Moderators: Robert H.Young and Jaime Prat
Professor of Pathology
Director of Anatomic Pathology
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts, U.S.A.
A 58-year-old woman with abdominal pain was found to have
bilateral ovarian tumors with involvement of the bowel serosa. One ovary, from which slide obtained,
measured 11 cm and the other 5 cm. The largest neoplasm had a mottled appearance with tan-yellow areas
alternating with purple foci. The consistency varied from firm to soft.
The designation Krukenberg tumor should be reserved for tumors with an appreciable component
(arbitrarily defined as >10% of the tumor) of signet ring cells and no evidence of another specific
diagnosis such as clear cell carcinoma or mucinous carcinoid, or any other primary neoplasm that rarely
has signet ring cells. As recently emphasized  many Krukenburg tumors have a dominant microscopic
appearance that is not characterized by signet-ring cells lying in a cellular stroma, the "textbook"
morphology of the Krukenberg tumor. Summarizing the diverse spectrum of the Krukenberg tumor and
contrasting it with the much rare metastases of intestinal-type gastric cancer  will be the focus of
this case presentation.
The frequency of the Krukenberg tumor varies with that of gastric carcinoma in the population and
accordingly it is common in Japan but uncommon in North America and many other parts of the world. The
average age of the patients is about 45 years. This obviously indicates that many patients are
relatively young and accordingly, there should not be, as there sometimes is, reluctance to diagnose the
tumor in the reproductive years. This age distribution is due to the relative youth of many patients
with gastric signet-ring cell carcinomas and the greater vascularity of the ovary in young women, which
facilitates hematogenous spread.
The symptoms that patients with a Krukenberg tumor have are extremely variable. Most have symptoms
related to ovarian involvement similar to that of any patient with ovarian cancer. Notably, the
Krukenberg tumor is one of the ovarian tumors most often associated with stromal luteinization and
endocrine manifestations as a result ("ovarian tumor with functioning stroma"). This is seen
disproportionately in patients who are pregnant. This can be treacherous particularly if the Krukenberg
tumor has a tubular pattern, the combined clinical and pathological picture resulting in the tumor being
easily misconstrued as a Sertoli-Leydig cell tumor. This was a common error in a series of 13 tubular
Krukenberg tumors reported some years ago  and is an ever present trap for the pathologist; this issue
is considered further in the section on differential diagnosis.
Although symptoms related to the ovarian tumors usually dominate (only 25-30% of patients are
initially known to have a primary elsewhere) in some cases they are overshadowed by symptoms related to
the primary tumor at its original site or at other sites of metastatic spread. Examples of the latter
are as diverse as pulmonary symptoms due to pleural effusion or massive embolization of tumor in the
lungs, to gastric symptoms not related to primary gastric cancer but rather breast cancer that has spread
there as well as to the ovaries, to ureteral obstruction due to narrowing of the ureteral lumen due to
metastasis, and pain due to bone metastases. Diffuse infiltration of the marrow may result in
thrombocytopenia purpura, anemia and leukoerythroblastosis. In these various cases the ovarian tumors
may be "incidental" findings found during evaluation of the varied symptoms. At operation ascites is
common and liver metastases are rare. If not already known, the carcinoma that has resulted in the
Krukenberg tumor is usually either found intraoperatively (particularly if a frozen section provokes a
search for the primary) or becomes evident within the next six months. The primary neoplasm, however, is
hard to find because of its small size in some cases and is not detected until 5 or more years after the
metastatic tumor in the ovary in rare instances.
About 76% of Krukenberg tumors originate in the stomach, 11% in the intestines (usually colon or
rectum), 4% in the breast, 3% in the biliary system, 3% in the appendix, and the remaining 3% in
miscellaneous sites such as pancreas, uterine cervix, urinary bladder (including urachus) and renal
Krukenberg tumors, at least 80% of which are bilateral (in some series all have been bilateral at
least microscopically), are typically solid with external surfaces that are characteristically
bosselated, sometimes strikingly so, and devoid of appreciable adhesions
The features of
their sectioned surfaces are quite variable. They vary from soft, even spongy or gelatinous, to firm,
depending on the degree of edema or mucin spillage into the stroma, or stromal hypercellularity and
fibrous transformation. The sectioned surface may be uniform but ill-defined nodularity or sometimes
discrete nodules may be seen. The color is equally variable, white to yellow-tan to dusky red-purple
with, in some cases, extensive hemorrhage. Cystic degeneration is occasionally seen and rarely
thin-walled cysts are present. The gross appearance contrasts with the typically softer more necrotic
appearance of typical metastatic colon cancer and the rare metastatic cancers from intestinal-type
adenocarcinoma of the stomach . The size is variable; most are over 5 cm., with an average size of
about 10 cm, but they are typically not huge neoplasms, uncommonly exceeding 20 cm.
