• paleopathology;
  • comparative pathology;
  • history of medicine

Cancer's relationship with the genetic characteristics of the hosts and environmental conditions has been demonstrated convincingly in modern populations. Environmental conditions and the genetic characteristics of human populations have changed markedly over our long history, and these changes have inevitably caused changes in the epidemiology of cancer.

From a genetic standpoint the changes are so important as to seem banal. The first representatives of our genus, for example Homo habilis, which lived in East Africa roughly 2 million years ago, were phenotypically characterized by small body size (maximum stature = 1.20 m), relatively low cranial capacity (about 400 cc), perfectly erect posture and bipedal gait. They likely used some sort of primordial articulate, symbolic language, and were surely able to produce artefacts, such as stone and wood utensils, which represent the first technology on Earth. Beginning at this time technology assumed an important role in human evolution, with humans furthering their evolution not just through slow biological modifications but also through rapid technological advances. This is a unique development in the history of life on Earth. These primordial humans differed considerably from modern humans in terms of biology, cultural capabilities and social organization, and it is quite obvious that these differences must have produced variations in their ability to contract, develop and spread diseases, including the types and prevalences of neoplasms. In conclusion, it would seem likely that genetic changes in humans caused biological variations, including susceptibility to cancer over time, and socio-cultural changes also changed the patterns of human cancer. The role of paleopathology is to detect these variations, extending the research to pre-humans, and obviously non-human animals, observing the presence and prevalence of neoplasms in fossil animals, comparing ancient and modern evidence and creating a comparative pathology not limited to differing extant species, but that also extends to individual species during their evolution.

The environment also changed markedly over time, as did the relationship between humans and the ecosystem, which itself changed during our evolution, in part because of our changing lifestyles. The first humans were nomadic, obtaining the food they needed by hunting and by gathering spontaneous vegetables. Only about 12,000 years ago did humans introduce farming and herding, developing sedentary habits, and then and gathering into densely populated communities. Environmental and ecological changes can also be linked to human activities, especially those that have occurred recently in the more developed countries. All these environmental changes and the tremendous changes in human habits may have modified human cancer in terms of both the types of neoplasms and their prevalence. Paleopathology must also determine the history of the relationships between human cancer and environmental, cultural and socio-economic changes.

Only through the paleopathologic analysis of both pre-human remains (including the non-human fossil record) and ancient human remains we can reconstruct (i) the existence of cancer in antiquity, for example the evidence for cancer in the fossil record (also before the relatively recent origin and rise of our species), (ii) the type and prevalence of cancer in both pre-human and ancient human populations, (iii) the relationship between cancer prevalence and the demographic structure of human populations and its variations over time, (iv) the variations in type and prevalence of cancer as related to the genetic or environmental changes that occurred during biological, social, cultural and economic human evolution and (v) the general biological significance of cancer with respect to life on the Earth over a very long interval of observation (i.e., millions of years). These analyses can only be made if one considers cancer as a phenomenon strictly linked to life, studying the pathologic events comparatively and (vi) considering the types and prevalences of cancer with respect to the systematic relationships of the animals that this disease affects today.

Difficulties in diagnosis and interpretation

  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References

According to Brothwell,1 the interpretation of neoplasms is one of the more interesting and difficult aspects of paleopathology.

The most important difficulties are linked to the particular materials available to paleopathologists. In fact, with the rare, but very important exception of mummified tissues, paleopathological materials consist of osseous remains; the digenetic processes that affect the skeletons can produce post-mortem alterations that either simulate or overshadow cancer-linked lesions that occurred during life. Chemical factors (such as soil acidity), physical agents (such as mechanical erosion and micro-fractures) and biological factors (such as fungi, bacteria and viruses) can produce focal erosions, including multiple, confluent erosions that can mimic the osteolytic lesions characteristic of primary and metastatic bone lesions. In addition, the digenetic phenomena can superimpose alterations (both erosions and incrustations) that can hide the lesions produced during life or change their original appearance. These difficulties are more serious in the case of the differential diagnosis of possible multiple lesions linked to possible bone metastasis of carcinoma, or to multiple myeloma. Finally, one must keep in mind that the lesions due to cancer may have changed over time, with the result that our diagnostic techniques and criteria may be inappropriate for detecting and diagnosing cancers on ancient and fossil remains.

The difficulties inherent in paleopathological analysis involve not just the diagnosis of the single case at the individual level, but also epidemiological aspects. Indeed, the materials examined represent samples selected from the original populations, and the criteria of selection are largely unknown. In addition, the size of the samples that survived to be examined can be not representative of the original population. Both these factors may be important sources of error in estimating cancer prevalence among ancient populations, be they human or pre-human.

Comparative pathology of cancer

  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References

No clear evidence of cancer has been demonstrated on living plants, and cancer seems to be absent in modern invertebrates, excluding some experimental conditions (i.e., tumour-like conditions induced in Drosophyla sp.). Even though Harshberger2 has suggested the possibility of neoplasms in invertebrate animals, and Kaiser3 has demonstrated some sorts of “growths” in plants and inferior animals, we have no clear evidence of true neoplastic diseases other than in the vertebrate animals.

At present true neoplastic diseases, including cancer, seem to be restricted to vertebrate animals, and only one observation of a true cancer has been described in one of the more simple living vertebrates, specifically hepatomas in a jawless hagfish.2 This is a very important case for the comparative pathology of cancer, because lampreys are among the simplest living vertebrates. The presence of neoplastic diseases beginning with the lesser vertebrates seems to be consistent with the hypothesis that cancer is a pathology characteristic of vertebrate animals.

