Ovarian Serous Cancer. Clonality is a Circus, it Should be Called “Clownality”

One of the main supporters of the origin of ovarian cancer in the fallopian tube is clonality between the STIC and the peritoneal lesions, but is clonality being interpreted in a similar way by all authors?

Clonality studies started in the 70’s with two promising goals, to separate neoplastic from non- neoplastic lesions, and to determine if two different neoplastic lesions in one patient represent metastases(monoclonal) or independent primaries(polyclonal). The first goal failed when it was found that endometriosis, synovial chondromatosis, and pigmented nodular synovitis can be monoclonal lesions. The immediate reaction was that they are preneoplastic lesions, which is obviously incorrect.

Regarding the use of clonality to determine if two neoplastic lesions in one patient are independent primaries, or if one is a metastasis, numerous obstacles have been found that resulted in many different interpretations. Inconsistent results were found in studies of surface serous papillary carcinoma of the peritoneum, some favor metastases, and some favor independent tumors. Probably the most important issue is the lack of relationship between clonality and the prognosis of the tumors. Most authors believe that clonal tumors are metastatic, and therefore aggressive lesions. However, clonality have been found in peritoneal leiomyomatosis, papillary carcinoma of the thyroid, low grade carcinoma of the bladder, and endometrioid carcinoma of the uterus and ovary, all neoplasms with an excellent prognosis. Different explanations have been given to this controversial issue, like intraepithelial metastases, or cells coming from a patch of cells with similar genes favoring multicentricity, or that the important feature is the grade of the tumor. This last proposal, made in cases of endometrioid carcinomas, suggests considering the different tumors as “clinically indolent spread and not a sign of “fully” metastastatic disease”. This would change the real meaning of metastases. Besides, it would be difficult to apply this theory to peritoneal leiomyomatosis, because early lesions are clearly seen under the mesothelium. Adding to this controversial issue a study of the whole genomic sequencing in an endometrioid carcinoma of the endometrium and ovary, despite shared mutations, the authors classified the tumors as synchronous independent lesions. I believe that if we need to choose between the possibility of multicentricity, supported by the follow-up of the patients, something that cannot be argued, and metastatic lesions supported by a technique, clonality, with many different interpretations, from different authors, the answer is very obvious.

Currently when tumors have the same clone, they are considered metastases, and when they have different clones, but shared some mutations, the interpretation is clonal evolution. Therefore, it is not possible to confirm multicentricity with clonality studies, because shared mutations are found frequently. It is difficult to accept in our practice, ancillary techniques with controversial interpretations, that propose to change our basic knowledge of oncology, for example, the meaning of metastases. Of all the different theories about the interpretation of clonality, the one that proposes that clonal lesions could be independent tumors, but originated from a patch of cells, seems reasonable, and this could apply to our current proposal that the ovary and sub mesothelial space should be considered one organ, both are part of the secondary Mullerian system, both have a similar origin.