Department of Surgery,
Hospital, . Camden, New Jersey
A Krukenberg tumor is a rare tumor of the ovary derived from metastatic gastrointestinal tissue. Although the eponym is attributed to Dr. Friedrich Krukenberg, a German gynecologist and pathologist, the Krukenberg tumor was actually described by both Paget (1854) and Wilks (1859). Worldwide, they account for about 1% of all ovarian neoplasms. Gastric cancer is the most frequent primary source, followed by breast, colon and appendix. For those carcinomas originating from the intestinal tract, about 80% are found within either the sigmoid colon or rectum. Presenting symptoms include nonspecific abdominal pain, distention, ascites, virilization, hirsutism and menometrorrhagia.
The Krukenberg tumor was originally described by Paget (1854). The eponym is attributed to Dr. Friedrich Krukenberg, a German gynecologist and pathologist. In 1896, he published five case reports on what he believed to be at the time a new type of ovarian tumor. However, in 1902, Dr. Schlagenhauffer determined that these tumors were in fact of metastatic gastrointestinal tract origin.
Krukenberg tumors are pathologically “signet ring cell” ovarian adenocarcinoma. They account for 1-2% of all ovarian tumors world-wide. In Japan, their prevalence is greatly increased to almost 20% (due to the increased prevalence of gastric cancer).3 The stomach is the primary site in 70% of these cases, followed by breast, colon, and appendix, in that order.1 For those tumors originating from the intestinal tract, 80% are found to be within the sigmoid colon or rectum.1 Unfortunately, these primary colonic tumors are often too small for endoscopic detection (i.e. colonoscopy), thereby necessitating either CT scan or ultrasound.
Women are typically diagnosed with Krukenberg tumors in the perimenopausal fifth decade of life, with the average age of diagnosis being 45 years-old. It is hypothesized that this young age of diagnosis is related to the great vascularity of their ovaries, which facilitates vascular metastasis.1 It is interesting to note that for those patients with Krukenberg tumors originating from the colon, the mean age of presentation is subsequently delayed. Presenting symptoms usually include, but are not limited to, vague abdominal pain, distention, and/or ascites. Occasionally, abnormal vaginal bleeding, virilization and hirsutism can be seen.4
Krukenberg tumors are bilateral in 80% of cases.3 The route of metastasis from the gastrointestinal tract to the ovaries is hypothesized to be via lymphatics. The mortality rate for Krukenberg tumors is relatively high and a majority of patients die within two years of diagnosis, with a median 5-year survival of 14 months.3 The prognosis is poor if the primary tumor is identified after ovarian metastasis has occurred, and even worse if the primary is unidentified.5
Metastatic adenocarcinoma to the uterine cervix from the gastrointestinal tract is rare and very few cases are reported. The route of metastasis to the cervix is surmised to be retrograde via lymphatics, similar to the pathway of metastases to the ovary.6 Cervical metastasis may often be the presenting symptom, discovered either synchronously or after the diagnosis of gastro-intestinal carcinoma has been made. Unfortunately, for this subset of Krukenberg tumor patients, their diagnosis is poor no matter when their cervical metastasis is identified.6
Gross findings of a Krukenberg tumor-containing ovary include asymmetrical enlargement, lobular contour, and either solid or cystic consistency. Commonly, the ovaries are spared from intra-peritoneal adhesions and present without any peritoneal deposits.3 Kiyokawa et al. reported that Krukenberg tumors can range in texture from firm and solid to edematous and gelatinous, with only approximately 30% containing cysts. They also found the mean size to be 10.4 cm.4
Microscopically, the Krukenberg tumor is composed of mucin-laden signet-ring cells and ovarian stromal cells. Krukenberg tumors can either display a prominent tubular pattern or one that is clustered. Lobular patterns, with nodules separated by stroma, can also be seen. Mucin-laden signet ring cells are essential for the diagnosis of a Krukenberg tumor.3 However, sometimes the desmoplastic reaction of the stromal cells can be so severe that it obscures the signet-ring pattern. The literature describes great variation in the different cellular atypia. The stroma can range from cellular to paucicellular and from edematous to mucoid. The degree of signet-ring cell prominence also varies from case to case.4 The overall morphology of the adenocarcinoma is graded based on the presence of mucin, edema, stromal patterns and the number of signet-cells. Often it is difficult to differentiate between primary and metastatic ovarian carcinoma. Careful attention must be paid to the microscopic finding of invasion and implantation to distinguish the two metastatic modes.1 Based on 120 Krukenberg tumor cases, Kiyokawa determined that the histological spectrum is much more diverse than what has been previously reported.4
In these aforementioned cases, special diagnostic stains can be used to highlight the presence of signet cells. Immunohistochemistry can also be used to decipher metastatic carcinoma from primary ovarian neoplasms.1 The ovarian tumors that are immunoreactive to CEA, stain positive for cytokeratin 20 (CK20) and negative for cytokeratin 7 (CK7), are more likely to be of colorectal origin and increase the pathologist’s confidence in making the diagnosis of a Krukenberg tumor.3 This differs from primary ovarian tumors, since they usually test positive for CK 7 and negative for CK 20. Other immunohistochemicals currently under investigation include CD44v6, vascular endothelial growth factor, and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Lou et al. compared 35 cases of Krukenberg tumor to normal tissue and found that the expression rate of CD44v6, VEGF, MMP-2 and MMP-9 were significantly higher in those with Krukenberg tumors.7 However, these factors were also found within primary epithelial ovarian carcinomas and were therefore not exclusive to Krukenberg tumors.5 CA-125 is a tumor marker elevated in patients with Krukenberg tumors and usually found to decrease after resection. Therefore CA-125 can be used either for post-operative follow up and/or for patients with a history of adenocarcinoma with no identifiable ovarian metastasis.3
There is currently no optimal or curative treatment strategy for Krukenberg tumors. Surgical resection has only been shown to be effective in patients with limited metastasis confined to the ovaries.3 Patients often experience recurrence after curative surgery thereby preventing them from receiving further treatment. For these types of patients, Cheong et al. investigated the role of metastectomy for the management of metachronous tumors following curative surgery. Their study found the median survival for patients undergoing metastatic resection was significantly increased versus the non-resection control group (17 months vs. 3 months).5 Further investigation is warranted to decide the optimal role of surgery in patients with Krukenberg tumors.