Cancer has been reported throughout the entire spectrum of vertebrates. In the elasmobranch fish a case of chondroma in a lumbar vertebra has been described in the species Squalus mitsukurii (dogfish),4 and a case of fibrosarcoma has been described in Raja macrorhyncha (skate).4

Rising along the biological scale, in the bony fish (osteichthyians) neoplasms seem to be more frequent, and we have some descriptions of both benign tumours (i.e., osteoma, chondroma, osteocondroma) and malignancies (i.e., fibrosarcoma in a dorsal fin of a carp, the fin of a skate ray and in the mandible of a codfish).4 In addition, osteosarcoma has been clearly identified in a bone of the anal fin of Esox lucius (a pike) and in the pectoral fins and opercular bones of some codfish.4 Carcinoma without skeletal involvement has been reported in trout,5 climbing perch6 and perch.5, 6 Lymphoma2 and lymphosarcoma have also been observed in a northern pike.2 Hyperostosis is relatively frequent in many living species of bony fish and seems to be a form of so-called osteomata.7 The focal neoformation of compact bone is one of the more frequent benign neoplasms in all living fish, and researchers invariably discuss the nomenclature linked to these forms. We prefer to follow the older nomenclature (i.e., focal hyperostosis, osteoma, ivory osteoma) that were introduced in comparative pathology by Gervais8 at the end of the 19th Century. I have demonstrated the phylogenetic relationship between focal hyperostosis in living fish and the osteoma in modern humans.7 Osteoma is one of the more common neoplasms. We have been aware of its presence and its high prevalence in fish 2 centuries.8 Osteoma has been documented in butterfly fish, file fish, red tai, angelfish, codfish, pike, flounder, croaker, flatfishes, scabbard fish, coal fish, rock fish, speckled trout, carp.4

No cases of neoplasms have been found among the amphibians. The only case4 reported in literature may simply be a callus subsequent to a fracture.9

In modern reptiles there have been occasional cases of parathyroid adenoma in turtles.10 Researchers have also observed chondroma4 and osteochondroma11, 12 in the representatives of the genus Varanus. A clear case of osteosarcoma has been observed in the spine of a rufous-beaked snake.13 In addition, chondrosarcoma has been reported in corn snakes2, 14 and osteochondrosarcoma has been described in the vertebral column of an individual attributable to Natrix melanoleuca.15 Neurofibrosarcoma has been reported in a Korean viper,16 and presumed melanoma has been observed in a snake from the Everglades.15 Lymphatic tumours seem to be relatively frequent in modern wild reptiles. Lymphatic leukemia has been described in boa constrictors17 and in Python.18 Lymphoma has been reported in rhinoceros vipers, death adders, Indian rock pythons, and hog nose snakes.16 In addition, lymphosarcoma has been reported in rhinoceros vipers and spitting cobras.16 Leukaemia has been observed in Acanthophis antarctica, Bitis arietans and Bitis nasicornis.16

Neoplasms in birds are relatively common but are strictly limited to captive animals. In wild bird populations neoplasms seem to be extremely rare if present. No cases of neoplasms have been described in wild birds. In 25–33% of captive budgerigars tumours are the cause of death and in psittaci formes at least 3.5% of deaths are caused by malignancies.19 Pituitary tumours are particularly common although osteosarcoma has also been reported with particular frequency in domestic budgerigars and canaries.19

According to Jubb and Kennedy,20 wild living mammals neoplasms are rare. In domestic dogs there is a greater prevalence of neoplasms, which is concentrated in the 6–8-year age span, a fact that is of particular interest considering that these animals have a life expectancy of 10–14 years.20

In wild mammal populations neoplasms are surely more rare. Epidemiological data exists only for chimpanzees and we know that 1.8% of the deaths in chimpanzee communities are due to cancer. Single observations of chondrosarcoma have been reported in the femur of a kangaroo,18, 21 and in the caudal vertebra of a ferret.22 A single case of fibrosarcoma was observed in a Northern fur seal.23 Neoplasms of the lymphatic cells seem to be slightly more common in many mammals. A case of possible myeloma of the lumbar vertebra associated with plasma cells dyscrasia has been reported in a ferret.22 Hodgkin's lymphoma, without skeletal involvement, has been reported in Orcinus orca.24 Lymphosarcoma has been noted in many marine and terrestrial mammals including harbor seals, sea lions, Northern fur seals, harp seals23 and deer.18 Leukaemia has been documented in pacaranas18 and in gibbons.25

The focal hyperostosis known as osteoma, which produces compact bone buttons on the cranial vault and more subordinate buttons on the surfaces of the long bones (commonly called ivory osteoma),7 merit special consideration. This type of benign bone neoplasm has been induced in mice by the RFB osteoma virus.26 Osteoma is frequent particularly in many mammals, as well as in bony fish,7 and has been documented in wild species (i.e., ferrets and Platecarpus).9, 27 Diffuse hyperostosis is also relatively frequent in bony fish and mammals. It is characteristic of 3 orders of mammals and present in all subjects: Proboscidea (i.e., sirenia), Hyracoidea (i.e., trichecus) and Tubulidentata (i.e., dugongo). In all these animals, the axial skeleton is replaced completely by medullary bones,28 a congenital condition called pachyostosis. Focal hyperostosis in the form of mandibular swelling, however, has also been documented in dogs.29

Multiple hereditary osteochondromata is relatively common in some other modern mammals: domestic horses, cats and dogs.30, 31, 32, 33, 34 In the family Canidae only domestic dogs are affected.35, 36, 37, 38 Malignant degeneration into osteosarcoma or chondrosarcoma has been demonstrated in about 18% of the cases.32 Multiple hereditary osteochondromata have also been observed in Nothocyon, Tomarctus, Daphoenus and Cynodictis.39, 40

The prevalence of neoplasms in the modern human population as cause of death is particularly high. This datum is an exception within the general framework of the comparative pathology of neoplasms. The very high prevalence of neoplasms in modern humans seems similar to the high prevalence of neoplasms in the population of domestic dogs or in populations of captive birds.

In conclusion, the comparative pathology of extant neoplasms shows the following remarkable points: (i) neoplasms are a pathology typical of all the extant vertebrates, starting from jawless fish; (ii) neoplasms in extant wild vertebrate populations seem to be extremely rare in amphibians and birds, and slightly more frequent in fish, reptiles and mammals; (iii) one of the more frequent forms of extant neoplasm in both bony fish and mammals seems to be the focal (osteoma) and the regional (pachyostosis) benign bone tumour; and (iv) in captivity the prevalence of neoplasms, including cancer, seem to be considerably higher, perhaps independently from the systematic position of involved populations (i.e., both in birds and in mammals).

