Possible prostate cancer in northern Peru: Differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease

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Research article

Possible prostate cancer in northern Peru: Differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease Haagen D. Klaus a,b,c,∗ a

Department of Sociology and Anthropology, George Mason University, United States Museo Nacional Sicán, Peru c Museo Nacional de Arqueología y Etnografía Hans Heinrich Brüning de Lambayeque, Peru b

a r t i c l e

i n f o

Article history: Received 11 July 2016 Received in revised form 19 September 2016 Accepted 25 November 2016 Available online xxx Keywords: Neoplasm Venous plexus of Baston Caleta de San José Zarpán Eten Lambayeque

a b s t r a c t This paper describes four possible cases of metastasized prostate cancer in archaeological human skeletons from the north coast of Peru spanning the Middle Sicán to Colonial eras (roughly A.D. 900–1600). Varying combinations of exuberant abnormal new bone formation and some abnormal bone loss affecting lumbar vertebrae and the bony sacrum were observed in these individuals. Detailed lesion descriptions are followed by a differential diagnosis that systematically eliminates pseudopathology, infectious diseases, sclerosing bone disorders, and most metastatic processes. However, metastasized prostate cancer cannot be rejected and is highly consistent with the observed lesions. Metastasized pancreatic, bladder, or carcinoid tumors represent additional, though far less likely, diagnostic options. Anatomical and molecular signaling factors further validate this differential diagnosis. The paravertebral venous plexus of Baston plays an anatomical role in the metastatic seeding of lumbar vertebra from prostate cancer. Further, abundant molecular signaling mechanisms upregulate multiple bone-forming mechanisms in prostate metastases, though initially such lesions may originate as lytic phenomena. These multiple lines of evidence help demonstrate a multi-level framework for explanation in paleopathology and especially to help better elucidate the complexities of ancient neoplastic diseases. © 2016 Elsevier Inc. All rights reserved.

1. Introduction The skeleton is a primary target of metastatic cancers, and clinical data illustrates that skeletal metastases generate the greatest suffering and morbidity for afflicted individuals (Coleman, 2006; Clines, 2013). The potential antiquity of cancer in humans appears quite deep, with the earliest definitive case of metastatic disease in the bioarchaeological record extending back 4500 years BP (Lieverse et al., 2014). The evolution of fixed Homo-specific homeobox retro-oncogenes such as NANOGP8 likely arose before or with the last common ancestor with Neandertals (Fairbanks et al., 2012), and among hominins, the earliest osteosarcoma has been identified in australopithecine fossil material dating to approximately 1.7 million years ago (Odes et al., 2016).

∗ Correspondence address: Robinson Hall B, Room 305, George Mason University, MSN 3G5, Fairfax, Virginia 22030-4444, United States. E-mail address: [email protected]

The extent of bone destruction and bone formation in various cancers tends to be quite dramatic (Ortner, 2003). While the topic garners considerable interest, cancer has received relatively limited attention in paleopathology and bioarchaeology (Micozzi, 1991). Questions involving the evolution of cancer, prevalence patterns, and the roles of behavior, economy, and ecology in relation to cancer predisposition over time and space remain thoroughly unresolved. Fuller evaluation of these key issues are impeded by the fact that cancer is infrequently observed in archaeological skeletons while the confident identification of suspected metastatic abnormalities represents a technically daunting task (Ortner, 2003; Brothwell, 2012). Today, one of the most commonly encountered types of cancer in modern clinical practice is prostate cancer. Among men, it is the most prevalent non-dermatological cancer (Coleman, 2006). While likely cases have been identified in the paleopathological record (Ortner, 2003), ancient prostate cancer is only rarely described, especially in Andean South America. This paper describes four archaeological skeletons from northern Peru that feature a suite of specific skeletal abnormalities that bear strong similarities to

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Please cite this article in press as: Klaus, H.D., Possible prostate cancer in northern Peru: Differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease. Int. J. Paleopathol. (2017), http://dx.doi.org/10.1016/j.ijpp.2016.11.004

