Krukenberg tumor
Synonyms and keywords: Carcinoma mucocellulare; Ovarian tumor

# Overview
Krukenberg tumor  is a rare metastatic signet ring cell adenocarcinoma of the ovary. Krukenberg tumor was first described as a new type of primary ovarian malignancy by Friedrich Ernst Krukenberg (18711946), a German gynecologist and pathologist, in 1896 which was later confirmed to be of metastatic gastrointestinal tract origin. The pathogenesis of Krukenberg tumors involves metastasis of tumor cells from the stomach, appendix or colon to the ovaries. Metastasis is more likely via the lymphatic spread. However, direct seeding across the abdominal cavity may also occur. On gross pathology, asymmetrically enlarged ovaries with a bosselated contour, usually solid, yellow or white cross sectioned surfaces, and the absence of adhesions or peritoneal deposits are characteristic findings of Krukenberg tumors. Krukenberg tumor must be differentiated from primary mucinous carcinoma, mucinous carcinoid tumor, signet ring stromal tumor, sclerosing stromal cell tumor, clear cell adenocarcinoma of the ovary, and Sertoli-Leydig cell tumor. The incidence of Krukenberg tumors is estimated to be approximately 0.16 per 100,000 individuals. Krukenberg tumor is more commonly observed among women in their fifth decade of lives, with an average around 45 years of age. The majority of patients with Krukenberg tumor remain asymptomatic or have non-specific gastrointestinal symptoms. Early clinical features include abdominal pain and distension (from the large, bilateral ovarian masses). If left untreated, patients with Krukenberg tumors may progress to develop virilization from the excessive hormone production from the ovarian stroma. Prognosis is generally poor, and the 5 year survival rate of patients with Krukenberg tumor is lower in patients in with a preoperative serum CA-125 levels greater than 75 U/mL when compared with patients with CA-125 levels less than 75 U/mL. The median survival of patients is between 7 to 14 months. X rays, ultrasound, CT, MRI and immunohistochemistry help in the diagnosis of Krukenberg tumors. Management of Krukenberg tumors is driven by the identification and treatment of the primary cancer. Bilateral oophorectomy may only be performed for patients where the metastasis is localized to the ovaries. The significance of early detection of ovarian metastasis and the importance of monitoring serum CA-125 level may improve the prognosis. Surgical resection may not be an option if the tumor has already metastasized to other sites.

# Historical Perspective
Krukenberg tumor was first described as a new type of primary ovarian malignancy by Friedrich Ernst Krukenberg (18711946), a German gynecologist and pathologist, in 1896 which was later confirmed to be of metastatic gastrointestinal tract origin.

