I first had the idea of writing this article when I was reading a paper on NEJM about ovarian cancers. The ovaries, as we all know, house the lovely ova which will one day be fertilised (or not - women can choose whether or not to have babies, for misogynists out there) into a zygote which then flourish into a embryo, and ultimately, a foetus. Sperm cells undergo development and maturation within the testicles in men. However, what if things go wrong? What if these cells acquire undue genetic mutations which bounce them off the designated path? This is a very interesting question. In fact, it is so interesting that it is exhibited by the fact that this is the only cancer (tumour)* which has the potential of having a face of its own. Literally. Look at the image below and you'll realise that I am not joking.
Small Teratoma (extracted from: https://i.pinimg.com/originals/1b/8b/77/1b8b77f21372ba1c429e9743032b4f31.jpg)
This is the most interesting of all tumours, in my opinion: the teratoma. It is hard not to use David Attenborough's voice when introducing such wondrous beauties that reside in the most eccentric corners of our world. The teratoma is primarily a benign tumour which is believed to arise from the primordial germ cells (more on this later). They are tumours that consist of multiple cell types, therefore there is the potential for them to recreate the face. In the image above, the mutated cells developed into teeth, gums, hair and so forth. Germ cells come from the start of time - right from the beginning of the development of the embryo. Developed from embryonic stem cells, germ cells normally form the basis of reproduction. Their primordial forms move to the gonads at around weeks 4-6 of embryonic development. Over there, different factors at play suppress further maturation. During adolescence, the production of certain hormones from the anterior part of the pituitary gland revs up the engine. These germ cells will normally be developed into their mature forms, i.e. either sperm cells or ova (egg cells). [1-4]
[2] Diagram of migration and development of primordial germ cells into sex cells (gametes), namely the sperm and the ovum. Note that this diagram shows a model in mice, but is largely comparable with that of humans.
I've got to be honest here. It's quite confusing. There is conflicting information regarding the source and mechanism of the tumour at every juncture. While the predominant theory suggests that teratomas are verifiably from primordial germ cells, some insist that they come from embryonic stem cells. These embryonic stem cells are 'pluripotent', meaning that they can be developed into multiple cell types. This makes great sense, since teratomas feature different cell types, as shown above. Primordial germ cells are usually unipotent, meaning that they only have one fate and destiny - developing into sex cells. Naturally, if you think about it, it is more likely for teratomas to arise from embryonic stem cells, where the possibilities are immense, instead of primordial germ cells, where there is only one way out. But then, science has, as always, provided us with numerous ways to reconcile the two. Firstly, there is the theory that these primordial germ cells mutate. During mutation, they retain their pluripotency (i.e. their potential of differentiating into different cell types). They proliferate. They also produce differentiation-related factors earlier. More significantly, there is a higher risk of teratoma development if these events happen on embryonic development day 15.5. Moreover, what if these developed primordial germ cells simply go back? Papers have suggested they can. By utilising an array of signalling pathways, they can initiate a process called 'de-differentiation'. They go back to the stage where possibilities are vast and being a sex cell is not the only option. Multiple cell types can be derived thus. Imagine an adult life equivalent. This world would be a better place. [5-7, 9] There is also discovery that benign teratomas can arise from primordial germ cells at different stages of their development into sex cells (meiosis; the type of cell division for sex cells). The different stages postulated are derived from genetic differences of the germ cells. [8]
Since both males and females can be afflicted, we naturally assume that the teratoma behaves the same in both genders. Unfortunately, it is not the case. For ovarian teratomas, they are mostly benign and cystic. They rarely undergo malignant transformation (rate at roughly 0.17-2.00%). For testicular teratomas, it depends on the age group. For pre-pubertal males, teratomas found are usually mature and benign. The same cannot be said for post-pubertal males, they are mostly malignant and immature. The higher the level of immaturity, the higher the level of malignancy since the cell is less differentiated and has greater potential of proliferation. It is rare to find as well, in males, pure teratomas. 'Pure' here means that it does not contain any other type of germ cell tumour. Most of them are admixed with other tumours, such as yolk sac tumour and choriocarcinoma. This leads to the thinking that ovarian teratomas originate from benign germ cells in females, whereas testicular teratomas, malignant germ cells in males. Moreover, testicular teratomas can actually evolve from other types of germ cell tumours. [10-12]
