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Abstract
Recent years have seen a dramatic change in the pathological approach to ovarian mucinous neoplasms. A substantial proportion of tumours previously considered to be ovarian primaries actually represent secondary ovarian involvement by tumours elsewhere in the body. Two major categories of tumour have completely disappeared from the diagnostic spectrum: ovarian ‘borderline’ mucinous tumour associated with pseudomyxoma peritonei, and widely disseminated mucinous carcinomas. The emergent picture of true ovarian primary carcinoma of pure mucinous morphology is that this is a rare malignancy that is low grade and low stage at presentation in the vast majority of cases, with a very low likelihood of aggressive clinical behaviour. A large volume of literature has appeared concerning the pathological distinction of primary from metastatic ovarian mucinous neoplasms in view of the dramatically different prognosis and treacherously similar morphology. Clinicopathological parameters useful in the distinction of primary from metastatic mucinous ovarian carcinomas are reviewed. Major features favouring metastases are bilaterality, size <10 cm, surface involvement, extensive intra-abdominal spread and an extensive infiltrative pattern with desmoplasia. Two morphological patterns essentially exclude ovarian origin: colloid and signet ring carcinomas. Features favouring primary ovarian origin are unilaterality, large size >12 cm, smooth external surface and association with other ovarian pathology. An admixture of benign, borderline and malignant patterns in the same tumour favour primary origin, but can be misleading as a ‘maturation’ pattern in metastases can result in the same appearance.
- Ovary
- neoplasm
- metastasis
- mucinous
- pathology
- histopathology
- gynaecological pathology
- cytology
- cytopathology
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Introduction
Recent years have seen a dramatic change in the pathological approach to ovarian mucinous neoplasms. Although difficulties in distinguishing between primary and metastatic ovarian tumours are well recognised,1–8 over the last three or so decades it has emerged that a substantial proportion of tumours previously considered to be ovarian primaries actually represent secondary ovarian involvement by tumours elsewhere in the body. Two major categories of tumour have completely disappeared from the diagnostic spectrum of ovarian primary neoplasms. The first is ovarian ‘borderline’ mucinous tumour associated with pseudomyxoma peritonei: these are now considered to be of appendiceal, and rarely other, origin in the vast majority of cases, with an exceptionally rare case arising in the ovary from a background of teratoma.9 ,10 Second, widely disseminated mucinous carcinomas are currently seldom proven to be of ovarian origin if completely investigated; in the past a widely disseminated mucinous malignancy was considered consistent with ovarian origin due to the presence of ovarian masses, while nowadays this would prompt a concerted search, usually successful, of an alternative site of origin and more appropriately targeted management. The emergent picture of true ovarian primary carcinoma of pure mucinous morphology is that this is a rare malignancy that is low grade and low stage at presentation in the vast majority of cases, with a very low likelihood of aggressive clinical behaviour.11 ,12
This has led to several important changes. There is a reduction in the relative incidence of malignant and, to a lesser extent, borderline, mucinous ovarian neoplasms, making this a rare malignant subtype exceeded by serous, clear cell and endometrioid carcinomas. A large volume of literature has appeared concerning the pathological distinction of primary from metastatic ovarian mucinous neoplasms in view of the dramatically different prognosis. This has been necessary as metastatic tumours are treacherously difficult to identify because of their ability to present clinically and morphologically as ovarian primaries. This literature is the subject of the current review which will focus on the traditional clinicopathological parameters useful in the distinction of primary from metastatic mucinous ovarian carcinoma.
Reasons for accurate identification of primary and metastatic mucinous carcinomas
Although these may seem fairly obvious, it is important to begin with an iteration of the reasons why it is essential to get this distinction right, as this is one of the easiest and worst diagnostic errors that a gynaecological pathologist can make. There are a few settings in which this question applies:
Apparent low stage ovarian carcinoma with no obvious extraovarian primary.
An ovarian neoplasm in the presence of a known other primary where confirmation of an unrelated primary versus metastasis is required.
Disseminated malignancy where the primary site is unclear and ovarian origin is one possibility.
The distinction can influence patient management in a number of ways:
In centres where frozen sections are carried out, a pathologist may be asked to make this distinction to avoid unnecessary staging.
Accurate diagnosis is needed for further patient management; while in disseminated cancer the identification of the exact primary site may be of no more than academic value, targeted treatment nevertheless offers the patient the best possible chance.
Accurate diagnosis enables the patient and her family to obtain correct prognostic information and appropriate counselling.
Cancer treatment has entered an era of personalised management; accurate recognition of the site and nature of a malignancy are essential to ensure that patients are considered for novel therapies whether or not in a trial setting.