Chirurgia (Bucur). 2008 Jan-Feb;103(1):23-38.
[Features of Krukenberg-type tumors--clinical study and review].
Mateş IN, Iosif C, Bănceanu G, Ionescu M, Peltecu G, Dinu D, Constantin A, Hoară P, Mitru C, Constantinoiu S.
Clinica de Chirurgie Generală şi Esofagiană Sfânta Maria, U.M.E Carol Davila, Bucureşti. firstname.lastname@example.org
Krukenberg-type tumors (KT) are rare among ovarian metastases, but responsible for the most frequent diagnostic confusions with ovarian cancer. They are peculiar: uncertain pathogenesis, challenging etiological diagnosis, poorer prognosis for the primary. We studied 9 cases, with a mean age of 52 years, operated since 2001; no case was discovered as a result of prophylactic oophorectomy. Timing of TK diagnosis: 3--metachronous, 4--synchronous, as incidental discovery and 2--retrospective pathological diagnosis. Site of primary: 3--gastric, 5--colonic or appendiceal, 1--breast. Imaging appearance was useful only if interpreted in clinical conditions. Morphology: 7/9 bilateral, solid or mixed gross appearance, oval, mean diameters 9.4/7.8 cm. Microscopy: in 8 KT of digestive origin, 3--signet-ring cell carcinoma, 3--mucinous adenocarcinoma, 2--mixed pattern; 1 KT or breast origin was diagnosed by immunohistochemistry; 6/9 presented microscopic peritoneal despite a lack of strong correlation with the appearance of carcinomatosis or cytology of ascites. Survival: 3--no evidence, 5--disease-free after 4-13 months, 1--survived 2 years after debulking (4 years after colectomy). Clinical, evolutive and prognostic features of KT are determined by the biologically behavior of the primary (rapid lymphatic and hematogenous spread to the ovary), so the benefit of surgery is limited. Bilateral ovarian tumors, particularly in premenopausal women, must raise a high index of suspicion for KT, before or during surgery; diagnosis is a team challenge.
Adv Anat Pathol. 2006 Sep;13(5):205-27.
From krukenberg to today: the ever present problems posed by metastatic
tumors in the ovary: part
perspective, general principles, mucinous tumors including the krukenberg
James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. email@example.com
This review considers historical aspects of metastatic tumors to the ovary, general principles that aid in their evaluation, and metastatic mucinous tumors, including the Krukenberg tumor. The historical timeline on the Krukenberg tumor dates back to the legendary Sir James Paget and the story is followed through the well-known, albeit flawed, contribution of Friedrich Krukenberg and others who have contributed important papers over the years, including the overlooked contribution of the French investigator Gauthier-Villars. Knowledge of metastatic colorectal carcinoma is traced back to the famed British surgeon Sir John Bland-Sutton and followed through to more recent contributions, including the important one of Lash and Hart. Contributions on mucinous tumors conclude the historical perspective, note being made of the recent evidence suggesting that the long held contention of Dr Robert E. Scully that ovarian mucinous tumors in patients with pseudomyxoma peritonei usually originate from the appendix is correct. The section on general principles highlights the many clinical, gross, microscopic, and special techniques such as immunohistochemistry that may aid in determining that an ovarian tumor is metastatic with emphasis on the first 3 mentioned aspects. Problematic features such as a tendency for metastatic tumors to be cystic, even when the primary tumors are not, and for many metastatic tumors to mature in the ovary (so-called maturation phenomenon), are emphasized. Of the many helpful findings that resolve the problem, the characteristic features of surface implants are highlighted. The contribution on the Krukenberg tumor reviews the varied microscopy of this tumor pointing out that the well-known pattern of signet-ring cells in a cellular stroma, albeit characteristic, is often not striking and frequently overshadowed by other microscopic features. The latter include, in many cases, a rather unique microcystic pattern. The final portion of the essay reviews mucinous tumors of non-Krukenberg type, beginning with those that originate from the appendix. The appendiceal neoplasms have distinctive features in most cases being particularly well differentiated, and this is also seen in their ovarian metastases. Other mucinous tumors that commonly simulate closely metastatic neoplasms, include those from the pancreas in particular, but also diverse other sites, are then reviewed.