Ovary tumor
Metastases to ovary
Upper gastrointestinal tract

Author: Carlos Parra-Herran, M.D. (see Authors page)

Revised: 6 June 2016, last major update May 2016

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Upper gastrointestinal tract [title]

Cite this page: Upper gastrointestinal tract. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/ovarytumorupperGItract.html. Accessed December 17th, 2017.
Definition / general
  • Secondary ovarian involvement by an adenocarcinoma of gastric, pancreatic or biliary tract origin is, by definition, evidence of advanced tumor stage (pM1), and carries a poor prognosis
  • Significant overlap of clinical, radiologic and pathologic features between primary and metastatic ovarian adenocarcinoma
  • In the work up of a mucinous ovarian neoplasm, a secondary malignancy should always be excluded pathologically or clinically
Terminology
  • Although commonly used to refer to all metastatic carcinoma involving the ovary, the term Krukenberg tumor strictly refers to adenocarcinoma with signet-ring cell differentiation; most (76%) arise from the stomach (J Clin Pathol 2012;65:585)
Epidemiology
  • The rate of secondary (metastatic) ovarian malignancies varies from 6 - 22% (Pathol Int 2005;55:231)
  • The rate of metastatic tumors from non-gynecologic organs is 9 - 14% (World J Gastrointest Surg 2010;2:109)

  • Gastric carcinoma
    • Average age of diagnosis is 45 years
    • An ovarian mass is usually the presenting sign, and 70 - 75% of patients have no primary identified at time of diagnosis
    • Rates of ovarian involvement by gastric carcinoma depends on:
      • Prevalence - more frequent in regions with high prevalence such as Japan and Colombia
      • Type of cancer – diffuse (signet ring cell) type is more likely to metastasize
      • Young patients (< 36 years) have higher rates of diffuse-type cancer, with reported ovarian involvement in 55% of cases (Adv Anat Pathol 2006;13:205)

  • Pancreatic and biliary tree carcinoma
Pathophysiology
  • Poorly differentiated tumors (most with signet-ring cell morphology) are more likely to metastasize to the ovary
Clinical features
  • Symptoms related to a pelvic mass include abdominal pain or discomfort, bowel obstruction, abnormal vaginal bleeding
Laboratory
  • Elevated CA-125 levels (> 100 U/mL) are common; suggested as a useful feature to distinguish from primary ovarian mucinous carcinoma (Gynecol Obstet Invest 2011;72:196), which have elevated CEA levels (> 5 ng/mL) and CA19-9 levels (> 37 U/mL) in a minority of cases
Radiology description
  • Bilaterality is a strong indicator of secondary origin, and occurs more frequently in gastric cancer (~ 80%) than in colon and pancreatobiliary tumors (Ultrasound Obstet Gynecol 2012;39:581)
  • Krukenberg tumor: bilateral complex masses with hypodense solid components (due to prominent stromal reaction) and internal hyperdensity (mucin) on T1 and T2 weighted MRI images
  • Other types: cystic and solid masses with multinodular and necrotic solid components
Treatment
Gross description
  • Mass is frequently complex (solid and cystic) or purely solid
  • Purely cystic unilocular lesions are rare
  • Solid tumors have a multinodular appearance and extend to the ovarian / tumor surface
  • Some authors have reported a predominant small size (< 10 cm) and bilateral ovarian involvement; algorithms based solely on laterality and size have been proposed to separate primary from secondary neoplasms with high accuracy (Am J Surg Pathol 2003;27:985, Am J Surg Pathol 2008;32:128)
  • There is, however, reported evidence of significant overlap of such features: in a recent series, all metastatic carcinoma of upper GI origin were unilateral (2 / 6) or > 10 cm (4 / 6) (Int J Gynecol Pathol 2016;35:191)
Gross images

Images hosted on other servers:

Krukenberg tumor of gastric origin

Microscopic (histologic) description
  • Metastases frequently mimic the appearance of an ovarian mucinous neoplasm
  • May have areas mimicking a borderline or even benign primary mucinous tumor

