There are various reasons for pathological misdiagnosis, among which unclear definition and concept of the disease is one of the common reasons for misdiagnosis. 2014 new edition of WHO Classification of Tumors of Female Genital Organs mentions many new terms, concepts and definitions, and these changes represent the new understanding of gynecologic tumor diseases in current academic circles. In this article, we would like to briefly review the changes in the section on epithelial ovarian tumors.
1. “Junctional tumor/ atypical proliferative tumor”
The original meaning of junctional tumor is that the morphology and biological behavior of the tumor is between benign cystic adenoma and carcinoma, but this concept has changed with the advancement of research. Currently, only plasmacytotic junctional tumors are considered to be relatively “junctional” in nature, while other types of lesions, such as mucinous, endometrioid, clear cell, Brenner, etc., which are called “junctional” tumors, do not have reliable evidence of “junctional” nature. There is no reliable evidence that they have a “junctional” biological behavior, i.e., a continuum from “junctional → development of cancer → patient death”. Therefore, more scholars tend to call them “atypical proliferative tumors”.
The diagnostic terminology of these tumors is quite confusing in the literature, taking the most common plasmacytoma as an example, there are three commonly used names: serous junctional tumor (serous border:1px solid #000; “EN-US”>SBT), atypical proliferative serous tumour (APST), and serous tumour of low malignant potential (STLMP), the diagnostic term STLMP is used at the M.D. Anderson Cancer Center. Theoretically, for plasmacytotic junctional tumors, SBT should be used, while for other types of tumors, “atypical proliferative XX tumor” is appropriate, but habit becomes nature and this edition adopts a compromise approach to classification, i.e., “junctional tumor/ atypical proliferative tumor “Both terms are considered synonymous and can be used. In this edition of WHO classification, this spirit of compromise is reflected in many places.
2. Heterogeneity of mucinous tumors of the ovary
It is worth noting that mucinous neoplasm of the ovary (intestinal type) is a highly heterogeneous tumor. Many patients diagnosed with “mucinous junctional cystadenoma” recur quickly and even die, probably because of inadequate material collection. The principles of sampling for mucinous junction cystadenoma of the ovary are
1) For tumors smaller than 250 px, at least 1 piece of material should be taken for every 25 px of tumor diameter on average.
2) For tumors larger than 250 px, with microinfiltration or intraepithelial carcinoma, at least 2 pieces per 25 px of tumor diameter on average.
(3) Particular attention should be paid to solid papillae and attached nodules, which require additional sampling.
In fact, the mucinous cystadenoma that we usually encounter can also be retrieved with reference to the above method, because we often encounter “mucinous cystadenoma with focal hyperplasia”, which is customarily called “focal junctional” lesion in China, and sometimes we can even see focal intraepithelial carcinoma lesion. Mucinous tumors with thin cyst wall can be placed in a wax block with 2~3 pieces of cyst wall tissue.
3. “Non-invasive implantation” and “infiltrative implantation/low grade plasmacytoma” of plasmacytotic junctional tumor
Plasmacytoid junctional tumors can involve the peritoneum (including lymph nodes), and there are two types of cases, which are called non-invasive implantation and infiltrative implantation.
1) non-invasive implantation: the lesion is often confined to the surface of the organ and is divided into epithelial type and pro-fibrous tissue proliferation type.
2) Infiltrative implantation: the lesions often infiltrate into deep tissues, and the tumor cells are arranged as solid small nests, micropapillae, sieve-like, and there are large spaces around the cancer nests.
Infiltrative implantation is equivalent to low-grade serous carcinoma (LGSC) in terms of histomorphology and biological behavior, which is the biggest change in the new classification; poor prognosis of plasmacytic junctional tumors is associated with the occurrence of LGSC in this tumor.
In the previous version of the classification, peritoneal implantation lesions with limited biopsy specimens and no visible underlying tissue were diagnosed as “non-invasive implantation”; in the new version, the diagnosis of “invasive implantation” is made as long as the histologic and cytologic features are consistent, regardless of the size of the biopsy material. The size of the biopsy material is not considered.