Distinction of primary and metastatic ovarian mucinous carcinoma
Clinical parameters
Ideally, the diagnostic process should begin before pathological examination. A history or operative finding of malignancy at another site should always prompt careful consideration of the possibility of the ovarian mass being metastatic.13 The ovary is a frequent site of metastases, from primary tumours of both the genital tract and extragenital sites.13 Primary sites include colon, pancreaticobiliary tract, endocervix, appendix, gallbladder, stomach, endometrium and breast,3 ,4 ,14–19 and more rarely, lung,20 small bowel21 ,22 and urinary tract.23 ,24 The most likely metastatic tumours to masquerade as primary ovarian mucinous tumours are gastrointestinal, pancreatic or biliary tract and endocervical adenocarcinomas.1 ,3 ,4 ,25–27 The large intestine is the most frequent primary source of ovarian metastasis; detection of the ovarian tumour often precedes diagnosis of both primary colorectal carcinoma and appendiceal tumours or may be discovered synchronously at the time of surgery.27–30 Metastatic tumours from the appendix can be potentially difficult to diagnose, as the primary appendiceal tumour can be small in comparison to the large ovarian tumour.30 Although pancreaticobiliary carcinomas are rare, these should be considered as occult primaries, especially in places with a relatively higher incidence, such as intrahepatic cholangiocarcinoma in Thailand which may be silent primaries due to their peripheral location and few clinical symptoms or signs such as jaundice.31 Pancreatic adenocarcinomas can also mimic primary mucinous ovarian carcinomas as they often present synchronously or may be discovered after the ovarian tumour.32 ,33
The extent of disease may be helpful in differentiating between primary and metastatic mucinous tumours. The majority of primary mucinous ovarian carcinomas are usually FIGO stage I or II at presentation,34 ,35 that is, the tumour is limited to the ovaries with or without pelvic extension.36 A recent study12 identified a small number of women with advanced stage primary mucinous ovarian carcinoma associated with poor survival (estimated 0.5–1.5% of advanced ovarian epithelial invasive neoplasms). These were stage III and IV disease—that is, ovarian tumours with peritoneal and lymph node metastasis, with or without distant metastasis. It has also been reported that occasional apparent stage I primary mucinous ovarian carcinomas can behave in an aggressive fashion.37 However, the rarity of these advanced stage and aggressive primary mucinous ovarian carcinomas is emphasised. In broad terms a widely metastatic mucinous carcinoma is far more likely to be a non-ovarian primary. In two studies,27 ,38 all the primary colonic tumours metastatic to the ovaries were at least Dukes stage B (tumour invades beyond the muscularis propria). Extrapelvic spread including omental, hepatic and mesenteric lymph node metastasis favours a diagnosis of metastatic colonic carcinoma over an ovarian primary. Metastasis to the left supraclavicular lymph node, pleura and lung was seen in a study of metastatic intrahepatic cholangiocarcinomas to the ovary,31 and there was metastasis to extraovarian sites including omentum, retroperitoneum, small bowel and retroperitoneal lymph nodes in a study of four patients with intestinal type gastric carcinoma.39
Other clinical features which may be helpful are symptoms related to the primary tumour rather than the ovarian mass, such as abdominal pain or rectal bleeding. It should be noted that a raised serum CA125 is non-specific and may occur in significant numbers of cases of metastatic ovarian tumours.40
Gross morphology
Size and laterality
In general, primary mucinous carcinomas are larger than metastatic mucinous carcinomas. One of the reasons for this is that primary mucinous carcinomas appear to develop from benign and borderline mucinous neoplasms which tend to be the largest ovarian masses overall.18 It is widely accepted that primary mucinous carcinomas (not including rare advanced stage neoplasms12) are usually unilateral, and metastatic mucinous carcinomas are usually bilateral. Using these criteria, a number of algorithms have been proposed to differentiate between primary and metastatic neoplasms. The algorithms15 ,17–19 classify bilateral tumours as metastatic, with or without an added size criterion: one study stated <10 cm.41 Unilateral tumours are more problematic, with sizes of over 10 cm17 ,18 and 13 cm15 favouring a primary tumour. One study stated that unilateral tumours between10 cm and 15 cm should be considered indeterminate and other clinical and pathological features should be taken into account.19
Exceptions to these rules occurred most frequently from pancreatic, small and large bowel, and endocervical primary tumours as these can give rise to metastatic tumours that are large, unilateral and often cystic masses.15 ,18 Additionally unilateral dominant enlargement of bilateral metastases can occur.19 Therefore, although rules of size and laterality may be helpful, other clinicopathological factors should be considered, especially if these parameters are relied on to influence a frozen section diagnosis.