Microscopic examination may show various quite different appearances as recently highlighted in what
is the largest experience published to date . The nature of the stroma and the prominence of signet
ring cells are the first two variables that affect the morphology of the tumor. The stroma may be
cellular, the feature that led to the misdiagnosis of the tumor in its first description as a "mucinous
sarcoma." The cellularity is only rarely pronounced enough to provide a true sarcoma-like look despite
the historically interesting trap this presented. In addition to densely cellular areas there may be
regions with the cellularity of the usual ovarian fibroma, with in some cases a storiform pattern. In
yet other cases there is a relatively acellular often edematous stroma which when it separates cellular
areas may result in a pseudolobular appearance on low power examination. Finally, in some other cases
the stromal reaction is unimpressive or absent and the profile is that of a glandular and solid
epithelial neoplasm, albeit one, by definition, with signet-ring cells at least focally. Although
mucin-filled signet-ring cells are a requirement for the diagnosis their frequency is variable. In many
cases much of the tumor may be free of signet ring cells, or they are at least scant and not a striking
feature such that a Krukenberg tumor diagnosis does not immediately come to mind. In other cases
signet-ring cells are numerous and closely packed or pools of mucin may contain variable, sometimes
innumerable, numbers of them.
The signet-ring cell is such a typical cell of this tumor that it is sometimes forgotten that not only
may it vary in appearance, but other cell types are usually present. The cytoplasm of the pathognomonic
signet-ring cells is typically pale and vacuolated but occasionally it is dense and eosinophilic; the
cytoplasm sometimes has a bull's-eye appearance, containing a large vacuole with a central eosinophilic
body. Some mucin-rich cells have central rather than eccentric nuclei and small mucin-poor or
mucin-negative cells with non-specific features are usually present. Rarely sheets of clear cells are
present and exceptionally even squamous cells or cells with a transitional appearance are seen.
The aforementioned stromal aspects and signet-ring cells represent the aspects generally emphasized
when these tumors are reported but other features, which in aggregate are almost equally distinctive, are
common. Gland differentiation is present in most of the tumors. The glands are typically small to
medium sized and often have flattened cells that result in a rather characteristic microcystic appearance
in many cases. When these glands lined by innocuous-appearing epithelium lie in a paracellular fibrous
stroma an adenofibroma-like appearance results. Intestinal-type glands may also be seen but a picture
reminiscent of metastatic colon cancer is in rare part because "dirty necrosis" is not a feature, with
rare exceptions, of the glands within a Krukenberg tumor. Occasionally, small or large cysts lined by
minimally atypical-appearing mucinous epithelium or completely flattened benign-appearing epithelium are
present and merging with obvious neoplastic glands, which is almost invariably seen, helps to indicate
that the cysts are due to the Krukenberg tumor, rather than being an independent primary tumor. When
considering the diversity of morphology noted above it is important to reflect that many primary gastric
signet-ring cell carcinomas have focal gland differentiation and indeed a sizable minority of gastric
cancers are of mixed signet-ring cell (diffuse) and intestinal types. Accordingly, when such tumors
spread to the ovary and fall in the Krukenberg group by having signet-ring cells, their glandular
component is also reflected in the ovarian morphology. Small regular round acini, larger hollow tubules
and elongated solid tubules are seen less often but treacherous when conspicuous, so-called tubular
Krukenberg tumor. Entirely non-specific patterns of carcinoma such as growth as cords, masses, and
single cells are present to at least a minor degree in most cases.
Blood vessel and lymphatic invasion is common . It is seen at the periphery of the ovary, in its
substance in cases in which the parenchyma is not effaced, and particularly in the adjacent tissue such
as around the ovarian hilus, the tube, and within the uterine wall. Another characteristic feature of
metastases, surface involvement either observed grossly or microscopically, is less common than with
other gastrointestinal metastases presumably because the spread to the ovary is dominantly hematogenous
or by lymphatics, rather than transperitoneal, in cases of Krukenberg tumor. Lutein cells are often
present in the stroma, particularly if the patient is pregnant. Some Krukenberg tumors, perhaps most
often those that originate in the appendix, contain nests reminiscent of those seen in mucinous
carcinoids but generally lack neuroendocrine cells. However, the latter may be seen but their focal
presence in an otherwise typical Krukenberg tumor is acceptable as is their presence in diverse other
Particularly when there is no known extra-ovarian primary the Krukenberg tumor causes numerous issues
in differential diagnosis. For various reasons Sertoli-Leydig cell tumor is a frequent misdiagnosis.