Plasmacytoid junctional tumor itself is not related to patient’s prognosis, but the patient’s prognosis becomes worse after infiltrative implantation (low-grade plasmacytoid carcinoma) occurs; non-infiltrative implantation also does not affect patient’s prognosis, but it may lead to abdominal adhesions and recurrence, sometimes requiring surgery.
4. “Microinfiltrative” and “microinfiltrative carcinoma” of plasmacytic junctional tumor
In the new classification, “microinfiltrate” and “microinfiltrative carcinoma” of plasmacytotic junctional tumor are two lesions with different nature.
(1) SBT/APST with microinfiltrate: the presence of epithelial cell clusters with abundant eosinophilic cytoplasm in the mesenchyme, similar to the eosinophilic cells on the papillary surface in junctional tumors, with negative ER and PR and low Ki-67 index, may be a sign of terminal differentiation or aging, and does not affect the prognosis of SBT/APST.
(2) SBT/APST with microinvasive carcinoma: the histological and cellular morphology is the same as that of low-grade plasmacytoma, and the lesion is less than 5 mm in maximum diameter, which is actually an “intraepithelial” low-grade plasmacytoma; at this time, extensive sampling should be performed, except for LGSC with larger scope in other areas.
5. “Micropapillary subtype SBT/non-invasive LGSC”
These lesions are plasmacytic junctional tumors with unique histologic features, mainly with three histologic changes: (1) elongated papillae radiating in the form of “sun rays” around the thick fibrous axis, whose length is more than 5 times the width; (2) a few surface papillae may have a sieve-like structure; (3) in a few cases, the epithelial cords are curled and have a “labyrinth-like” structure. (3) in some cases, there are curled epithelial cords with a “labyrinthine” structure; (4) lesions with the above structures should have a maximum diameter of ≥5 mm; (5) lesions with the above structures and a maximum diameter of less than 5 mm are diagnosed as “SBT/APST with focal micropapillary features”. “
6. “Low-grade plasmacytoma” and “high-grade plasmacytoma” of the ovary
The 2003 edition of WHO recommends a three-level grading system, namely the Silverberg grading system, which classifies tumors into Grade 1 (highly differentiated), Grade 1 (highly differentiated), and Grade 1 (highly differentiated). Recent studies have shown that there are two main types of ovarian plasmacytoma, which differ in terms of mechanism of occurrence, morphology, immunohistochemistry,, molecular genetics and response to chemotherapy. This has led to a secondary grading system, namely, low-grade plasmacytoma (LGSC, low grade serous carcinoma) and high-grade plasmacytoma (HGSC, high grade serous carcinoma), the former mostly through KRAS and BRAF mutation pathways, and the latter often with abnormal TP53 and P16 alterations The latter is often associated with TP53 and P16 abnormalities. The secondary classification system is simple to use, reproducible, and can better guide clinical treatment, which is why it was adopted by the 2014 edition of WHO.
The primary indicator of the secondary classification system proposed by Malpica et al. is nuclear heterozygosity, and the secondary indicator is the number of nuclear divisions.
[High-level].
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Nucleus polymorphism with more than 3-fold difference in size
Number of nuclear divisions greater than 12 per 10 HPF
Common necrotic and multinucleated tumor giant cells
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[Low grade].
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Nuclei are uniform, with only mild to moderate anisotropy
Nuclear division number <=12 per 10HPF
No necrotic or multinucleated tumor giant cells
Nucleoli may be obvious, and intracytoplasmic mucus may be present
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7. Missense mutation, nonsense mutation and wild type of TP53
Immunohistochemical p53 positivity is seen in almost 100% of high-grade plasmacytoma of the ovary and about 75% of high-grade plasmacytoma of the endometrium; there is also a portion of hypodifferentiated endometrioid carcinoma of the endometrium that is also p53 positive, and currently most hospitals treat this type as type II carcinoma as well.
1) Diffuse strong positivity of p53 (TP53 missense mutation)
M.D. Anderson’s standard is more than 90% of tumor cells positive, Crum’s book is 75%, WHO published last year changed it to 60% of cells positive; in practice, almost all cells encountered are 100% positive. This situation is because a codon of TP53 gene is mutated, thus producing a very stable p53 protein, which is not easily degraded, and therefore immunohistochemistry is strongly positive, representing a missense mutation of TP53. At this point, the p53 immunohistochemistry result is judged to be “positive”.