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Fig. 1. A map of the north coast of Peru displaying the locations in the Lambayeuqe River Valley Complex where Cases 1,2,3, and 4 were excavated. Map by Haagen Klaus.

modern clinical expectations of metastatic prostate cancer. Following lesion description, multiple differential diagnoses are evaluated and are further considered in terms of both anatomical and molecular signaling factors that underscore cancer dissemination to the skeleton that leads to new questions in the paleopathology of cancer in Peru. 2. The archaeological setting The arid Lambayeque Valley Complex is located approximately 750 km north of the Peru’s modern capital of Lima (Fig. 1). This expansive five-river valley system was a center of independent and influential pre-Hispanic societies, including the Cupisnique, Moche, and Sicán (or Lambayeque) cultures that rose and fell in the region from ca. 1500 B.C.–1375 A.D. (Alva and Donnan, 1993; Shimada 1994, 2000; Klaus, 2008). Between A.D. 1375 and 1532, the Chimú, Inka, and Spanish sequentially conquered Lambayeque, with each imperial power drawn to the area’s large population, strategic location, and economic productivity (Ramírez 1990, 1996). Under the surface of all late pre-Hispanic and Colonial developments was an ethnic group known as the Muchik, who emerged out of a process of ethnogenesis that created a social identity that persisted well beyond the decline of the first millennium A.D. Moche culture (Bawden, 2001; Klaus, 2014a). In 2003, the Lambayeque Valley Biohistory Project initiated a long-term, regional, and multidisciplinary study of the region from the Formative to Colonial eras (2600 B.C. to 1750 A.D.). Complex paleopathological patterns have come to light, especially following European conquest (Klaus and Tam, 2009, 2010; Klaus et al., 2009; Klaus and Alvarez-Calderón, in press). Pathological conditions observed in the region span multiple non-specific markers

of biological stress (Klaus and Tam, 2009), tuberculosis (Klaus et al., 2010), treponemal disease (Klaus and Ortner, 2014), and ritual violence (see chapters in Klaus and Toyne, 2016). Neoplasms are perhaps the most rarely encountered abnormality. Baraybar and Shimada (1993) described one likely example of metastasized prostate cancer in a Middle Sicán individual (A.D. 900–1100). An incomplete postcontact subadult in Eten likely was affected by acute childhood leukemia (Klaus, 2016). Other neoplastic formations observed in the Lambayeque bioarchaeological record included identification of a large ovarian teratoma (Klaus and Ericksen, 2013) and possible benign dermoid inclusion cysts (Klaus and Byrnes, 2013). Beyond these examples, tumor-like processes are unobserved in skeletons in this valley and along the north coast of Peru in general. Moreover, cancer is not a particularly well-defined focus within Andean paleopathology (Verano, 1997; Klaus, 2016) despite the considerable growth of bioarchaeological approaches in the region over the last 20 years. 3. Materials and methods 3.1. Case 1: El Truinfo Tomb 7 In 2015, archaeological excavations by the Museo Tumbas Reales de Sipán at the site of El Triunfo in the mid-Lambayeque Valley complex documented extensive evidence of a 3600- year long occupational sequence from the Formative to the Middle Sicán eras (Bracamonte, 2015). The Moche period findings were particularly valuable to clarify aspects of local Moche chronology, architecture, and metallurgy. Among the ten funerary contexts documented at this site, El Triunfo Tomb 7 contained the remains of a robust adult individual. This person dated to the Middle Sicán period (A.D.

Please cite this article in press as: Klaus, H.D., Possible prostate cancer in northern Peru: Differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease. Int. J. Paleopathol. (2017), http://dx.doi.org/10.1016/j.ijpp.2016.11.004

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900–1050/1100) and was buried in classic Muchik style (Klaus, 2014a), with the extended body oriented in the grave on a southnorth axis. Given the lack of ornate or otherwise sumptuous grave goods, it is quite likely that this individual was of a low social standing (Klaus et al., 2017). Significant abnormal bone growth was noted in the inferior lumbar region.