Cancer before man: the fossil record of neoplasms

  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References

There are only a few dozen cases of neoplasms in the fossil record, most of which have doubtful diagnoses.

The earliest known possible case of neoplasm is in a Dinichthys, an armored fish from Cleveland, Ohio that dates to the Upper Devonian (about 350 million years BP).41 The case consists of a dip pit on the internal surface of the lower jawbone. The authors41 interpret this lesion as the result of bone reabsorption due to a tumour, suggesting the presence of a Stafne' defect. As an alternative diagnosis, it is also possible that the lesion, which certainly occurred during the life of the fish, was caused by trauma. Some researchers have shown that the armored fish living in fresh waters were aggressive animals, and indeed some individuals present lesions that are obviously traumatic in origin and can be linked to intra-specific aggression.42 If a tumour of the soft tissues of the mouth floor produced the lesion, however, it is worth noting that the armored fish were one of the first groups of vertebrates to appear on the Earth. It would follow that neoplasms appeared on our planet with the first vertebrates, confirming the supposed biological link between vertebrates and neoplasms.

The earliest known unequivocal neoplastic case was noted on the partial skeleton of a North American lower carboniferous (about 300 million years BP) fossil fish, Phanerosteon mirabile.43 The pathology presents as the classic fish osteoma including a bone focal hyperostosis of the sort also observed in living representatives of bony fish. This indicates that this type of neoplasm was among the first of the neoplastic diseases to appear on Earth.

The 2 examples from the Paleozoic fossil record show that neoplasms occurred occasionally in all the prevalently aquatic vertebrates living during the Paleozoic Era. There are also many well-documented, unequivocally diagnosed cases of neoplasms among the animals, especially the terrestrial animals, that lived during the Jurassic, and, to a greater degree, the Cretaceous, from about 200–70 million years BP.

Indeed, the analysis of millions of fossil bones from extinct Jurassic and Cretaceous reptiles has showed the presence of a bone osteoma in a vertebra of a mosasaurus (a large marine reptile). This is the earliest known case of a bone tumour in a terrestrial fossil.44, 45, 46 An additional case of osteoma has been observed in a Platecarpus sp.,9 and a possible additional case of osteoma has been observed on the left scapula of a Pachyrhinosaurus from Alberta, Canada, although scientific documentation is required to confirm the diagnosis.47

Focal bone hyperostosis was also observed in a caudal vertebra of a Cretaceous hadrosaur from Alberta, Canada, and likely represents an additional case of osteoma in dinosaurs.48 Other possibly benign neoplasms have been noted in dinosaur bones.49 For example, an intraosseous cyst interpreted as a neoplasm was observed on the cranial crest of a Stenonychosaurus inegualis from the Cretaceous of Alberta, Canada,50 and a possible hemangioma was described by Moodie46 in a tail vertebra of a Cretaceous herbivorous dinosaur from North America.46

Exostosis of the right scapula was observed in a Triceratops from the Mesozoic of North America. The attribution of the lesion to a neoplasm remains doubtful51 because exostoses can also be linked to ossification of soft tissue after traumatic events. We have noted this in the dinosaur bones of the collection of the museum at the University of Chieti (Italy). There is also a case of fused caudal vertebrae with new bone formation in a Jurassic sauropod from Wyoming (USA) that Moodie52 interpreted as possibly neoplastic. A more recent evaluation and comparison with similar cases has shown that these vertebral ankyloses are due to a rheumatic condition, for example diffuse hydropathic skeletal hyperostosis (DISH).53

In the paleopathological collections of the Biomedical Museum of the State University of Chieti (Italy), we have one of the earliest known cases of neoplasm in a dinosaur. The specimen (Fig. 1) is a fragment of a right rib of a giant Apatosaurus sp., found in Jurassic sediments in Wyoming (USA). This specimen presents a sub-rounded mass with multilobulated surface implanted on the external surface of the rib (Fig. 1a). The radiograph shows that the mass consists of high density bone tissue and the normal cortical bone appears to be eroded under the area of insertion of the neoformed mass (Fig. 1b). We think that the gross morphology and the radiographic picture are consistent with a possible osteochondroma (this is the first time this case has been mentioned).

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Figure 1. Fragment of a right rib of a large dinosaur, Apatosaurus sp. (a), which presents a sub-rounded mass with multilobulated surface (c), and high radiographic density (b) (Jurassic, Wyoming, USA; sample 323 of the University Museum, Chieti).

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The earliest known case of hemangioma, observed in a possible vertebral centra from a large sized terrestrial dinosaur from the Morrison Formation (Utah),54 dates to the Jurassic.

The first clear, well-documented case of malignancy also dates to the Jurassic, as does the first unequivocal case of metastasis. In the humerus of a theropod dinosaur (Allosaurus fragilis) from the late Jurassic Morrison formation in Utah (USA), Stadtman observed a large mass of new-formed bone (surely due to neoplastic disease invading the surrounding normal bone) and interpreted it as a probable chondrosarcoma.55 The evidence for metastatic cancer consists of multiple lytic lesions with cortical bone invasion that were observed histologically and radiographically in a fossil bone fragment from a large-sized terrestrial dinosaur from the Jurassic Morrison formation in Colorado (USA).56

A possible multiple myeloma affecting the squamosal bone of a latest Cretaceous horned dinosaur, Torosaurus latus, has been suggested by Norman57 and a similar interpretation has been proposed for a case involving extra openings in the cranial bone of an ornithischian dinosaur.58

As these considerations show, all our knowledge of neoplasms during Jurassic and Cretaceous periods, including our first consistent information on the antiquity of cancer, are linked to the study of dinosaur bones. The very impressive sizes reached by many representatives of this group during the last part of the Mesozoic Era may have been related to endocrine disturbances. Some researchers suggest that the huge size typical of some dinosaurs was a form of gigantism, perhaps due to acromegalia linked to an increase in the endocrine function of the hypophysis.59, 60

Although a vast number of fossil dinosaur bones have been excavated perfectly and examined by specialists, no more than a dozen possible neoplasms have been observed, some of which are not confirmed. This number is minute.