Another teratoma...(extracted from http://www.pathologyoutlines.com/imgau/testis/testisteratomazynger01.jpg)
As if things aren't complicated already, I have inadvertently spent three more hours agape at how weird sometimes things can be. So far, we've been talking about ovarian and testicular teratomas. This operates on the premise that primordial germ cells give rise to teratomas. As primordial germ cells spend most of their maturing lives in the gonads (sex organs), this suggestion is seemingly logical. However, this premise is flawed. First, it assumes that the process of migration of primordial germ cells to the gonads from the yolk sac, is normal. Second, it assumes the total rejection of the other theory, where embryonic stem cells directly give rise to teratomas, without involving primordial germ cells. In a dusty old report published by Nature, it is found that extragonadal teratomas (meaning teratomas found outside the sex organs) can arise from somatic cells (normal body cells) or primordial germ cells which fail in the migration process and carry out meiosis. They instead adopt the type of cell division utilised by somatic cells in general, mitosis. [13] Although not exactly proven and rather controversial, I also postulate that due to the fact that adult stem cells are present in multiple tissue types, any aberrancy arising from their self-renewal and differentiation also increases the risk of extra-gonadal teratoma formation. However, at an age where even the existence of adult stem cells has been hotly debated, I doubt this theory will gain traction. [14]
Weird things also don't stop here. There's also a condition called 'foetus in fetu', basically meaning that a foetus has developed inside a foetus. This is logically plausible, since, provided that there are aberrant germ cells developing within the foetus, they can take matters in their own hands and fashion a brand new foetus. This 'second' foetus therefore resides within the original foetus. Alternatively, it can be explained by the 'parasitic twin theory'. We all know that one sibling who always leeches you off, asking you for money. But this is frankly a matter on another level. The parasitic twin develops from the point of fertilisation, inside the host twin. This is extremely are and only 200 cases have been reported worldwide, occurring at a rate of 1 out of 500,000 live births. This has also reignited a controversy - how can well tell apart a foetus in fetu and a teratoma, if we can say that a foetus in fetu is only a more highly-developed teratoma? The answer is: we cannot be sure. Nonetheless, Willis in 1935 proposed that the main difference lies within the name. For a teratoma, it is more of a tumour and therefore lacks the organisation we expect from a foetus. Pluripotent cells differentiate into different cell types but that is the end of the story. For foetus in fetu, organs and limbs are arranged around a vertebral axis, which hence assumes a humanoid figure. Having said so, many report cases as foetus in fetu without regard to the criteria - there only exists an advanced degree of organogenesis (organ formation). [15-16]
[17] A foetus in fetu with well-differentiated upper and lower limbs and external genitalia, complete with a vertebral column.
Although I am still slightly confused regarding the detailed pathophysiology of the disease, with the core of my knowledge on this subject totally dismantled by a whirlwind of theories, I can do nothing but gape in awe. The foetus in fetu and teratoma remind me that medicine is living and breathing. Medicine does mean extremely hard work, but the wonders and miracles it offers are worth the sweat and tears.
*For lay people, cancer and tumour are interchangeable. However, in medicine, we are pickier when it comes to words so cancer is only used when referring to malignant lesions which exhibit manifestations of malice such as evading one's immune response, invading through the basement membrane of the epithelial tissue, and developing blood vessels for their own gain, i.e. spreading to other organs to wreak havoc. Tumours can be anything ranging from benign to malignant lesions. Both arise from genetic mutations. However, cancers typically arise from more mutations than benign tumours.
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