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[FAQ] Hominin tumour and cancer

 

Context of neoplastic disease in the fossil record

What is cancer?

A neoplasm (‘new-growth’ or tumour) is a mass of tissue in which cellular growth is no longer subject to the effects of normal regulating mechanisms. The general term is ‘neoplastic disease’, and a tumour may be benign or malignant in nature; malignant tumours are often colloquially referred to as a cancer. Cancers are aggressive, and can be very destructive locally or spread through the bloodstream or other mechanisms to cause destruction elsewhere in the body. They are often invasive. The organ or tissue where the tumour starts is called the primary site. From here it can spread to bone or other organs, and these are then called secondary sites or metastases.

What is a tumour and how does it differ from cancer?

Tumours are usually described as neoplastic or proliferative diseases, implying a condition where new growth or formation of cells occurs. This new growth is often uncontrolled – so the regulation mechanisms no longer control the proliferation of new cells. Tumours can stay localized, and then they are often termed “benign” as a result. However, these benign tumours can be locally destructive or can cause problems based on their locality – for example a benign tumour in the brain may not spread, but can be highly problematical because it may not be possible to remove it and may cause a raise in intracranial pressure. Benign tumours usually have a limited potential for growth. This is in opposition to cancers which have more growth autonomy and often grow faster than benign tumours.

How old is neoplastic disease in the fossil record?

At present true neoplastic diseases, including cancer, seem to be restricted to vertebrate animals. Within the human lineage, the oldest evidence of neoplastic disease found in the hominin fossil record is fibrous dysplasia (a benign but still serious, bone tumour) in a rib fragment of a 120,000-year-old Neanderthal from Krapina, Croatia. The earliest description of a tumour in modern human bone was from a 3000-year-old Egyptian mummy from Egypt. There is no definitive evidence of a hominin tumour older than the Neanderthal specimen until now.

However, tumours have been observed in the fossil record affecting non-hominins. This includes the earliest unequivocal case of benign neoplasia is an osteoma from 300 million years ago, affecting a fish from North America. Later cases include diagnoses of primarily benign (though rare cases of metastatic disease are noted) in Jurassic dinosaurs, mosasaurs, Cretaceous hadrosaurs, and later European mammoths dating from 24 to 23,000 years ago. The earliest evidence for malignant cancer comes from the humerus of a theropod dinosaur (Allosaurus fragilis) from the late Jurassic of Utah (USA), which has been interpreted as chondrosarcoma.

Do only humans get cancer or tumours?

No. Neanderthals were also affected by tumours as noted above. Today various cancers and tumours are prevalent in animals as well as humans – some of these such as Devil Facial Tumour Disease (a parasitic cancer) is implicated in the collapse of wild populations of Tasmanian Devils, and may even exacerbate their extinction. Cases of cancer (chondroma have been observed in dogfish (chondroma) and in skates (fibrosarcoma), and hereditary osteochondromata is common in the domestic dog – in about 18% of cases this becomes a malignant cancer (osteosarcoma or chondrosarcoma).

Why is it important to study cancer and its history?

Because cancer is the world’s number one killer disease, it is important that medical researchers find methods to detect cancer early and early and find preventative medical approaches to deal with cancers. It is also important to study the evolution of disease and finding it in the fossil and archaeological record will assist in this understanding. Clinical and medical sciences study cancer to educate people to become healthier by following better diets and healthier lifestyles.

What is a hominin?

A hominin consists of modern humans, extinct human and near-human species, and all our immediate ancestors; this includes member of the genus Homo, Australopithecus, Paranthropus and Ardipithecus amongst others). The term hominid was used in the past and generally denoted the same as hominin, but the definition has now been broadened and refers broadly to all Great Apes and their ancestors. Hominins are members of the human branch after the human lineage split from that of chimpanzees, and thus include living humans and extinct human ancestors, such as the Australopiths. Hominins are characterised by bipedal locomotion, although this may not have been the case for the very earliest members of the group, and relatively small canine teeth. Later members of this group (those in the genus, Homo) are characterised by larger brains than those of living apes like chimpanzees, bonobos, gorillas, orangutans and gibbons.