Causes of Confusion Between Krukenberg Tumor and Sertoli-Leydig Cell Tumor
The above similarities not withstanding, the pathologic differences between the two tumors are such
that distinguishing them, particularly given good sampling, should not be difficult. Although, as noted
above, they may be grossly similar in some cases and microscopy is ultimately definitive, the solid,
fibroma-like gross appearance of some Krukenberg tumors is almost unheard of for a Sertoli-Leydig tumor.
Alternatively, although some Krukenberg tumors may be yellow, at least in part, the striking uniform
yellow cut surface of many SLCTs would be most unusual for a Krukenberg tumor. The signet-ring cells in
SLCTs invariably occur in association with neuroendocrine cells in clusters that typify the mucinous
carcinoid component of occasional heterologous SLCTs. Signet-ring cells in most Krukenberg tumors have a
much more random distribution than those in the typical little clusters of cells that typify the mucinous
carcinoid elements just noted. Many Krukenberg tumors have at least minor foci of non-specific
adenocarcinoma inconsistent with a diagnosis of Sertoli-Leydig cell tumor. Cytologic atypia is generally
more striking in Krukenberg tumors although some SLCTs have bizarre nuclei of degenerative type.
- The tumors often occur in the third to fifth decades.
- Each tumor may be androgenic, the Krukenberg tumor being one of the commonest "non-endocrine
tumors" of the ovary with this feature (so-called ovarian tumor with functioning stroma).
- Both may be soft and edematous on gross inspection.
- Both tumors may have a striking pseudolobular pattern on low power.
- Both may have a striking tubular pattern.
- Signet-ring cells may be seen in SLCTs (those of heterologous type with small nests of mucinous
- Both tumors have usually morphologically indistinguishable lutein-Leydig cells in their stroma,
(only the finding of crystals of Reinke in such cells distinguishes them and they are rarely found).
Two stromal tumors with signet-ring-like cells may cause confusion. The sclerosing stromal tumor may
contain cells resembling signet cells as well as a proliferating fibroblastic component, but the former
cells contain lipid rather than mucin. The diagnosis should be readily made on high-power microscopic
examination, especially with the aid of mucin stains, which are negative. Holtz and Hart  rightly
emphasized the potential for Krukenberg tumors with a prominent relatively acellular fibroblastic stroma
to be misdiagnosed as a fibroma, even on permanent sections, and example of this error can be found in
the older literature. This can be particularly treacherous at the time of frozen section particularly
given gross similarities between the two neoplasms. The rare signet-ring stromal tumor also may enter
the differential diagnosis but its cells also are negative with mucin stains. The unusual luteinized
thecomas that are associated with sclerosis peritonitis have a cellular stromal component similar to the
cellular stroma of some Krukenberg tumors but they lack signet-ring cells.
Surface epithelial carcinomas can be in the differential with a Krukenberg tumor
rarely. Clear cell carcinoma has small tubules in the tubulo-cystic pattern of that neoplasm which are
to a degree simulated by the "microcystic" tubules of Krukenberg tumors. Additionally, rare clear cell
carcinomas have signet-ring cells. In the clear cell carcinoma, mucin, when present, is typically
luminal and extracellular. In portions of the tumor that contain signet-ring cells the presence of
other characteristic features of the tumor, such as papillae (never seen in Krukenberg tumors) permit its
recognition. To complicate the matter, however, misdiagnosing a Krukenberg tumor as clear cell carcinoma
is possible when, rarely, a Krukenberg tumor contains numerous clear cells. The co-existence of typical
foci of Krukenberg tumor is diagnostic. Primary mucinous tumors may contain signet-ring cells but rarely
in great number and confusion with a Krukenberg tumor is almost never a realistic problem. Even when the
latter contains mucinous cysts, non-cystic solid areas of typical Krukenberg tumor are present.
High-grade non-cystic carcinoma in mucinous cystic tumors is usually conventional non-signet ring cell
mucinous adenocarcinoma or in some cases anaplastic carcinoma with differing morphology (large cells with
abundant eosinophilic cytoplasm) from that of a Krukenberg tumor.