At the end of the Mesozoic Era (the passage from the Cretaceous to the Tertiary, also known as the K-T boundary) a massive extinction affected life on Earth, with the disappearance of millions of animal species (including all the dinosaurs) and the rise of mammals began. Despite the major changes that affected many animal groups and despite the dramatic changes in the relative importance of the various animal populations present on Earth during the Tertiary and Quaternary Eras, the prevalence of neoplasms remained constant: they did not disappear, but remained quite rare.

We have several dozen reports of neoplasms in fossils from several countries and dating to the various periods of the Tertiary and Quaternary Eras. Benign neoplasms include osteoma that was reported in fossil elephants from Poland,61 as well as solitary bony cysts and bone defects in Tertiary Bovidae.62, 63 Other possibly benign neoplasms in Tertiary and Quaternary mammals have been observed in Nototerium sp.,64Canidae65, 66 and Ursusus spelaeus.67

Many cases of fish osteoma have been observed in the fossil record of the Tertiary and Quaternary Eras. These types of focal and regional hyperostoses were so frequent in both fossils and extant species of fossil fish that Konnerth68 named the hyperostotic fish bones “Tilly Bone,” in honor of the vertebrate paleontologist Tilly Edinger from Harvard University, who spent part of her life studying these neoplastic items. Because of their swollen and thickened nature, fish bones affected by focal hyperostoses are more durable and should better resist mechanical erosion and chemical dissolution and thus be preserved frequently. Indeed, Tilly bones are often found in Tertiary and Quaternary soils in both North America and Europe (Fig. 2).69 although some researchers consider hyperostoses to be part of a normal aging process,70 others have shown that they can be considered true neoplastic lesions.7, 69 Some species developed focal hyperostoses often, for example Platax artriticus and the Miocene Aphanius crassicaudatus.70, 71 Recent observations suggest that the affected fossil and extant species develop focal and regional hyperostoses because their habitats are highly saline.72 We have shown recently that all the Tertiary ancestors of extant sirenidae show pachyostosis,72 for example regional hyperostosis.

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Figure 2. Two fish vertebrae with focal bone hyperostosis (fish-osteoma or Tilly-bones), compared to a normal vertebra of the same species of fish and from the same locality (right) (Glades Country, Florida, USA, Pleistocene (sample 439-1,2,3 of the University Museum, Chieti, Italy).

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Focal hyperostosis in fish and pachyostosis in sirenidae could be phenotypic adaptations on the part of these aquatic animals to increase their body weight and thus facilitate swimming (the fish) or browsing shallow sea bottoms (the sirenidae) in hypersaline waters.72 Multiple hereditary osteochondroma have been observed in Oligocene Canidae Hesperocyon sp.73

Neoplasms derived from dental tissues are also well demonstrated in the Tertiary and Quaternary fossil record. It would seem that this type of neoplasm had a fairly high prevalence during this time, although one must keep in mind that teeth, which are the hardest animal tissue, are one of the more common elements of the fossil record. Odontoma has been reported in Tertiary ungulates from Argentina,74 in fossil horses,75 in European mammoths76 and in some Japanese fossil elephants.77 In our Museum we have a well-documented, unpublished case of odontoma in a Holocene fossil walrus from Alaska.

There are also some examples of malignancy in the Tertiary and Quaternary fossil record, including osteosarcoma in a Pleistocene buffalo78 and a Holocene Capra79 and chondrosarcoma in some species of fossil Canidae.32, 80

Two final aspects regarding neoplasms in Tertiary and Quaternary Time must be considered. The first aspect is the rarity of neoplasms, especially in light of the vast number of fossil bones of reptiles, birds, and especially mammals that have been recovered. For example, Rancho La Brea, in California (a Pleistocene freshwater lake associated with a tar seep where a great many animals were trapped and died more than 2 million years ago) has yielded millions of fossil bones that have all been examined by paleontologists. No bone neoplasms have been found and the situation is similar in all other Tertiary and Quaternary fossil locations. It is also worth noting that most of the Tertiary and Quaternary neoplasms observed affected mammals, which were the most common class of vertebrate at the time, much the way that in Mesozoic Time the majority of neoplasms observed involved reptiles.

The observed rarity of cancer may be explainable by the fact that the affected animals were presumably more vulnerable to predation, and in eating them the predators would have destroyed the traces of the pathologies they suffered from.

In summary, the pre-human fossil record leads to some interesting conclusions (Fig. 3) : (i) neoplasms have existed since the Paleozoic Era and the first cases involved aquatic vertebrates such as primitive fish; (ii) during the Paleozoic Era neoplastic diseases were extremely rare; (iii) only during the Mesozoic Era did the incidence of neoplastic disease increase (although remaining rare), and the increase was concurrent primarily with the rise of terrestrial vertebrates such as the reptiles; (iv) the K-T boundary marks one of the most significant mass extinctions to strike life on Earth, with new Tertiary species replacing those of the Cretaceous; even so, the prevalence of neoplasms remained very low; (v) during the Tertiary and Quaternary Eras neoplastic diseases remained rare, although they now primarily affected mammals; (iv) focal hyperostosis of fish and pachyostosis of sirenidae seem to be forms of neoplasms adopted by these kinds of aquatic animals over millions of years as mechanisms by which to increase their body weights and thus facilitate bottom browsing at shallow depths or swimming in hypersaline waters; and (vii) the rarity of cancer in the fossil record must have been influenced by predatory activity, because sick animals were more vulnerable and therefore less likely to be fossilized.

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Figure 3. Incidence of neoplasms (including cancer) over the evolution of the vertebrates. The incidence is calculated on the basis of the ratio between the number of pathological specimens and the total number of fossils studied.