Who was involved in the discovery of the earliest tumour and cancer?

The research was conducted by two (overlapping) teams of multi-disciplinary scientists, some with specialisation in human evolutionary anatomy, and others in ancient and modern diseases, whilst others are specialists in the latest medical and research-based non-invasive imaging techniques. In both papers we tried to marry the work of scientists who work extensively in the morphology of dry or fossil bone (including diseases of bone) with medical specialists who are practised in the diagnosis of disease in living humans.

What did our studies find?

For our two fossil hominid cases we have an example of both a benign tumour and a malignant cancer. The earliest evidence for a benign tumour in a hominin comes from Malapa, and is dated to 1.98 million years ago. In this case it was an osteoid osteoma, with an alternative diagnosis of osteoblastoma, which is also a benign tumour. The earliest evidence for malignant cancer in a hominin comes from Swartkrans, and is dated to roughly 1.7 million years ago. Comparisons with modern clinical cases suggest that this is an osteosarcoma, which is a primary bone malignancy or cancer. This means that the tumour actually started in the bone tissue itself.

The Malapa fossil site

Where and what is Malapa?

The Malapa cave site is located in the Malapa Nature Reserve, and located about 45kms northwest of Johannesburg very close to Sterkfontein and other hominin bearing sites within the Cradle of Humankind. Since its discovery in August 2008, the site of Malapa has yielded well over 220 bones of early hominins representing more than five individuals, including the remains of babies, juveniles and adults – all attributed to the species Australopithecus sediba. The most famous of these are MH1 and MH2 (a juvenile male, and adult female) which have been extensively reported in the journal Science. The hominin fossils from the site date to 1.977 to 1.98 million years in age. The site where the fossils were discovered is technically the infill of a de-roofed cave that was about 30 to 50 metres underground just under two million years ago. The individuals appear to have fallen, along with other animals, into a deep cave, landing up on the floor where they partially mummified after death. The bodies were then washed into an underground lake or pool probably pushed there by a large rainstorm. They did not travel far, maybe a few metres, where they were solidified into the rock, as if thrown into quick setting concrete. The rock they are preserved in is called calcified clastic sediment. Over the past 2 million years the land has eroded to expose the fossil bearing sediments.

What else was found at the site?

Besides Australopithecus sediba, several other hominins and a variety of faunal remains including bovids, suids, primates, equids, carnivores, microfauna and birds, were subsequently discovered at the site.

Who was affected by the earliest evidence for a tumour?

MH1 (named Karabo) was a member of the species Australopithecus sediba. He was probably around 10 – 13 years old in human developmental terms when he died. He was probably a bit younger in actual age (perhaps as young as eight or nine) as he is likely to have matured faster than humans. The age estimate is based on modern human standards by which the eruption stages of the teeth are evaluated and the degree of development of the growth centres of the bones. Studies are presently underway to attempt to precisely determine the age of this child at death.

What evidence do we have for neoplastic disease at Malapa?

The tumour is present as a penetrating lesion (tunnel-like structure) which affects the spinous process of MH1’s sixth thoracic vertebra (you can feel the tip of this process on your own back as the series of bony lumps which run down the spine under the skin). The lesion is visible on outside of the bone, but is best understood by looking inside the fossil (in this case using phase contrast X-ray synchrotron microtomography) which is an incredibly precise way of seeing the internal morphology of fossils without damage to the specimen. What synchrotron imaging shows is that the lesion penetrated the spinous process of the vertebra, and the tumour process was active at the time of death of MH1; this is evidenced by an attack on the spongy bone inside the vertebra, close to the neural canal. Part of the lesion showed evidence of sclerosis (slowing down with new bone being formed) which suggests that the tumour had been growing for some time (moving from back to front) and was most active in a region deep within the structure of the vertebra.

Could he have died from this pathology?

In the case of the Malapa fossil – no, as this is a benign tumour. It would have caused pain and discomfort, though, and may have limited the ability for him to climbing assisted by his upper limbs. This may have been implicated in the manner of his death – results published in 2015 (Nature Scientific Reports) suggest that MH1 was the victim of a fall from a height into a natural death trap.