Surface involvement
Gross features favouring a primary mucinous ovarian tumour are a smooth surface with no excrescences or surface implants.17 Borderline tumours usually have similar smooth surfaces.25 ,41 Tumour on the surface of the ovary, sometimes without involvement of the underlying parenchyma, suggests metastasis, and may be due to transcoelomic spread of tumour to the ovary.3 Some studies suggest that blood-borne spread is also significant via the ovarian hilum14 ,42 and surface involvement is not an invariable feature of metastases.
Marked necrosis (in the absence of torsion)
Necrosis or haemorrhage was seen in almost one third of cases in a study of 106 Krukenberg tumours.43 Half of 22 cases of metastatic colon carcinoma showed partly necrotic and haemorrhagic areas.27 However, necrosis was seen in both primary and metastatic tumours and was a non-discriminatory finding in one study of 50 cases.17
Microscopic features
General features
There are some general features common to all primary and metastatic tumours that are useful in distinction. Findings favouring a primary tumour include: an expansile invasive pattern in which back-to-back neoplastic glands are seen with no intervening stroma41; a complex papillary pattern; mural nodules which are solid areas of a cyst wall and may contain anaplastic carcinoma or sarcomatous components; background endometriosis; and association with primary teratoma, adenofibroma, Brenner tumour or a Sertoli–Leydig tumour.3 ,17
Features favouring a metastatic tumour include: an infiltrative invasive pattern; small glands or tubules and single cells; lymphovascular space invasion; a nodular growth pattern in which there are discrete nodules of infiltrative tumour with intervening ovarian tissue containing normal ovarian structures often with stromal desmoplasia; hilar involvement; microscopic surface involvement; and the presence of signet ring cells.3 ,15 ,17–19 ,25
An important feature no longer considered useful in distinction of primary from metastatic tumours is seen in well differentiated mucinous carcinomas. Primary mucinous carcinomas have traditionally been described as having a heterogeneous appearance, incorporating benign, borderline and intraepithelial and invasive carcinomatous areas, which was thought to reflect the progression from benign to borderline to carcinoma.25 ,34 ,35 ,41 However, metastatic ovarian tumours, especially from pancreaticobiliary primaries, may also show a wide range of appearances and may differ from the appearance of the tumour at the primary site. This has been described as a ‘maturation phenomenon’,3 in which the metastatic tumour of mucinous type matures within the ovary to benign or borderline-type epithelium, resulting in a range of mucinous epithelium. Careful sampling of the ovarian tumour and consideration of other gross and microscopic features is recommended to avoid misdiagnosing these tumours as primary ovarian neoplasms.
Microscopic features of metastases from specific sites
Colorectal
Metastases from the colon can have an endometrioid, mucinous or rarely clear cell appearance, or may show a combination of these. The endometrioid-like differentiation resembles endometrioid ovarian adenocarcinoma, with glands lined by stratified epithelium which does not show mucin secretion. Mucinous differentiation mimics mucinous ovarian carcinoma and contains cysts and glands lined by mucinous epithelium, sometimes with focal goblet cells, with extracellular mucin, and often with areas resembling benign or borderline mucinous neoplasm. Therefore these metastases may be confused with primary endometrioid or mucinous carcinomas. However, there is often marked cytological atypia and frequent mitoses which may be helpful in diagnosing a metastatic tumour. Other helpful features in metastatic mucinous carcinoma are abundant extracellular pools of mucin and segmental necrosis in glands and cysts, features rarely seen in ovarian primaries. Two characteristic histological features have been described: a ‘garland pattern’ in which cystic glandular structures containing necrotic debris are surrounded by round tubular glands; and ‘dirty necrosis’ consisting of necrotic material with karyorrhectic debris (due to breakdown of carcinoma cells) which can be seen within garlands and neoplastic glands. In metastatic tumours with endometrioid differentiation, absence of squamous metaplasia may help differentiation from primary endometrioid carcinomas.27 ,28 ,38 ,44–46
Pancreaticobiliary
Metastatic tumours of pancreaticobiliary origin may display cystadenomatous, borderline areas and carcinomatous areas with atypia ranging from mild to marked. In some tumours the benign or borderline areas can closely resemble a primary mucinous ovarian neoplasm. These primary tumours are also often clinically silent, diagnosed synchronously or after the ovarian tumour, and the metastases may be large and unilateral; they are therefore notorious for causing diagnostic difficulty. However, features such as bilaterality, size <12 cm, nodular surface and hilar involvement can help in diagnosis.16 ,31 ,32 ,47–50
Endocervical
Ovarian metastases from endocervical carcinomas may have admixed areas of benign, borderline and carcinomatous mucinous epithelium resembling a primary mucinous neoplasm as well as areas of endometrioid differentiation. The tumours may have confluent glandular, cribriform and papillary patterns, and may have an expansile rather than infiltrative stromal invasion pattern. A helpful feature in identified metastasis from an endocervical carcinoma is that the ovarian tumours may contain epithelium showing a mixture of mucinous and endometrioid features or mucinous epithelium with pleomorphic nuclei, frequent apical mitoses and numerous basal apoptotic bodies, which are features seen in human papillomavirus-related endocervical adenocarcinomas.6 ,26 ,51