  • Several clinical and pathologic features have been described as indicative of secondary (metastatic) origin, including:
    • Bilaterality
    • Size less than 10 cm
    • Surface involvement
    • Infiltrative pattern of invasion
    • Presence of signet ring cells
    • Extensive lymphovascular space invasion
    • Mucin extravasation
  • If any of the above is present, the possibility of a metastasis should be considered and prompt ancillary testing and clinical investigation should be conducted

  • The term Krukenberg tumor should be reserved for adenocarcinoma involving the ovary with a signet ring cell component > 10% of tumor volume
  • Krukenberg tumors are usually solid and show a prominent fibromatous background
    • Stroma is variably cellular and edematous
    • Tumor cell infiltration is subtle, but diffuse
    • Carcinoma cells have a dense eosinophilic cytoplasm and hyperchromatic irregular nuclei
    • Signet-ring cells are usually dispersed between stromal fibers, but can also aggregate in clusters

  • Upper GI adenocarcinoma without a significant (> 10%) signet-ring cell component tends to be moderately to poorly differentiated
    • The amount of intracellular mucin varies according to the degree of mucinous differentiation

  • Adenocarcinoma with mucin depletion mimics the architecture and cytoplasmic appearance of primary endometrioid tumors; however, nuclear pleomorphism and hyperchromasia tends to be prominent, and exceed what is expected for a primary ovarian tumor
Microscopic (histologic) images

Images hosted on PathOut servers:

Gastric (left four images) and pancreatic (fifth image)
Contributed by Carlos Parra-Herran, M.D.

Positive stains
  • Immunohistochemistry is useful to distinguish primary ovarian tumors from lower GI tract metastases (colon, rectum, appendix), but its role in identifying upper GI primaries (gastric, pancreatic, biliary tract) is limited given the significant overlap with primary ovarian tumors
    • CK7: 88% (vs 95% of primary ovarian tumors)
    • CK20: 43% (vs 45% of primary ovarian tumors)
    • CDX2: 65% (vs 50% of primary ovarian tumors)
    • SATB2: 11.5% (vs 5% of primary ovarian tumors)

  • Mucins MUC1, MUC4 and MUC5AC may be useful markers of GI adenocarcinoma:
  • MUC1 and MUC5AC may discriminate among different origins (Int J Gynecol Pathol 2014;33:166, Int J Clin Exp Pathol 2013;6:613)
    • Pancreatic: MUC1+, MUC5AC+
    • Biliary: MUC1+, MUC5AC-
    • Ovary: MUC1-, MUC5AC+
    • Gastric and colorectal: MUC1-, MUC5AC-

  • Keratin 17 (CK17) is expressed in 90% of pancreatic and 50% of pancreatobiliary adenocarcinoma, whereas esophageal and gastric cancers tend to be negative (Am J Surg Pathol 2005 Mar;29:359)
Negative stains
  • Rates of expression in upper GI tract tumors are as follows:
    • PAX8: 2.8% (vs 30 - 65% of primary ovarian mucinous tumors and 80% of primary ovarian endometrioid tumors)
    • Among upper GI tumors, PAX8 expression has only been documented in pancreatic and esophageal adenocarcinoma (Am J Surg Pathol 2011;35:816)
    • ER: 0% (vs 30% of primary ovarian tumors)

  • Inactivation of DPC4 / SMAD4 tumor suppressor gene is seen in approximately 55% of pancreatic ductal adenocarcinoma (Am J Clin Pathol 2001;116:831)

Images hosted on other servers:

An algorithm to determine origin using currently available markers

Differential diagnosis
  • Primary ovarian neoplasm (benign, borderline or malignant): no suspicious features described above (bilaterality, surface involvement, signet-ring cell morphology, etc), PAX8+
  • Metastases from lower GI tract: positive for SATB2 / CK20 / CDX2 / MUC2, CK7-
  • Metastases from cervix: p16+ (strong, diffuse)
  • Sertoli-Leydig cell tumors: main differential with Krukenberg tumors given the solid appearance, the fibromatous background and the presence of cells with dense eosinophilic cytoplasm seen in both entities
    • The former lacks signet-ring cells and cytokeratin expression (pan-cytokeratin, CK7, CK20), and will conversely express inhibin and calretinin