The Swartkrans fossil site

Where and what is Swartkrans?

Swartkrans Cave is located approximately 40 kms northwest of Johannesburg, Gauteng Province, in area known as the Cradle of Humankind, and classified in 1999 by UNESCO as a World Heritage Site. Palaeoanthropological exploration work by Robert Broom and John Robinson began at Swartkrans in 1948, leading to the discovery of numbers of Paranthropus robustus specimens.  Swartkrans cave stratigraphy is complex (and parts of this are uncertain), having formed with many depositions and erosive sequences. Five stratigraphic members are recognised, with each one separated by erosional features. Member 1 consists of Hanging Remnant and Lower bank - with each of them yielding Paranthropus robustus and early Homo fossils. Our fossil (SK 7923) is derived from the Hanging Remnant of Member 1. ESR (Electron Spin Resonance) and faunal dating methods have indicated that the age of the Hanging Remnant deposit is between 1.6 - 1.8 million years old, and is thus a little bit younger than the Malapa deposit.

What else was found at the site?

Besides Paranthropus robustus, fossil remains of Homo ergaster have also been found. The site is rich in faunal remains, Early Stone Age stone artefacts, bone digging tools, and butchered animal bones. There is also purported evidence of the early use of fire.

Who was affected by the early evidence for cancer?

As the foot bone fragment is fractured in such a way that it is difficult to make a precise assessment of the species at this stage, we are not able to assign it to species (although we can say it is definitely a bipedal hominin). Based on what else has been found in the Hanging Remnant deposit we may be looking at either Paranthropus robustus or early Homo (possibly H. ergaster) or some other (as yet unrecognised hominin species).

As such, we can say that an early hominin relative was affected by an aggressive form of cancer, termed osteosarcoma.  This is based on a large mass of bone growth which is present on the surface of the bone, but also through the presence of new bone growth within the medullary cavity (the hollow part of the normal bone tube) which has completely obliterated the internal morphology. Based on a comparison with modern clinical specimens we have diagnosed a case of osteosarcoma. An osteosarcoma is a primary bone tumour, occurring mostly in fast growing regions of bone. It is most common in adolescents, and can be fatal (especially in the case of an early hominin, of course, since there would not have been treatment available). It usually starts through proliferation of osteoblasts (the bone cells that form bone). Osteosarcoma usually starts in the metaphysis of a bone (the region near the growth plates). From here it then grows circumferentially through the cortex and raises the periosteum (the membrane around the bone). This condition is more common in males.

Could they have died from this pathology and how would it have affected them?

Yes. Such cancers are invariably life-threatening if untreated, and would lead to death if allowed to divide and spread. The presence of the cancer would also likely have affected the gait (walking ability) of the hominin.

The imaging methods

How do doctors normally diagnose bone cancers?

In modern medical practice the definitive diagnosis of a bone cancer rests with the pathological analysis of a biopsy specimen (tissue) from the tumour. However, imaging assists with defining the extent of bone involvement by the tumour (CT scanning and plain film X ray) and the soft tissue component of the cancer (MRI scanning). A description of the cancer from the images obtained, allows a prediction of whether the tumour is malignant (cancer) or benign (not cancer). Correlation between the imaging characteristics and the patient demographics (including age, sex, multiplicity or singularity of lesions, site of lesions) allows for the differential diagnosis to be narrowed.

Why would these not work on fossils?

Fossils are a heavy, rock - like copy of the original object.  The fossil often has the same shape as the original object, but is chemically like a rock. The process of fossilization involves the dissolving and replacement of the original minerals in the bone with other minerals, as well as often crystal formation within spaces and other alterations to the material. Thus a fossil does not contain tissue for pathological assessment. The imaging characteristics, however, can still be used to assign a diagnosis or differential diagnosis to the tumour. That is the approach we have used in both cases reported here.

What techniques did we use to investigate these diseases in hominin fossils?