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Cancer in ancient human populations

  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References

Paleopathologists have spent decades discussing the “Kanam mandible,” a fragment of mandibular ramous attributable to a Homo erectus from Kanam, Kenya, which presents a bizarre pathological growth in its symphysial region. This lesion was attributed initially to a possible Burkitt's lymphoma81 or an ossifying sarcoma,82 although some researchers have suggested recently it might be an overabundant bone callus associated with a healed fracture.83 If this case, with dates to about 1.5 million years ago, is a true neoplasm, it is the earliest known example of these diseases in man.84

Anthropologists have recovered and studied thousands of fossil bones pertaining to Neanderthal men in Europe, finding only one lesion possibly related to a neoplasm. It is the Stetten II parietal bone (from Germany, dating to about 35,000 years BP). The lesion consists of new bone formation theoretically linked to a possible meningioma although the evidence is neither clear nor convincing.85

Possible cases of neoplasms remained rare in prehistoric and ancient historic human populations and increased significantly only relatively recently in medieval and modern populations. As a general rule, the number of cases of possible neoplasms increases with the physical number of human remains available for analysis and also increases with decreasing antiquity.

Almost all types of modern human neoplastic diseases have also been documented in ancient human remains and for a complete discussion of all the references made in the literature we suggest consulting one of the major analyses (i.e., Aufderide and Rodriguez-Martin, Capasso and Mariani-Costantini, Ortner).84, 86, 87 We summarize these reports to provide a general discussion on the topic of cancer in human antiquity.

Cartilaginous exostoses have been demonstrated from early on, with one of the earliest known cases dating to the 12th Dynasty in Egypt.87 They were also present in ancient Europe.84 Hereditary multiple exostoses have also been demonstrated in ancient remains. The earliest known case dates to about 2,000 years ago and is from Poland.88 The earliest known case of giant cell tumour occurred in young skeleton from Chile dating to 1100–1220 AD.89 Meningioma has been described in many ancient human populations, with the earliest clear occurrence involving a skeleton from Egypt dating to the First Dynasty.90 This tumour was present also in prehistoric America91 and many other reports indicate that this type of neoplasm was probably relatively frequent in various prehistoric and ancient historic populations.84 Hemangioma and fibrous tumours of the bones have also been reported in some ancient human remains.84

Malignant primary bone tumours were very rare in antiquity and continue to be rare in modern populations. The earliest known case affected a male Celt (about 800–600 BC) who was about 15 years old and lived in what is now Switzerland.1 The lesion is a neoformed bone mass at the level of the metaphysis of the humerus, whose gross pathology and radiographic aspect are consistent with a possible osteosarcoma or chondrosarcoma. A few additional cases of malignant primary bone tumours have been mentioned in literature. A possible osteosarcoma of the pelvis has been reported in a young individual from Ancient Egypt, dating to about 250 AD,92 and a well-documented case of osteosarcoma, with the typical radiographic “sunburst” pattern, has been observed in the femur of a native Peruvian dating to 800 BP (Fig. 4).93 Possible additional cases of osteosarcoma have been reported in a young female femur from the prehistoric population of Oahu in Hawaii,94 in a zygomatic bone from the French Middle Ages,95 in a 17th century mandible from West Virginia,96 in a young male from the Saxon necropolis of Standlake, England97 and in medieval skulls from the Czech Republic98 and France.99 Probable cranial hemangiosarcoma has been documented in an elderly female who lived in the 3rd Century BC in central Italy,100 and in a humerus from Peru dating to the 12–14th Centuries AD.93

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Figure 4. Osteosarcoma of the femur in a native Peruvian dating to ca. 800 BP (a), with the typical radiographic “sunburst” pattern (b). Reproduced with permission from Aufderheide et al.93

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Other extremely rare neoplastic forms have also been documented in the paleopathological literature: histiocytoma in ancient Egypt,101 osteoclastoma in England1 and Italy,102 Hand-Schuller-Christian disease in a prehistoric Native American from New York State,103 eosinophil granuloma in a prehistoric Native American child from Illinois104 and possible Ewing's sarcoma in a juvenile skull from Bronze Age of Tartaren, Spain.105

Human bones can be affected by neoplasia involving other organs. For example, pituitary adenoma produces an enlargement of the sella turcica due to abnormal pressure. These types of tumour have been described in the paleopathological literature but are very rare.106

Finally, evidence for some tumours that produce calcifications can be found in ancient human burials. For example, the ossified masses produced by fibroleiomyomas of the uterus have been found in correspondence of the small pelvis in many Iron Age female burials in Italy,107 in Neolithic burials in France108 and Switzerland,109 in Dynastic burials in Egypt110 and in medieval burials in Spain.111

Despite the difficulties involved in the diagnosis of multiple lithic lesions on dry human bones, we can state that the scarcity of cases in ancient human populations is not limited to primary bone tumours, but also to bone metastasis of carcinoma, which are only occasionally reported in the paleopathological literature. In Eurasia the earliest known cases are from Mokrin (ex-Yugoslavia), dating to about 1900 BC112 (this case involves the skeleton of an elderly woman, and the author suggests bone metastasis of possible breast cancer), and from Russia, dating to the 15th Century BC.113 More recent cases have also been reported in the same part of Russia.113 Additional cases ranging from Bronze Age to the Middle Ages have been reported from the Czech Republic,114 Poland,115 Hungry,116 the former Yugoslavia,117 England,1, 118, 119 Denmark120 and Switzerland.121 More cases of multiple lithic skeletal lesions probably due to metastasis have been reported in Pre-Columbian American populations122, 123 including cases from pre-historic California124 and Kentucky,125 pre-Hispanic Peru125 and St. Lawrence Island (Alaska).125 Only a few dozen of the cases of skeletal metastasis of cancer have been reported in the human material from ancient Egypt.126, 127

In ancient Egypt and pre-Columbian Central and South America archaeologists have recovered many thousands of human skeletons and mummies. Their examination shows that the ancient populations of these regions rarely suffered from primary or metastatic neoplasms.84