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3.5. Skeletal documentation

The Reque river drainage within the greater Lambayeque region was a cradle of the earliest complex cultures, particularly at the monumental Ventarrón complex beginning about 2600 B.C. (Alva Meneses, 2012). The area was continuously occupied from the Formative to Inka occupations. A particularly prominent Middle Sicán occupational settlement (A.D. 900–1100) existed at the monumental complex of Zarpán. Burial 9 was one of 43 funerary contexts documented at Zarpán by the Ventarrón Archaeological Project. This individual was also buried according to the tenets of traditional ethnically Muchik funerary ritual that emerged from the practices and social identities of earlier Moche culture (Klaus, 2014a). The individual was not accompanied by any grave goods. Abnormal patterns of bone loss and bone formation were observed on this person’s L5 vertebra and S1 sacral segment.

Preliminary documentation of pathological conditions began with in situ observations with Case 3 during excavation in 2010, while formal data collection for both Cases 3 and 4 occurred in 2005 and 2011, respectively, in the laboratories of the Museo ˜ Cases 1 and 2 were documented in Nacional Sicán in Ferrenafe. 2016 at the field laboratory at the Ventarrón Archaeological Complex and the Museo Tumbas Reales de Sipán, respectively. Using data collection protocols based on Buikstra and Ubelaker (1994), inventory data were first collected. Age estimation was based on visual scores of the pubic symphysis and auricular surface morphology along with cranial suture fusion using the summary age statistical technique developed by Lovejoy et al. (1985). Sex was estimated using standard morphological variation of the os coxae. Any pathological locus was observed macroscopically and under 10× magnification using a hand-held loupe under LED, incandescent, or natural light. Abnormalities were scored and described, defining all macroscopic characteristics involving (1) lesion characteristics (osteoblastic/osteoclastic/characteristics of lesion margin, size, and shape); (2) lesion location within each affected skeletal element, and; (3) distribution of all abnormalities within the skeleton.

3.3. Case 3: burial CJS-17

4. Results

In 1996, archaeological rescue excavations by the Museo Nacional de Arqueología y Etnografía Hans Heinrich Brüning de Lambayeque uncovered 26 late pre-Hispanic burials dating the Chimú and Chimú-Inka era (ca. A.D. 1375–1532) at the seaside Lambayeque fishing village of La Caleta de San José. Distinctly Moche-style burial patterns and dental traits strongly indicate all the individuals here were ethnically Muchik and social commoners. The skeletal sample contained a fairly high prevalence of destructive osteoarthritis, healed rib fractures (Klaus, 2008), and at least one probable case of tuberculosis (Klaus et al., 2010). Burial CSJ17 was interred at the site with a few utilitarian ceramic objects (Rodríguez, 1995). CSJ-17 also possessed distinctive osteoblastic and osteolytic lesions on lumbar vertebrae.

4.1. Case 1: El Triunfo Tomb 7

3.2. Case 2: Zarpán Burial 9

3.4. Case 4: burial CNS U4-60 From 2009-11, the Lambayeque Valley Biohistory Project excavated the ruins of historic Eten on the valley’s southwestern coastline as part of a long-term bioarchaeological study of Peru’s postcontact period. Local folklore describes the founding of a small mission during the 1530s. Around 1560, surrounding villages were forcibly relocated into a large colonial reducción named Santa María de Magdalena de Eten that had an estimated population of nearly 1000 Muchik natives by 1590 (Ramírez, 1996). Eten maintained a strong local economy and appears to have endured measurably less biological stress than Mórrope (Klaus and AlvarezCalderón, in press). Abandoned during the mid-18th century, the site and its pair of churches were subsequently consumed by littoral sand dunes. Excavation documented 492 burials between the two ˜ Serranito churchyard cemeteries in Eten. At the Chapel of the Nino (CNS), one Early/Middle Colonial period funerary context (ca. ∼A.D. 1533–1620) designated CNS U4-60 exhibited skeletal anomalies involving abnormal periosteal new bone formation on a single lumbar vertebral body. This individual was one of the first people to be buried in the mission church not long after the mission church was built, and was part of a mass grave containing more than 20 people buried simultaneously. The body was aligned on a north-south axis facing the altar with their hands folded in a Christian praying position.

