Ovary

• Secondary ovarian involvement by colorectal cancer (CRC) is, by definition, evidence of advanced tumor stage (pM1)
• There is significant overlap of clinical, radiologic and pathologic features between primary and metastatic ovarian adenocarcinoma
• In the workup of mucinous or endometrioid-like ovarian neoplasms, a secondary malignancy should always be excluded, either pathologically or clinically

• Metastases to the ovary (OM) are also known as secondary tumors of ovary (STO)
• Although commonly used to refer to all metastatic carcinoma involving the ovary, Krukenberg tumor (KT) strictly refers to adenocarcinoma with signet ring cell differentiation, most of which (76%) arise from the stomach (Am J Surg Pathol 2006;30:277)

• Spread to the ovaries can be hematogenous, lymphatic, transperitoneal or by direct extension (Clin Exp Metastasis 2017;34:295)
  • Hematogenous spread may be more important for colorectal primary than other sites of origin (Obstet Gynecol Int 2011;2011:612817)

• See Figure 5 for algorithm to determine origin using currently available markers: Int J Gynecol Pathol 2016;35:191

Table 1. Most common immunohistochemical expression
patterns seen in primary ovarian mucinous neoplasms and
secondary epithelial tumors from gastrointestinal origin

	Lower GI	Upper GI	Ovarian
CK7	Negative	Positive	Positive
SATB2	Positive	Negative	Negative
PAX8	Negative	Negative	Positive*
CK20	Positive	Pos / neg	Pos / neg
CDX2	Positive	Pos / neg	Pos / neg
MUC2	Positive	Pos / neg	Pos / neg
ER	Negative	Negative	Pos / neg
Beta catenin	Pos / neg	Negative	Negative
MUC1	Pos / neg	Positive	Positive

• GI = gastrointestinal; pos = positive; neg = negative
• In this table, positive markers are those with expression in > 75% and negative markers those with expression in < 25% of tumors in the indicated category
• Expression ranging from 25 to 75% is coded as pos / neg
• *PAX8 expression was 75% in all primary ovarian neoplasms but lower in the subgroup of primary ovarian carcinomas (65%)
• Table contents adapted from Int J Gynecol Pathol 2016;35:191

• Most patients manifest changes in bowel habits, rectal bleeding and bloating; constitutional symptoms are less frequent
• Symptoms related to a pelvic mass include abdominal pain, discomfort or bowel obstruction
  • Abnormal vaginal bleeding or even virilization may result from metastasis induced luteinization of the ovarian stroma (Am J Surg Pathol 2006;30:277)
• Mean size of the metastatic lesion usually exceeds the size of the primary tumor
  • Right sided CRC with OM is more likely to present with peritoneal carcinomatosis than those with left sided primary (Curr Oncol 2021;28:2914)
• Most cases are stage pT3 (full thickness wall involvement) or pT4 (perforation of visceral peritoneum or direct invasion of adjacent structures); nodal involvement occurs in 87% (Int J Clin Oncol 2020;25:1822)
• Left sided CRC is more common among OM (Curr Oncol 2021;28:2914)
  • Rectosigmoid is most common site (Int J Colorectal Dis 2020;35:1035, Virchows Arch 2015;467:79)

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Contributed by Adam Lechner

• Metastatic colorectal adenocarcinoma to the ovary usually has a mucinous or a conventional glandular appearance
  • Mucinous carcinomas have intestinal (goblet cell) differentiation
  • Mucin extravasation and signet ring cell morphology can be seen
  • Krukenberg tumor is a term that should be reserved for adenocarcinoma involving the ovary with a signet ring cell component > 10% of the tumor volume, regardless of its site of origin (Adv Anat Pathol 2006;13:205)
  • Conventional tumor cytomorphology with mucin depletion mimics the architecture and cytoplasmic appearance of a primary ovarian endometrioid tumor
  • Nuclear pleomorphism and hyperchromasia tend to be prominent and exceed what is expected for a primary ovarian tumor
  • Central glandular necrosis (dirty necrosis) is also more typical of colorectal tumors, although it is not entirely specific
  • Desmoplastic stromal response
  • Mucinous metastases frequently mimic the appearance of an ovarian mucinous neoplasm and 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 (Am J Surg Pathol 2003;27:281, Diagn Pathol 2021;16:20):
  • Bilaterality
  • Size < 10 cm
  • Surface involvement
  • Infiltrative pattern of growth with intervening benign ovarian stroma
  • Presence of signet ring cells
  • Extensive lymphovascular space invasion
  • Mucin extravasation
• If any of the above features is present, the possibility of a metastasis should be considered and prompt ancillary testing and clinical investigation should be performed

Contributed by Carlos Parra-Herran, M.D. and Adam Lechner

• See Colon - adenocarcinoma

• PAX8: 0% (versus 30 - 65% of primary ovarian mucinous tumors and 80% of primary ovarian endometrioid tumors)
• ER: 0% (versus 30% of primary ovarian tumors)
• See Diagrams / tables

A 51 year old woman presents with a 6 month history of menorrhagia and abdominal discomfort. Pelvic imaging identifies bilateral complex cystic adnexal masses of 7 and 9 centimeters. Whole body PET / CT identifies an additional hypermetabolic lesion in the cecum and in the liver. A representative section taken from a bilateral salpingo-oopherectomy specimen is shown above. Which of the following immunohistochemical results provides the strongest support for the diagnosis?

1. CDX2+
2. CK7+
3. MUC2+
4. SATB2+

D. SATB2+. Bilateral, small (< 10 cm) ovarian masses are concerning for a metastatic process. The presence of a lesion in the cecum with an additional metastatic focus in the liver raises the possibility of colorectal origin. Histology shows punched out, angulated glands with intraluminal dirty necrosis consistent with metastatic colorectal adenocarcinoma. The immunoprofile of this tumor is CK7- / CK20+, CDX2+, SATB2+, MUC2+, PAX8-. Although MUC2, CDX2 and SATB2 are both positive in CRC, primary ovarian malignancies (particularly mucinous neoplasms) are often positive for CDX2 and MUC2 as well (usually with patchy distribution).

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Reference: Colorectal adenocarcinoma

A 60 year old woman is diagnosed with colorectal adenocarcinoma with isolated metastases to the left ovary. She undergoes cytoreductive surgery, including low anterior resection and oophorectomy. Which of the following statements is correct?

1. Adjuvant chemotherapy is contraindicated
2. The presence of signet ring cell differentiation would indicate better overall survival
3. This patient's colorectal cancer likely originated in the cecum
4. This patient has a relatively better prognosis compared to those with additional metastases beyond the ovary

D. This patient has a relatively better prognosis compared to those with additional metastases beyond the ovary. Isolated ovarian metastasis in colorectal adenocarcinoma shows improved survival over additional metastases to extraovarian sites. Unilateral ovarian metastasis in CRC most commonly originates from a left sided primary. HIPEC adjuvant therapy at the time of cytoreductive surgery improves survival. Signet ring cell differentiation is a uniformly negative prognostic factor.

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Reference: Colorectal adenocarcinoma