2) p53 immunohistochemistry “all negative” (TP53 nonsense mutation)
The TP53 gene is nonsense mutated, resulting in a “truncated” p53 protein, because the truncated protein has no antigenic determinants that can bind to the p53 antibody, so the immunohistochemistry is completely negative (make sure the staining system is normal, and add positive control tissue on the same section). p53 immunohistochemistry is also judged as “positive”.
3) P53 immunohistochemistry is “strongly or weakly positive” (TP53 wild type)
The p53 protein is also expressed in normal tissues. The normal p53 protein degrades quickly, so immunohistochemistry can only show a part of the cells, and the result is that some cells are p53 nuclear positive, some are weakly positive, and some are negative, which indicates that the TP53 gene is “wild type” and there is no mutation, so the p53 immunohistochemistry result should be judged as The p53 immunohistochemistry results should be judged as “negative”.
8. Ovarian plasmacytoma
The whole spectrum includes plasmacytic mucinous cystadenoma, junctional plasmacytic mucinous cystadenoma and plasmacytic mucinous carcinoma.
Junctional plasmacytomucinous tumor is defined as both endocervical mucinous epithelium and plasmacytomucinous epithelium, with either cell greater than 10% ratio. This is not a newly discovered tumor, but is derived from ovarian (junctional) mucinous cystadenoma (endocervical type, Mullerian duct type) as well as from the original mixed plasmacytic-mucinous tumor, and there is no clinical significance in distinguishing between the two, so they are collectively referred to as plasmacytic-mucinous tumors. In about 1/3 cases, endometriotic lesions are also seen, indicating that the tumor may have developed from endometriosis. Clinically, patients with a long history of endometriosis and sudden onset of elevated serum CA125 are often found to have plasmacytic mucinous cystadenoma or plasmacytic mucinous junctional tumor at the time of ovarian surgery, but some patients have only mucinous epithelial hyperplasia.
Ovarian junctional plasmacytic mucinous tumors have unique pathologic histologic features: (i) broad papillae; (ii) edematous papillary interstitium; (iii) mixed plasmacytic and mucinous epithelium; and (iv) massive neutrophil infiltration. In daily consultations, we often see some pathologists misdiagnose junctional plasmacytoma as “mucinous carcinoma”.
Plasma mucinous carcinoma is the malignant end of the spectrum of these tumors, which often has both plasma and mucinous carcinoma, and can also be accompanied by endometrioid carcinoma, clear cell carcinoma, squamous cell carcinoma and other components.
9.Ovarian cancer with mixed epithelial components
In the old classification, such tumors with more than 10% of secondary components were classified as mixed epithelial tumors. The new classification mentions that in such cases the classification should be based on the major cell type, but the minor components can also be indicated in the diagnostic report. For example, a diagnosis of “high-grade plasmacytoma with endometrioid differentiation” can be made when an endometrioid component with clear squamous differentiation is observed in a high-grade plasmacytoma.
10. Two magic numbers: “5 mm” and “10%”
Whether the length and diameter of the lesion is greater than or equal to 5mm is the demarcation point between “microinvasive plasmacytoma” and “infiltrative low-grade plasmacytoma”, and is also the demarcation point between “intraepithelial carcinoma” in mucinous cystadenoma It is also the demarcation point between “intraepithelial carcinoma” and “swelling (fusion) invasive carcinoma” in mucinous cystadenoma, and between “junctional plasmacytoma with focal microcapillary features” and “non-invasive low-grade plasmacytoma”. It is also the cut-off point between “junctional plasmacytoma with focal microcephaly” and “non-invasive low-grade plasmacytoma. The original monographs used “3mm” or “10mm2”, but this edition of WHO has standardized it to 5mm.
The 10% lesion ratio is the cut-off point between plasmacytosis, mucinous, pulpy mucinous cystadenoma and junctional tumor, with the former being less than 10% and the latter being greater than or equal to 10%.