The complete skeleton in Tomb 7 was a male between the ages of 35–45 years old at the time of death. Abnormal bone growth was observed spanning the left anterior and lateral aspects of the L3, L4, and L5 vertebrae (Figs. 2 and 3). The most extensive osteoscelerotic reaction was present on the anterior surface of the L5 vertebral body consisting of complex array of small and irregular bridging bony spicules that appear as the result of an active and disorganized process of new bone formation, along with a minor degree of superior marginal lipping. Similar new bone formation was also present on the anterior L4 vertebra. On the left lateral aspect, extensive asymmetrical new bone formation was observed between the L3, L4, and L5 bodies (Fig. 4). This mass was probably in the process of creating a functional ankylosis, which was still incomplete at the time of death. This large and irregular bone mass also exhibited characteristics of rapid disorganized growth, particularly on the left L4 vertebral body. Portions of the mass, however, exhibit a greater degree of remodeling suggestive of the longer-standing nature of some lesions. Abnormal bone loss was also present affecting the superior vertebral endplate of the L5 vertebral body (Fig. 5). These lesions possessed lytic cavitations with geographic borders and exposure of internal trabecular structures that extended some 2–4 mm into the underlying trabecular structure and penetrated the left anterior, right anterior, and midline portions of the L5 endplate. They were also characterized by ragged irregular margins, and while no new bone reactive formation related to inflammation was apparent, much of the anterior aspect of the remaining endplate structure exhibited abnormal degrees of fine superficial porosity. This individual also exhibited a solitary mixed osteoblastic/osteolytic lesion on the left lateral T4 vertebra. 4.2. Case 2: Zarpán Burial 9 This individual was well preserved, though the tibiae were fragmented, and most of both feet were missing. This adult male was 40–45+ years old at the time of death. A complex mixture of bone resorption and new bone formation were observed on the anterior and lateral surfaces of the L5 vertebra and S1 segment of

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Fig. 4. Extensive asymmetrical new bone formation on the left lateral aspect of the L3, L4, and L5 vertebral bodies, Case 1 (El Triunfo Tomb 7). Photo by Haagen Klaus.

Fig. 2. Anterior view of the L2-L5 lumbar vertebrae, Case 1 (El Triunfo Tomb 7). Photo by Haagen Klaus.

Fig. 5. Abnormal multifocal bone loss affecting the superior vertebral endplate of the L5 vertebral body, Case 1 (El Triunfo Tomb 7). Photo by Haagen Klaus.

Fig. 3. Detailed anterior view of the L5 lumbar vertebrae, Case 1 (El Triunfo Tomb 7). Photo by Haagen Klaus.

the bony sacrum (Figs. 6 and 7). These abnormalities included a mixed reaction involving bone loss and bone formation. On the anterior aspect of the L5 and S1, dozens of areas of bone loss involved well-circumscribed oval or circular defects, some of the smallest examples of which could be mistaken for enlarged nutrient foramina. A larger area of contiguous bone loss destroyed the right anteroinferior margin of the L5 vertebra. These lytic loci were accompanied by the presence of areas of fine new bone formation initiated on the right anterior aspect of the L5, more advanced spiculated bone formation on the left anterior aspect of the L5, and areas

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Fig. 6. Mixed abnormal bone resorption and new bone formation on anterior and lateral surfaces of the L5 vertebra and S1 segment of the bony sacrum, Case 2 (Zarpán Burial 9). Photo by Haagen Klaus.