This rarity has led some authors to speculate that in ancient time human carcinoma was unable to produce bone metastasis. This speculation is clearly groundless because we have also the results of the paleopathological studies of human mummies. Thousands of mummified human bodies, both natural and artificial, have been excavated in Egypt, Peru, Chile, Alaska, China and many countries in Europe. The prevalence of primary and metastatic cancers was very low everywhere throughout all of pre-Medieval time.128 For instance, only 44 cases of neoplastic diseases (excluding cranial osteomas) are reported in a recent review of thousands of Ancient Egyptian mummies.129 Seven of these cases are interpretable of nasopharyngeal carcinoma130 and 9 are interpreted as multiple myeloma.131

Only a few cases of neoplasms have been documented in Central and South American mummies. We draw attention to a lipoma (12–13th Centuries AD) and a rhabdomyosarcoma (4–7th Centuries AD) in 2 children from Chile.132 In Europe we have only 2 cases (a carcinoma of the prostate or the rectum and a naso-orbital cancer) in 2 artificial mummies of members of the nobility buried during the 16th Century AD in the Church of San Domenico Maggiore in Naples (Italy).133

The rarity of neoplastic lesions, including cancer, in ancient human mummies has led some authors to speculate that neoplastic tissues do not undergo mummification due to some sort of (at this moment completely obscure) biochemical difference with respect to normal tissues. Zimmerman convincingly disproved this speculation134 by mummifying neoplastic tissues removed during surgical procedures using the techniques employed by the Ancient Egyptians. The pathologic tissues were clearly identifiable.

All the neoplastic lesions, both primary and secondary, only occur occasionally in collections of ancient human remains. As a result, the conditions that produced them can be considered rare or extremely rare in all past human populations. Indeed, from an epidemiologic standpoint we can consider Strouhal's recent revision of all the previous mentions of malignancies in ancient Europe.135 Strouhal counted 176 cases of malignant neoplasms in ancient European populations, observing that ancient (prehistoric and proto-historic Time) cases are very rare. Only after the Middle Ages was there a significant increase in the number of malignancies observed. Strouhal135 also estimates that about 43.2% of all the malignancies observed on ancient European skeletons are probably due to the metastatic carcinomas.

Considering the prevalence of malignancies in ancient Europe, we note that the total number of cases reported (176) is miniscule by comparison with the enormous number of skeletal remains examined by physical anthropologists in Europe. Indeed, relating the 176 cases of malignancies observed to the many tens of thousands of skeletal subjects examined, we can conclude that the prevalence of malignant tumours was considerably <1%.

From a diachronic standpoint it is very interesting to note that the reported cases of malignancies on skeletal materials were not homogeneously distributed over the different epochs. In Europe only 13.6% of the malignancies reported date to pre-Christian time, whereas 38.6% date to the first millennium AD and 47.7% to the second millennium AD. A completely opposite picture seems to emerge from the diachronic examination of the malignancies reported from ancient Egypt. Indeed, 71.2% of the reported cases date to pre-Christian time, and only 18.8% to the centuries after Christ's birth. This distribution seems to be related to population density, the richness of the populations, the number of houses, the size of the towns, etc. It would seem to reflect that the social aggregation level, which was high in pre-Christian time in northeast Africa, rose in post-Medieval time in Europe and never rose in the pre-Columbian Americas.

The paleopathological data gathered to date indicates that only the 3 following neoplasms were relatively frequent in ancient human populations: “ivory osteomas,” nasopharyngeal carcinoma and multiple myeloma.84

The “ivory osteoma” (or cranial osteomata) is one of the most common neoplastic lesions to occur in the archaeological record (Fig. 5). Osteoma has been documented since prehistory in France, Poland, England, Italy and Spain, and there are dozens of scientific reports with descriptions of hundreds of cases of osteoma, including statistical data regarding the topographic distribution of the lesions on the external surface of the cranial vault.136 This pathology has been reported in all ancient human populations and in some areas and some periods of the past its seems to have been more frequent than it is now.84 In the medieval populations of Central and Northern Europe and North Africa osteomas were probably more frequent than they are today. About 1% of all modern autopsies show the presence of at last one cranial osteoma,87 whereas the examination of many thousand Egyptian skulls dating from pre-dynastic times to the Roman conquest led the authors to estimate a prevalence of cranial osteoma of about 2.5%.128 We note that in Eastern Europe, 26 of 39 bone neoplasms in the paleopathologic record are osteoma.137

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Figure 5. Typical cranial osteoma on the external surface of the left parietal bone in a subject from the Grotta dello Scoglietto, Tuscany, dated to the Bronze Age (sample at the National Museum of Anthropology, Florence, Italy).

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Nasopharyngeal carcinoma is well documented in many ancient human bones through the vast destruction it works on the facial skeleton, sphenoidal region and cranial base.84 In the Ancient Egyptian population many cases that are also documented through histological analyses have been reported (Fig. 6). From an epidemiological standpoint the authors calculate that about 15% of all malignancies in Dynastic Egypt were nasopharyngeal carcinoma.84 The situation was quite different in ancient Eurasia, where we have just one paleopathological report of a possible nasopharyngeal carcinoma. This was a case of lytic lesions originating in the paranasal sinuses of a skull from Tepe Hissar, Iran, dating to 3,200–2,000 years BP.138 The high number of cases documented in ancient Egypt contrasts strongly with the current rarity of nasopharyngeal carcinoma, which accounts for only 0.25% of all malignancies worldwide. This cancer does, however, have a higher prevalence in some parts of Africa. In Tunisia, Algeria, Morocco, Sudan and part of Oriental Africa, it accounts for 7% of all malignancies. Moreover, in some parts of Asia (i.e., Singapore, Thailand, Vietnam, South China) and also in Alaska, this tumor's prevalence can reach 18–20% of all malignancies.139 In these areas the high prevalence of nasopharyngeal carcinoma has been linked to the combined presence of Epstein-Barr virus infection and exposure of the nasopharyngeal mucosa to chemical carcinogens from the local flora (for example diterpene hesters).140 One can infer that the high prevalence of nasopharyngeal carcinoma in ancient Egypt was related to the presence of the Epstein-Barr viruses and to the presence of chemical cofactors that encouraged carcinogenesis in the environments of large ancient Egyptian towns.84

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Figure 6. Osteolytic changes in the hard palate due to a primary carcinoma (a), probably nasopharyngeal carcinoma, in a 35–45-year-old male from Christian cemetery I at Sayala, Egyptian Nubia; the histological examination (b) shows enlarged and confluent osteoclastic lacunae (*) at the surface of the bony palatum, immediately under the mummified oral mucosa (m). From Strouhal.148 Histology courtesy of Prof. M. Schultz.