Gastric including Krukenberg tumours
Krukenberg tumours are ovarian neoplasms composed predominantly of signet ring cells within a cellular ovarian stroma. They may have a diverse appearance and may also contain mucin-free epithelial cells, small glands lined by flattened epithelium and larger glands lined by intestinal and mucinous type epithelium, but by definition, >10% of the tumour should be composed of signet ring cells. Stromal luteinisation may occur and be associated with endocrine manifestations. Most commonly these metastasise from the stomach, but may also arise from the intestines, breast, biliary system and appendix. The epithelial and stromal components may vary and conspicuous extracellular mucin may be seen. Although the mucinous component may mimic a primary mucinous carcinoma, these rarely contain great numbers of signet ring cells. Provided that the tumour is adequately sampled, confusion with a primary ovarian mucinous carcinoma is unlikely. It should be noted however that rare cases of primary ovarian mucinous tumours containing variable areas of signet ring cells have been reported. In these rare cases, there were other features such as unilaterality, endometriosis, and background elements such as benign or borderline cystadenoma or adenofibroma not normally associated with Krukenberg tumours.3 ,42 ,43 ,52 ,53
Pseudomyxoma peritonei
Pseudomyxoma peritonei is a clinical term describing the presence of abundant mucoid or gelatinous material within the pelvis and abdominal cavity surrounded by fibrous tissue,36 which is caused by rupture, leakage or metastasis of a mucinous neoplasm within the abdomen. It is accepted that this is almost always of appendiceal origin with secondary ovarian involvement, and not from a primary ovarian mucinous neoplasm. The appendiceal tumour is typically a low grade mucinous neoplasm which may not show obvious invasion. There are associated bilateral or right sided large multicystic ovarian mucinous tumours, which develop secondarily after incorporation of mucin and mucinous epithelium from the cortical surfaces into the ovarian parenchyma. This results in pseudomyxoma ovarii in which mucin dissects into the ovarian stroma, with cysts lined by tall mucinous epithelium usually ranging from benign to mildly atypical. Removal and histological examination of the entire appendix is necessary. Suggested guidelines are: if there is a mucinous appendiceal tumour, this should be considered primary with ovarian metastases, even if the ovarian tumour has an accompanying dermoid cyst; if the ovarian tumour is unilateral and associated with a dermoid cyst with no evidence of appendiceal tumour, the ovarian tumour should be considered primary; and if the appendix has been removed previously with no evidence of pseudomyxoma peritonei at surgery, and no other primary site is identified, then the ovarian tumour should be considered primary.3 ,6 ,9 ,25
A summary of the clinicopathological features favouring primary and metastatic mucinous ovarian tumours is presented in tables 1 and 2.
Features favouring metastasis in ovarian mucinous tumours
Features favouring primary ovarian origin of mucinous tumours
Take-home messages
The possibility of metastasis should always be strongly considered in cases with a known extraovarian primary
The index of suspicion for an extraovarian primary should be high in a widely disseminated mucinous malignancy
Algorithms based on size and laterality alone will identify about 85% of cases correctly; but the remainder could be wrongly categorised so other features should be taken into account
Certain patterns, such as signet ring morphology and abundant extracellular pools of mucin, are almost exclusively seen in metastases
Conclusion
Metastatic ovarian tumours, particularly those with mucinous features, are known to cause diagnostic difficulties. The possibility of metastasis should always be considered in cases with a known extraovarian primary. It should be noted that the metastatic tumour may not be identical to the primary but appear more mature. The index of suspicion for secondary ovarian involvement should be high in case of a widely metastatic malignancy. Algorithms based on size and laterality alone are useful in identifying 85% of metastases accurately, but it is important to be aware of exceptions: 15% will not be correctly categorised by applying these rules and other features must be taken into account. Certain patterns are almost exclusively seen in metastases, such as signet ring cells or abundant extracellular pools of mucin. Due attention should also be paid to any background pathology. It is important for the multidisciplinary team to have a low threshold of suspicion and that abdominal exploration at the time of surgery, appendicectomy, radiological review, cervical assessment or attention to cervical smear history are undertaken as appropriate. Currently available ancillary techniques are useful in only a small proportion of cases, and this is one area of diagnostic pathology where correct diagnosis in the majority of instances still depends on careful pathological assessment and clinical correlation.
References
Footnotes
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.