Fig. 8. Abnormal multifocal bone loss affecting the inferior vertebral endplate of the L5 vertebral body, Case 2 (Zarpán Burial 9). Photo by Haagen Klaus.

Fig. 7. Detailed left anterolateral view of the L5 lumbar vertebrae, Case 2 (Zarpán Burial 9). Photo by Haagen Klaus.

of fine new abnormal bone formation on the S1 sacral segment, especially on the left side. The inferior portion of the L5 vertebra exhibited bone destruction affecting most of the inferior vertebral endplate (Fig. 8). Anteriorly, substantial irregular areas of bone had been resorbed and were generally surrounded by erratically distributed additional circular or oval foci of penetrating bone loss. Additional vertebral margin bone loss was present on the left posteroinferior aspect of the L5 body. This lytic process extended into the superior endplate of the S1 segment of the bony sacrum (Fig. 9). There, the most significant destruction was again localized on the left side, extending into the superior left wing of the bony sacrum. Vertebral endplate destruction of both L5 and S1 sacral segment was not associated with marginal new bone formation. The only other pathological processes in this individual’s skeleton included wellhealed cribra orbitalia and porotic hyperostosis lesions as well as active periodontal disease. 4.3. Case 3: Burial CJS-17 Burial CSJ-17 was represented by a nearly complete skeleton of an adult male individual in an excellent state of preservation. Lesions on multiple lumbar vertebrae involved a complex mixture of contiguous disordered new bone formation, areas of focal bone loss, and marginal osteophyte formation spanning the L2, L3, and L4 vertebral bodies (Fig. 10). The affected area was localized between the L3 and L4 vertebral bodies, and each was affected similarly,

Fig. 9. Abnormal multifocal bone loss affecting the superior vertebral endplate of the S1 vertebral segment of the bony sacrum, Case 2 (Zarpán Burial 9). Photo by Haagen Klaus.

while only a small locus of abnormal new bone formation was present on the left anterolateral surface of the inferior L2 vertebral body. Related abnormalities were absent from the L5 vertebral body, which was only affected by unrelated mild expressions of osteophytes along the superior margin of the vertebral body. The lesions of the L3 and L4 vertebrae were primarily osteoblastic, with expansive and florid new reactive bone formation on both anterior vertebral bodies. The left and right lateral aspects of the L3 and L4 vertebrae featured the largest formations of relatively disorganized new bone, and on the L3 vertebrae, abnormal new bone extended posteriorly nearly to the pedicle on the right side (Fig. 11). Similar to Case 1, lateral new bone formations partially or nearly bridged the L3 and L4 vertebrae and the intervertebral space appeared narrowed, though fusion between these bony bridges had not yet occurred by the time of death. Multiple lytic defects were observed perforating the inferior vertebral endplate of the L3 and the superior vertebral endplate of the L4 vertebral bodies (Fig. 12). These contiguous defects ranged from small focal clusters of bone loss to much larger, expanded areas of bone loss that extended into the trabecular structure 2–4 mm in depth. These lesions were most pronounced and destructive on the inferior aspect of the L3 vertebral body. These featured highly irreg-

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Fig. 10. Lesions on multiple lumbar vertebrae involving a complex array of contiguous disordered new bone formation, areas of focal bone loss, and marginal osteophyte formation spanning the L2, L3, and L4 vertebral bodies, Case 3 (Caleta de San Jose Burial CSJ-17). Photo by Haagen Klaus.

ular borders and no marginal new bone formation. This individual possessed no other pathological skeletal lesions. 4.4. Case 4: Burial CNS U4-60 This Early Colonial period adult male was between the ages of 35–45 at the time of death. The skeleton was nearly complete but fragmented. Abnormal new bone formation was observed on the anterior surfaces of the L4 vertebrae (Fig. 13). A complex formation of disorganized and divergently spiculated new bone formation

