymphatic pathway means the tumor spreads through blood vessels or lymphatic channels. The transcoelomic pathway means the actual cancer cells directly spread through the abdominal route to adjacent organs. Given the tumor is diagnosed at an advanced age, it is believed that the tumor metastasizes through mixed pathways. Although the lymphatic route is favored over the vascular and, lastly, peritoneal.[12] The average age of diagnosis co-relates to increased vascularity of the ovaries, which supports the lymphatic and hematogenous spread hypothesis.[13][14][15]

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

1. Microscopically, the hilum and cortex have demonstrated lymphatic permeation.
2. Many cases have been reported where the primary tumor is confined to mucosa and submucosa. 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 an 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.[14][11]

Histopathology

Grossly, the ovaries are asymmetrically enlarged with a bosselated (protuberance-laden) contour. 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.

The characteristic finding of this tumor is the presence of mucin-laden signet-ring cells, which are present in at least 10% of the cases. The diagnostic criteria of WHO based on Serov and Scully's description are for making the diagnosis states:

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

Histochemically, the intracytoplasmic mucins of the signet-ring are neutral and acidic and stained with Mayer mucicarmine, periodic acid-Schiff with diastase digestion, and Alcian blue stain. The signet ring cells have eccentric hyperchromatic nuclei, often presenting as nests, cords, tubules, or acini.[11] They diffusely infiltrate the mesenchymal stroma. Immunohistochemically, these tumors stain positive for cytokeratin (AE1/AE3)(AKA "Pancytokeratin") and epithelial membrane antigen (AKA "EMA"), and they stain negative for inhibin and vimentin.[1][2] 

Approximately a third of patients will have either a positive cytokeratin-7 or cytokeratin-20.[16] About a quarter of the patients may have elevated CEA or CA125 levels. Even if the individual values aren't significantly high, they still could be used to gauge therapy.[11]

History and Physical

Krukenberg tumors have a highly variable presentation. Their symptoms can be non-specific, and their signs obscure. 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, oft with ascites.[16]

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.[12] These tumors can move about, leading to ovarian torsion and abdominal pain. Patients can manifest pain during sexual intercourse.[17]

Krukenberg tumors can cause a reaction of the ovarian stroma and thus provoke hormone production, resulting in vaginal bleeding, menstrual changes, hirsutism, and virilization. These signs can cause a delay in diagnosis leading to significant patient infirmity.  

Evaluation

Given the non-specific signs and symptoms, workup involves obtaining imaging, including computed tomography (CT) scan or ultrasound of the abdomen and pelvis. These 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. 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 is also necessary to diagnose metastatic spread to ovaries in patients with a history of other cancers (e.g., gastrointestinal, breast). The presence of a unilateral ovarian mass with an increased CA125 should alert one of a Krukenberg situation where there is a need to exclude colorectal cancer during the workup.[18]
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.[1][2]

Treatment / Management

No optimal treatment strategy for these tumors has been established. Radiation and chemotherapy offer a modicum of improvement in the overall prognosis. 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.[19] 

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.[4] Prophylactic bilateral oophorectomy is advocated in the setting of unilateral disease as a countermeasure to the risk of (eventual) contralateral involvement.[11] 

Metastatectomky is favored over no surgery for its increasing overall survival, especially when an R0 is felt to be an obtainable result.[20][21] 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.[4]

Differential Diagnosis

Classic Krukenberg tumors (i.e., tumors with signet ring cells that lack tubular formation) must be distinguished from ovarian tumors that contain signet ring cells with mucinous or nonmucinous material.

Ovarian tumors with mucin stain are similar to Krukenberg tumors, but they also stain positive for chromogranin and synaptophysin, which can differentiate them from Krukenberg tumors.

Ovarian tumor with signet ring cell without mucin is divided into a signet-ring stromal tumor (benign, unilateral, devoid of epithelial differentiation, stain positive for vimentin, and negative for cytokeratin), sclerosing stromal cell tumor (containing 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).

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 tumors (lack of signet-ring cells, stain positive for inhibin and negative to cytokeratin), endometrioid carcinoma, and tumor of Wolffian origin.[1][2]

One recent comparative study revealed several factors that can be key in helping to differentiate primary ovarian from Krukekenberg tumors.[22] Primary ovarian cancer is oft strongly positive for CK7 and negative for CK20. On the contrary, metastatic gastric cancer is less CK7 positive but is positive for CK20. 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. 

Staging

Since the Krukenberg tumor is a metastatic disease from the gastrointestinal site or other organs, it is classified as stage IV disease.

Prognosis

Given the bilateral and metastatic nature of this disease, the prognosis remains poor.[18] Patients usually die in 2 years, with a median survival of 14 months reported in the literature. The median overall survival of patients with Krukenberg tumors is reportedly 11, 21.5, 31, and 19.5 months for gastric, colorectal, breast, and other origins.[23][18] However, metastasectomy, expressive estrogen-receptor beta (ERB), progesterone-receptor (PR), peritoneal carcinomatosis, and signet ring cells were independent predictors of survival.[21] 

Generally, unilateral Krukenberg tumors fared better, as did those with R0 resection. Colorectal cancer was better than gastric cancer, particularly when adjuvant HIPEC was added to complete resection.[17][24][25] For gastric cancer subtypes, the presence of ERB and PR confers a better prognosis in synchronous patients.[21]

Pearls and Other Issues

Krukenberg tumor is a metastatic disease to the ovaries composed of mucin-rich signet-ring cells. The most common primary site for this tumor is the stomach. These tumors spread most likely through the lymphatic channels. 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 and assist with prognosis and monitoring of this disease. Currently, no established treatment is available, with an extremely poor prognosis for this tumor.

Enhancing Healthcare Team Outcomes

The diagnosis and management of the Kruckenberg tumor are complex and should involve an interprofessional medical team that includes hospice staff, palliative care nurses, a pain specialist, oncologist, surgeon, pathologist, and radiologist. In all cases, this is metastatic disease, and the patients are frail and debilitated. Many patients may benefit from hospice care and pain control. The majority of patients are dead within 12 to 24 months with or without treatment.[15][4] [Level 5] With such a doleful outlook, the art of medicine, with its focus on comfort and care, becomes just as important as medical or oncologic protocols.