Rarely serous carcinomas and less often endometrioid and undifferentiated carcinoma can have
signet-ring cells as documented by Che et al . In their 15 cases they were diffusely distributed in
nine and focal in six. They were all seen in tumors with microcystic patterns. All the cases had other
patters of surface epithelial neoplasia when well sampled and lacked stromal and other features of a
Krukenberg tumor. In our experience a microcystic pattern of the type described by Che et al. is
commonest (in the surface epithelial family) in transitional cell carcinoma but we have not been struck
to date by the presence of signet cells.
Primary mucinous carcinoid tumors that contain large numbers of signet-ring cells are distinguished
from Krukenberg tumors by the distinctive morphology of the former in differentiated areas and presence
of plentiful neuroendocrine cells, which can be confirmed by special stains. It is likely that at least
some of the primary Krukenberg tumors reported are high-grade primary mucinous carcinoids. The majority
of metastatic mucinous carcinoids to the ovary reported (perhaps all of them) in my opinion are best
placed in the category of a Krukenberg tumors so the differential of metastatic mucinous carcinoid with a
Krukenberg tumor is moot.
Mesothelial neoplasms may be a rare diagnostic consideration. The small vacuoles of an adenomatoid
tumor  may mimic signet-ring cells but always are associated with larger, more typical, adenomatoid
formations producing an overall distinctive morphology in aggregate markedly diffuse from that of a
Krukenberg tumor. Malignant mesothelioma may involve the ovary and although signet-ring-like foci may be
seen, other patterns, particularly the tubulo-papillary pattern of mesothelioma should be sufficiently
distinctive as to solve any problem that might arise.
I will conclude by making a few remarks on the other variant of ovarian metastasis of gastric cancer,
that of intestinal type, which is uncommon and has been the subject of limited coverage in the
literature. A recent small series of four cases  does, however, point out differences between this
ovarian metastatic neoplasm and the Krukenberg tumor. The intestinal-type metastases are typically seen
in patients older than those with Krukenberg tumors and are usually seen in patients with a known gastric
carcinoma in contrast to the situation in many cases of Krukenberg tumor. Grossly the resemblance is to
the familiar metastatic colorectal carcinoma and on microscopic examination some cases have the familiar
pseudoendometrioid morphology of ovarian spread of that cancer. Indeed, two of the four cases I recently
reported with Dr. Melinda Lerwill had such an appearance and their differential diagnosis is similar to
that which pertains to metastatic colorectal carcinoma versus primary endometrioid carcinoma. The
remaining two cases in our series were more reminiscent of mucinous primary neoplasms and were
distinguished from them using conventional criteria for distinction of primary and metastatic mucinous
neoplasia, including of course due consideration of the history and overall clinical background. It
should be noted that inevitably there is some overlap inasmuch as just as Krukenberg tumors may show
gland differentiation as recently emphasized , so some metastatic intestinal adenocarcinomas in the
ovary may have a minor component of signet ring cells. Nonetheless, the overall morphology is markedly
different in the two variants of ovarian spread of gastric cancer.
- Kiyokawa T, Young RH, Scully RE. Krukenberg tumors of the ovary. A clinicopathologic analysis of 120 cases with emphasis on their variable pathologic manifestations. Am J Surg Pathol 30:277-299, 2006.
- Lerwill MF, Young RH. Ovarian metastases of intestinal-type gastric carcinoma. A clinicopathologic study of 4 cases with contrasting features to those of the Krukenberg tumor. Am J Surg Pathol. In press.
- Bullon A, Arseneau J, Prat J, Young RH, Scully RE. Tubular Krukenberg tumor. A problem in histopathologic diagnosis. Am J Surg Pathol 5: 225-232, 1981.
- Holtz F, Hart WR. Krukenberg tumors of the ovary. A clinicopathologic analysis of 27 cases. Cancer 50: 2438-2447, 1982.
- Hart WR. Diagnostic challenge of secondary (metastatic) ovarian tumors simulating primary endometrioid and mucinous neoplasms. Pathology International 55:321-243, 2005.
- Che M, Tornos C, Deavers MT, Malpica A, Gershenson D, Silva EG. Ovarian mixed-epithelial carcinomas with a microscopic pattern and signet-ring cells. Int J Gynecol Pathol 20:333-328, 2001.
- Phillips V, McCluggage WG, Young RH. Oxyphilic adenomatoid tumour of the ovary: a case report with discussion of the differential diagnosis of ovarian tumours with vacuoles and related spaces. Int J Gynecol Pathol In press.