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Despite the considerable difficulties involved in making a differential diagnosis between the multiple skeletal lytic lesions due to multiple myeloma and those due to metastatic carcinoma, many researchers have examined this topic, concluding that multiple myeloma was relatively common in many ancient populations (Fig. 7).84 In ancient Egypt multiple myeloma is also well documented in mummified human remains, and the authors calculate that this tumour was the most frequent type of malignancy.84 Multiple myeloma was also present in pre-Columbian America, where the earliest known case dates to 3,300 BC. Steinbock reports 14 paleopathological cases dating from prehistory to 1600 AD.103 Finally, multiple myeloma has also been observed in some ancient European populations.135 Considering that this neoplasm now represents only 0.7% of all malignancies, the paleopathological cases seem to indicate a higher prevalence in the past. This discrepancy must in part be related to the difficulties posed by the differential diagnosis, especially with respect to metastatic carcinomas, but must be also related to malnutrition and to chronic infections, which are very well documented in human remains through both skeletal analysis (Harris Lines detections, lines of bone growth interruption caused by starvation), and dental enamel hypoplasia (due to interruptions in dental growth consequent to chronic infections or prolonged starvation in infancy).84 Both these conditions have been documented abundantly in all ancient populations, and may cause continuous stimulation of the immune system, which will encourage the emergence of transformed plasmacellular clones.84

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Figure 7. Adult male skull with multiple osteolytic lesions of the vault probably due to multiple myeloma; Bronze Age; CovaJoan d'Os, Llerida, Spain (courtesy of Prof. Domenec Campillo, Barcelona).

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In conclusion, the paleopathology of human neoplasm indicate the following: (i) neoplastic diseases have affected humans since their first appearance on the Earth; (ii) neoplastic disease, both primitive and secondary, was extremely rare for a very long time, becoming rare in pre-modern humans, as is shown by the paucity of all kinds of tumours in thousands ancient human mummies; (iii) this rarity seems to be independent of time (with the exception of the recent past) and locality, because no significant differences were found in the prevalence of neoplastic diseases in ancient human populations throughout the world; (iv) only a few forms of neoplasms seem to have had similar or greater prevalences in the past than they do now: cranial osteomas, nasopharyngeal carcinoma, and multiple myeloma; (v) primitive bone tumours, which now are rare and typical of growing individuals, seem to have been equally rare in the past; (vi) secondary bone tumours were rare in all past human populations, and this type of cancer seems to have undergone an impressive increase in prevalence only in relatively recent times; (vii) a greater prevalence of malignancies seems to be associated with highly civilized populations that have high social aggregation levels (i.e., Dynastic Egypt and post-medieval Europe); (viii) the relatively high prevalence of nasopharyngeal carcinoma may be related to the presence of ancient areas (i.e., large communities in ancient Egypt) where infection with the Epstein-Barr virus was common, and associated with environmental conditions favorable to the development of tumours, for example the presence of short-chain fatty acids derived from Euphorbiacea plants; and (ix) the relatively high prevalence of multiple myeloma in antiquity can be related to widespread malnutrition and starvation, as well as to high frequencies of chronic infections; all these conditions (that are also well documented through ancient skeletal and dental analyses) can excessively stimulate the immune system, encouraging the emergence of transformed plasmacellular clones.

Causes of rarity of cancer in ancient human populations

  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References

The conclusion one draws from the paleopathological evidence discussed above is that cancer, as well as all neoplasms, were rarer in human antiquity than they are now.

One possible reason for this is that cancers may have led to death sooner in antiquity than they do now, because of the way they interfere with vital functions, especially through complications that modern surgical procedures are able to alleviate, thus prolonging life.

It is undoubtedly true, however, that the prevalence of neoplastic disease has increased tremendously over the past century. Indeed, paleopathological data on the extreme rarity of cancer in antiquity meshes perfectly with historical information; for example we know that in Germany the mortality for cancer was only 3.3% in 1900, although it had climbed to over 20% in 1970. In addition we know that today about half of all men and one-third of all women develop cancer and about 20% of all deaths are due to cancer.141 This is an impressive increase and seems to demonstrate that the increase in cancer prevalence is only a recent biological event.

This phenomenon has been tentatively linked to the aging of modern populations. Indeed, over the past century, especially in recent decades and in developed countries, life expectancy has steadily increased from about 30–40 years to 70–80 years.84 This fact is certainly a major factor behind the increase in cancer prevalence over the past century because cancer is clearly an age-progressive disease whose prevalence ranges from about 1.8% for those <39 years old to 27.2% among those in the 60–79-year age group.141 In the United States in 1996 more than 87% of cancer deaths occurred in subjects aged 55 years or older. Because about 90% of ancient humans died before age 55, age alone could be expected to reduce the prevalence of malignancy in past centuries by about 90% with respect to the modern rate.84 The aging of populations increases the time of exposure of each individual to environmental carcinogens, both physical (sun light and natural radiation), and chemical. This can produce, at the population level, the increase in cancer prevalence.