# Pathophysiology
- The majority of Krukenberg tumors are bilateral.
- Stomach and colon are the primary sites in the majority of Krukenberg tumor cases (70%).
- The pathogenesis of Krukenberg tumors involves metastasis of tumor cells from the stomach, appendix, or colon to the ovaries.
Metastasis is more likely via the lymphatic spread. However, direct seeding across the abdominal cavity may also occur.
- Metastasis is more likely via the lymphatic spread. However, direct seeding across the abdominal cavity may also occur.
- On gross pathology, asymmetrically enlarged ovaries with a bosselated contour, usually solid, yellow or white cross sectioned surfaces, and the absence of adhesions or peritoneal deposits are characteristic findings of Krukenberg tumors.
- On microscopic histopathological analysis, Krukenberg tumors are characterized by the following features:
Tumor composed of two components:
Epithelial
Mucin-secreting signet ring cells with eccentric hyperchromatic nuclei
Cytoplasm may be eosinophilic and granular, pale and vacuolated, or a bull's eye (targetoid) appearance with a large vacuole with a central to paracentral eosinophilic body composed of a droplet of mucin
Signet ring cells may be single, clustered, nested, or arranged in tubules, acini, trabeculae, or cords
Stromal
Plump and spindle-shaped cells with minimal cytologic atypia or mitotic activity
Focal or diffuse stromal edema which may form pseudo cysts
Desmoplastic reaction may be present
- Tumor composed of two components:
Epithelial
Mucin-secreting signet ring cells with eccentric hyperchromatic nuclei
Cytoplasm may be eosinophilic and granular, pale and vacuolated, or a bull's eye (targetoid) appearance with a large vacuole with a central to paracentral eosinophilic body composed of a droplet of mucin
Signet ring cells may be single, clustered, nested, or arranged in tubules, acini, trabeculae, or cords
Stromal
Plump and spindle-shaped cells with minimal cytologic atypia or mitotic activity
Focal or diffuse stromal edema which may form pseudo cysts
Desmoplastic reaction may be present
- Epithelial
Mucin-secreting signet ring cells with eccentric hyperchromatic nuclei
Cytoplasm may be eosinophilic and granular, pale and vacuolated, or a bull's eye (targetoid) appearance with a large vacuole with a central to paracentral eosinophilic body composed of a droplet of mucin
Signet ring cells may be single, clustered, nested, or arranged in tubules, acini, trabeculae, or cords
- Mucin-secreting signet ring cells with eccentric hyperchromatic nuclei
- Cytoplasm may be eosinophilic and granular, pale and vacuolated, or a bull's eye (targetoid) appearance with a large vacuole with a central to paracentral eosinophilic body composed of a droplet of mucin
- Signet ring cells may be single, clustered, nested, or arranged in tubules, acini, trabeculae, or cords
- Stromal
Plump and spindle-shaped cells with minimal cytologic atypia or mitotic activity
Focal or diffuse stromal edema which may form pseudo cysts
Desmoplastic reaction may be present
- Plump and spindle-shaped cells with minimal cytologic atypia or mitotic activity
- Focal or diffuse stromal edema which may form pseudo cysts
- Desmoplastic reaction may be present
- Stomach is the primary site in the majority of Krukenberg tumor cases (70%).
- Bilateral ovarian neoplasm retaining the shape of ovary. Cut section of the tumor shows solid with mucinous areas

# Causes
- Krukenberg tumor may be caused by metastasis of the tumor cells from a primary cancer in the stomach, appendix, or the colon via:
Lymphatic spread or
Direct seeding across the abdominal cavity
- Lymphatic spread or
- Direct seeding across the abdominal cavity

# Differentiating Krukenberg tumor from other Diseases
- Krukenberg tumor must be differentiated from:
- Primary mucinous carcinoma
- Mucinous carcinoid tumor
- Signet ring stromal tumor
- Sclerosing stromal cell tumor
- Clear cell adenocarcinoma of the ovary
- Sertoli-Leydig cell tumor

# Epidemiology and Demographics

## Incidence
- The incidence of Krukenberg tumor is estimated to be approximately 0.16 per 100,000 individuals.

## Age
- Patients of all age groups may develop Krukenberg tumor.
- Krukenberg tumor is more commonly observed among women in the fifth decade, with an average age of presentation at 45 years of age.

# Risk Factors
- There are no known direct causes for Krukenberg tumors. Common risk factors for ovarian cancer may include:
Nulliparity
Early menarche
Late menopause
Hormone therapy
Fertility medications
- Nulliparity
- Early menarche
- Late menopause
- Hormone therapy
- Fertility medications

# Natural History, Complications and Prognosis
- The majority of patients with Krukenberg tumor remain asymptomatic or have non-specific gastrointestinal symptoms.
- Early clinical features include abdominal pain and distension (from the large, bilateral ovarian masses).
- If left untreated, patients with Krukenberg tumor may progress to develop virilization from the excessive hormone production from the ovarian stroma.
- Common complications of Krukenberg tumors include ascites, virilization, and pseudo-Meig syndrome.
Pseudo-Meig syndrome is defined as a hydrothorax with ascites, but with the absence of tumor cells.
- Pseudo-Meig syndrome is defined as a hydrothorax with ascites, but with the absence of tumor cells.
- Prognosis is generally poor, and the 5 year survival rate of patients with Krukenberg tumor is lower in patients in with a preoperative serum CA-125 levels greater than 75 U/mL when compared with patients with CA-125 levels less than 75 U/mL. The median survival of patients is between 7 to 14 months.