11.Type I and type II carcinoma of ovary
Ovarian epithelial carcinoma also has the concept of type I and type II carcinoma. type I carcinoma refers to carcinoma with evidence of transformation from benign, junctional to malignant, such as endometrioid carcinoma, low-grade plasmacytoma, mucinous carcinoma and clear cell carcinoma, etc. type II carcinoma mainly refers to high-grade plasmacytoma, carcinosarcoma, etc. Such tumors are high-grade at the stage of carcinoma in situ or difficult to detect at the stage of carcinoma in situ. Clear cell carcinoma in uterine body is type II carcinoma. type I carcinoma and type II carcinoma are only roughly distinguished, and the real pathological diagnosis should clarify the histological type of carcinoma.
12.Migratory cell carcinoma has been deleted
Migratory cell carcinoma of ovary is not an independent disease entity, most of them are HGSC, and a small proportion of them are low-differentiated endometrioid carcinoma, and typical HGSC areas can be observed in adequately sampled “migratory cell carcinoma”.
13.Histological grading of ovarian cancer
(1) Endometrioid carcinoma: As with endometrioid carcinoma of the uterine body, it is classified into three grades according to FIGO criteria.
Grade 1 Solid area <5%
Grade 2 Solid area 5%-50%
Grade 3 Solid area >50%
High nucleus grade, one grade up
2) Mucinous carcinoma: not graded, but divided into 3 types
Non-invasive (intraepithelial carcinoma), lesion less than or equal to 5 mm
Invasive (swelling or fusion) lesion >5mm
Invasive (infiltrative), pro-fibroproliferative destructive interstitial infiltration of ovary, greater than 5mm, but less than or equal to 5mm can still be called “microinvasive mucinous carcinoma”
(3) Plasmacytoid carcinoma: divided into high grade and low grade, the criteria are described above
(4) Clear cell carcinoma and undifferentiated carcinoma: itself is high grade, no longer graded
5）Plasmacytoid carcinoma: plasmacytoid carcinoma components are classified into high-grade and low-grade according to the aforementioned criteria
(6) Malignant Brenner’s tumor: its malignant components are classified into low-grade and high-grade according to the classification of uroepithelial carcinoma, but first of all, its internal components should be excluded from high-grade plasmacytoma or low-differentiated endometrioid carcinoma
14.Change of staging criteria for ovarian, fallopian tube and peritoneal carcinoma
In 2014, FIGO updated the staging criteria for ovarian, fallopian tube and peritoneal cancers, combining them into one, i.e. there are no longer separate staging criteria for fallopian tube, ovarian and peritoneal cancers. Stage I is when the lesion involves only the ovary and/or fallopian tube. Pathologists no longer have to worry about being forced by clinical physicians to distinguish what is primary. The current theory is that all three of these sites may have a primary origin in (i) the umbilical end of the fallopian tube, especially in patients with BRCA1/BRCA2 mutations; (ii) the mesothelium of the ovarian surface that is invaginated; ovarian cortical inclusion cysts, tubal epithelial ectoplasia of the ovary; and (iii) the peritoneum (so-called second müllerian system).
Should we also differentiate between the three in daily diagnosis? In view of the habit, the distinction can be made according to the following criteria.
1) if the main body of cancerous tissue is located in the ovarian cortex, with a small part involving the peritoneum and fallopian tubes, the diagnosis of ovarian cancer can be made.
2) If the lesion mainly involves the fallopian tube, especially if there is a BRCA1/2 mutation, the diagnosis is fallopian tube cancer;
3) if there is no lesion in the ovary, or only the surface of the ovary is involved, or a small amount of the superficial cortex of the ovary is involved, and most of the lesion is located in the peritoneal cavity, the diagnosis is considered to be peritoneal primary high-grade plasmacytoma.
(4) If the cancer is present everywhere in ovary, fallopian tube and peritoneum and cannot be judged, the diagnosis is high-grade plasmacytoma of pelvic peritoneal cavity with uncertain primary site.
There is an expert consensus that most plasmacytoma originates from the fallopian tubes, which has not been widely adopted.
In the epithelial ovarian tumor section of the new female genital tumor classification, there are many more contents and details that we should think about, which are limited by space and will not be detailed here. It should be emphasized that we should first fully communicate with clinicians when using the new diagnostic names and criteria in our pathological diagnostic work to avoid unnecessary misunderstandings that may lead to bias in diagnosis and treatment. In addition, it should be recognized that the WHO classification is only the current academic understanding and basic consensus, far from perfect, and still has many flaws, compromises and unsatisfactory areas.