A global historical interpretation cannot overlook the very strange fact that an increase in cancer prevalence has also been noted in countries in which life expectancy was minimal in the past century. Indeed, there is evidence that also geography is now a risk factor for developing cancer, relatively independent of the life expectancy characteristic of each country. The highest incidence of cancer occurs in countries that do not have the highest healthy life expectancy at birth (HALE), for example Hungary and Belgium. To the contrary, the highest HALE occurs in countries whose incidence of cancer is lower (i.e., Japan, Switzerland, Sweden). In addition, nearly equal incidences of cancer occur in countries whose HALE are quite different (i.e., United Arab Emirates has a high value and Ethiopia has a low value). Surprisingly large differences in cancer incidence (as much as a ratio of almost 1:7) occur between countries that are geographically close and have by similar HALE values (i.e., Paraguay and Uruguay; data for 2001).142

These data clearly indicate that the aging of the human population is not sufficient to explain the tremendous increase in prevalence of cancer in human populations over the past century.

Indeed, we must also consider the possibility that the modern causes of cancer might differ in typology and in intensity with respect to those of antiquity.

With regards to typology, it is certainly true that ancient humans were spared exposure to many of our modern, synthetic carcinogens,86 including all the physical factors (environmental radioactivity due to nuclear tests that only began in the 1950s) and chemical agents responsible for the modern environmental pollution that is especially evident in urban and metropolitan habitats.

Natural environmental carcinogens must have plagued our ancestors in antiquity, however, as did the artificial environmental carcinogens that were also present in ancient time. One especially stimulating aspect of this topic is that humans adopted indoor habits only relatively recently, and that the time that people spend indoors has increased significantly only in the past century, especially in those countries in which the industrial revolution led people to spend their working hours indoors as well. The indoor environment is characterized by particular types of pollution, and by particular modes of human interaction with it. Domestic occupations and working indoors, significantly increase exposure to radon gas, as well as to uranium and heavy metal ores. Dietz and et al.143 found a statistically significant correlation between cancer and the amount of time spent indoors. Prolonged exposure to indoor pollution has been locally documented in some ancient populations, for example Herculaneum during 1st Century AD,144 and in some primitive modern populations (i.e., New Guinea highlanders).145 In both these situations indoor pollution was significantly increased by smoke from wood fires, the use of oil or animal fat fed lamps to generate light and by organically-fed fires used for cooking foods. In both of these settings the authors demonstrated increases in pulmonary diseases including cancer.

Indoor pollution must have increased after the Middle Ages,146 and it is worth underlining that those living in the wealthy post-industrial revolution countries spend much of their time indoors, in part because of the prevailing socio-economic model, and this produces additional increased exposure to carcinogenic environmental factors.

The increase in human population density, which corresponds to an increase in sedentary habits, resulted in the development of the first large towns and cities, whose external environments presented levels of air pollution similar to those found indoors.

Human population density, associated with rapid intra-human exchanges, is a characteristic of modern societies in developed countries; these factors can increase the circulation of viruses, including oncogen forms.

These considerations lead to the conclusion that so-called “civilization” is associated with the increase in the prevalence of cancer over the past century. In addition, paleopathological evidence seems to confirm that a greater prevalence of malignancies is associated with highly civilized populations, high social aggregation levels, and a prevalence of indoor habits.

Cancer as a possible biological strategy?

  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References

Through the study of the fossil evidence for neoplasms in antiquity we collected proof that some animals adopt some sorts of tumours as a biological strategy. The fossil fish of the genus Pachylebias that lived in the hyper-saline water of the Mediterranean Sea about 8 million yeas ago adopted pachyostosis to facilitate immersion and swimming in the highly dense water by increasing the weight of their skeletons, through the development of diffuse hyperostosis that did not differ from a neoplastic form of benign tumour originating from bone tissue. One sees a similar strategy in mammals pertaining to the Sirenidae group from the Oligocene (about 30 million years ago), which acquired high-density bone in the axial skeleton to consent browsing on the bottom in shallow waters. The presence of these 2 groups of aquatic animals, both extinct and living, shows that neoplasms were adopted to obtain environmental advantages. Indeed, although bone neoplasm does represent a pathological condition, the individual disadvantage was largely compensated by the advantage for the species. In this sense we can assert that some neoplasia were adopted by some aquatic animals as a biological strategy to increase their adaptability to difficult environmental conditions. This fact allowed the pathology to survive generation after generation for millions years.

We know that some types of neoplasms may have disappeared. For instance, Moodie147 described a lytic lesion in a Pre-Columbian human skull from Peru that was due to a form of cancer unknown today. The existence of possible extinct forms of neoplasia indicates that neoplasms must be thought of as a phenomenon of life that evolves in close association with its vertebrate hosts. Extinct forms and long-surviving forms of neoplasms show a possible picture of the co-evolution of neoplasms and vertebrates over the history of life on Earth.

The impressive increase in cancer prevalence documented in human populations over the last century is associated with modern man. It is a completely new phenomenon and has no precedents in the history of animals on the Earth (Fig. 3). The high prevalence of cancer contributes to limiting the increase in life expectancy, and seems to be associated with the modern lifestyle. This lifestyle is characterized by living in a completely artificial environment (i.e., a prevalently indoor and metropolitan life in an environment in which we undergo prolonged exposure to environmental carcinogens associated with an increase in carcinogenic pollution). The high prevalence of cancer in vertebrates that share this new lifestyle with us in our almost completely artificial environments (i.e., domestic dogs and birds) seems to confirm this picture.

In conclusion, the modern lifestyle that has developed after the industrial revolution has produced (i) a worldwide increase in environmental pollution and (ii) a significant increase in life expectancy in part of the world, and the two factors seem to be in large part (but not completely) responsible for the increase in cancer prevalence over the past century; at the same time the increase in cancer prevalence seems to play a role, as biological feed-back, in limiting the excessive life expectancy of the human populations living in more developed countries.


  1. Top of page
  2. Difficulties in diagnosis and interpretation
  3. Comparative pathology of cancer
  4. Cancer before man: the fossil record of neoplasms
  5. Cancer in ancient human populations
  6. Causes of rarity of cancer in ancient human populations
  7. Cancer as a possible biological strategy?
  8. References
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