# Diagnosis

## Symptoms
- Krukenberg tumor is usually asymptomatic.
- Symptoms of Krukenberg tumor may include the following:
- Non-specific gastrointestinal symptoms
- Abdominal or pelvic pain
- Abdominal distension
- Bloating
- Dyspareunia
- Vaginal bleeding
- Menstrual irregularities
- Hirsutism

## Physical Examination
- Patients with Krukenberg tumor usually appear well in the early stages.
- Physical examination may be remarkable for:
- Abdominal or pelvic mass
- Ascites
- Hirsutism

## Laboratory Findings
- There are no specific laboratory findings associated with Krukenberg tumors.

## Imaging Findings

### X Ray
- On x ray, Krukenberg tumor may present with the following findings:
Prominent small bowel loops filled with gas
No air-fluid level
No radiographic signs of intestinal obstruction
- Prominent small bowel loops filled with gas
- No air-fluid level
- No radiographic signs of intestinal obstruction
- X ray showing prominent small bowel loops filled with gas, no air-fluid level, no radiographic signs of intestinal obstruction

### Ultrasound
- On pelvic ultrasound, Krukenberg tumor is characterized by the following:
Bilateral, solid ovarian masses with clear, well defined margins
An irregular hyper-echoic solid pattern and moth eaten like cyst formation is also considered a characteristic feature
- Bilateral, solid ovarian masses with clear, well defined margins
- An irregular hyper-echoic solid pattern and moth eaten like cyst formation is also considered a characteristic feature
- Large, solid, well defined bilateral ovarian masses
- Large, solid, well defined bilateral ovarian masses
- Large, solid, well defined bilateral ovarian masses
- Large, solid, well defined bilateral ovarian masses

### CT
- On CT, Krukenberg tumor is characterized by the following:
Large, lobulated, and multicystic masses with soft-tissue components which are indistinguishable from primary ovarian cancers
Presence of a concurrent gastric or colic mural lesion
- Large, lobulated, and multicystic masses with soft-tissue components which are indistinguishable from primary ovarian cancers
- Presence of a concurrent gastric or colic mural lesion
- Krukenberg tumour of the right ovary from colon cancer

### MRI
- On pelvic MRI, Krukenberg tumor is characterized by the following:
Bilateral complex masses with hypo-intense solid components (dense stromal reaction)
Internal hyperintensity (mucin) on T1 and T2 weighted MR images
Strong contrast enhancement is usually seen in the solid component or the wall of the intratumoral cyst
- Bilateral complex masses with hypo-intense solid components (dense stromal reaction)
- Internal hyperintensity (mucin) on T1 and T2 weighted MR images
- Strong contrast enhancement is usually seen in the solid component or the wall of the intratumoral cyst
- Coronal T2 image
- Axial T1 image
- Sagittal T2 image
- Axial T2 image
- Axial T1 C+ fat sat dynamic contrast study image

## Other Diagnostic Studies

### Immunohistochemistry
- Krukenberg tumor may also be diagnosed using immunohistochemistry.
- Findings on immunohistochemistry include:
Cytokeratins (AE1/AE3) positive
Epithelial membrane antigen positive
Vimentin negative
Inhibin negative
- Cytokeratins (AE1/AE3) positive
- Epithelial membrane antigen positive
- Vimentin negative
- Inhibin negative

### Serum CA-125
- Serum concentrations of CA-125 may be helpful  for:
Post-operative follow-up of patients for evaluation of complete resection of the tumor
Follow-up of patients with a history of primary adenocarcinomas (particularly gastrointestinal) for early detection of ovarian metastasis
- Post-operative follow-up of patients for evaluation of complete resection of the tumor
- Follow-up of patients with a history of primary adenocarcinomas (particularly gastrointestinal) for early detection of ovarian metastasis

# Treatment

## Medical Therapy
- Management of Krukenberg tumor is driven by the identification and treatment of the primary cancer.
- Chemotherapy/radiation has no significant effect on the prognosis of patients with Krukenberg tumors.

## Surgery
- Bilateral oophorectomy may only be performed for patients where the metastasis is localized to the ovaries.
- The significance of early detection of ovarian metastasis and the importance of monitoring serum CA-125 level may improve the prognosis.
- Surgical resection may not be an option if the tumor has already metastasized to other sites.

## Prevention
- There are no preventive measures available for Krukenberg tumors.

# Case Studies
Case #1