We used two main methods of non-invasive imaging to peer-inside the fossils from Malapa and Swartkrans. The cancer specimen (and a modern comparison) was scanned using Micro-CT imaging.  Micro-CT imaging, or Micro-Focus X-ray Computed Tomography is an analytical technique similar to the well-known medial CAT-scans, also known as Computer Assisted Tomography, which is being practised worldwide at most hospitals as a diagnostic tool with humans as object of interest.

The probe, being used in both techniques, is man-made generated X-ray radiation that has the capability to penetrate (pass) through the object of interest onto a 2D detector that records the material density differences within the object (e.g. Bone is denser than soft tissue). Through advanced mathematical reconstruction techniques, the object/human can then be visualised as a 3D virtual objective and can be studied from all directions and depths within, in a non-destructive manner. This means that the object can be studied without cutting it open and thus “destroying” or hurting the object/human. The non-invasive nature of the technique makes it attractive to be applied and used especially where, for CAT scans, safety and time is important and for research, using Micro-CT, clarity, high quality and high resolution is being required. How Micro-CT differ from CAT scans lies in the size of the spot where the X-rays are being generated (1-3-micron spot size for Micro-CT vs 500 microns for CAT scans) as well as in capability of Micro-CT to allow for geometric enlargement of the object.  The building blocks of the 3D virtual volume is called voxels (similar to pixels in a 2D digital picture) - the smaller the size of the voxels, the more detail can thus be observed. The combination of the small X-ray production spot and the geometric enlargement, allows Micro-CT to visualise and analyse objects in 3D down to 5 microns (5/1000ths of a millimeter) which is multiple times more improved than medical CAT scans.

Micro-focus X-ray CT is thus a much desired research method within the palaeo-sciences as it delivers highly detailed 3D digital copies of fossil remains in a completely non-destructive way – even when the fossils are still uncovered and imbedded in the calcified rock matrix.  Data from micro-focus X-ray experiments can thus be used to perform intricate measurements, quantify voids and fractures, as well as allows for the identification and segmentation of specific regions of interest (e.g. fossils, rocks, plants, soil) due to their different density compositions.

The specimen from Malapa was imaged using phase contrast X-ray synchrotron microtomography. The technique is similar to that of Micro-CT in that X-ray radiation penetrates through the object of interest onto a 2D detector. However, the x-rays are produced by a particle accelerator ring (not a small x-ray source as in Micro-CT) which allows the use of a monochromatic beam – this makes the quantitative evaluation of results possible, and eliminates artefacts from the reconstructed image – very important in analysing dense fossil material. This technique is nowadays widely accepted as the gold standard for high quality 3D non-destructive imaging of fossils.

The impact of this discovery

Why are these discoveries important?

They are important because they push back the earliest evidence for tumours and cancers in the human lineage. There has been a general impression that neoplastic disease (and cancers in particular) is disease of modernity. Recent studies on Egyptian mummies failed to identify any traces of cancer, leading some researchers to suggest that it was not present in the pre-modern world. This study falsifies that claim.

Whilst it does appear true that the rate of tumours and cancers are accelerating due to environmental toxins, viruses, and other tumour forming factors in the modern (particularly Western) lifestyle – such diseases were present in the past, even without the influence of modern lifestyles. We note in our papers that malignancy occurs in almost all complex animals (vertebrates), suggesting that the mechanisms behind tumours and cancer have an extremely old evolutionary history. A number of oncogenes (cancer causing genes) are particularly archaic - thus the capacity for malignancy is ancient.

The higher incidence of malignancy in today’s developed and developing world may be related to the unique interaction between environmental factors – which have no parallel in prehistory. It is interesting to find the presence of these diseases in the fossil record. In a sense, of course, it is not totally unexpected. Our cases are primary bone tumours and they mostly occur in young individuals. We would expect early hominins to have limited life expectancies, so we would be highly surprised to find metastatic tumours which take longer to develop, and which tend to appear in older individuals.

From a clinical standpoint we would thus expect that if tumours are present that they should be primary bone tumours. However, by any modern standard these primary bone tumours are very rare, and to find two of them in our fossil ancestors is highly unusual – and we now have to ask what mechanisms may be behind the presence of tumours and cancers deep in prehistory, and how that may impact on the evolution of cancer in the modern world.

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