Fig. 11. Right lateral view of lesions spanning the L3, and L4 vertebral bodies, Case 3 (Caleta de San Jose Burial CSJ-17). Photo by Haagen Klaus.

was confined to the anterior vertebral body. While some damage of the superior vertebral endplate and left superior vertebral margins was observed, this was consistent with postmortem damage seen in many of the skeletons from Eten as related to postdepositional salt crystal invasion of bone − and not a biological process that occurred during life (Fig. 14) (for other similar examples, see Klaus and Ortner, 2014). The margins of exposed bone were noticeably lighter in color than the external surfaces, which is fully consis-

Fig. 12. Multiple lytic defects were perforating the inferior vertebral endplate of the L3 and the superior vertebral endplate of the L4 vertebral bodies, Case 3 (Caleta de San Jose Burial CSJ-17). Photo by Haagen Klaus.

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thorough differential diagnostic evaluation (Appleby et al., 2015) can consider pseudopathology, infectious diseases, sclerosing bone disorders, and metastatic bone disease (Table 1).

Fig. 13. Abnormal new bone formation present on the anterior surfaces of the L4 vertebrae, Case 4 (Colonial Eten Burial CNS U4-60). Photo by Haagen Klaus.

5.1.1. Pseudopathology Various physical or chemical taphonomic factor(s) can mimic in vivo bone formation or destruction (Henderson, 1987; Child, 1995), but pseudopathology is convincingly excluded from this evaluation. First, the bony spicules in all cases are structurally bone and not any kind of mineral deposit or other additive taphonomic artifact. They represent a process of active de novo bone proliferation before death. Bone loss could represent the action of an erosive postmortem phenomenon. Yet, across sites, time periods, and formation processes, the patterns of bone loss are repetitive and quite anatomically specific such that the effects of a common phenomenon in these geologically and taphonomically diverse settings affecting only these individuals is quite improbable. The postmortem damage discussed in Case 4 is easily differentiated from a pathological process.

5.1. Differential diagnosis

5.1.2. Infectious disease Infectious processes such as osteomyelitis may be rejected as a diagnostic option in each case due to the lack of necrotizing foci or cloaca as well as the lack of marginal new bone formation associated with inflammation and areas of bone loss. Non-specific periostosis is equally unlikely, as anterior vertebrae are an exceptionally rare anatomical location for such lesions. Brucellosis should be considered but can be ruled out on the basis that brucellosis is intensely osteolytic and involves only minimal to no florid new bone formation (Ortner, 2003). Tuberculosis preferentially affects tissue rich in hematopoietic marrow, but again, the lack of large destructive foci and marginal reactive new bone formation strongly suggest another process is at work. The solitary lesion in the T4 vertebra of Case 2 may represent a disease process such as tuberculosis, as it is anatomically and morphologically highly consistent with other documented cases in the Lambayeque region (Klaus et al., 2010). Thus co-morbidity is possible, if not likely, in this case. Further, lumbar lesion morphology in Case 2 and Case 3 entertains considerations of tuberculosis as a co-morbid condition. In Cases 2 and 3, this is far less probable, as the presence of dozens small foci of bone loss (Figs. 6, 7) are more consistent with arrays of metastatic invasion of bone rather than characteristic suppurative (pus producing) lesions that tend to be larger and fewer in number in tuberculosis. The larger cavitation and new bone formation spanning the right aspect of the L3 and L4 vertebrae of Case 3 again could reflect co-morbidity with tuberculosis (Fig. 11), but its association with the specific arrays of contiguous and shallow vertebral endplate destruction of both the L3 and L4 points more towards a metastatic condition; a differential diagnosis favoring tuberculosis would be more probable in his individual if the lesions had originated deeper in the hematopoietic tissue (Ortner, 2003). Still, co-morbidity with tuberculosis cannot be completely ruled out in the lumbar lesions of Cases 2 and 3 until a future radiographic assessment is conducted. Brucellosis may also be ruled out in each case due the fact that brucellosis lesions are primarily lytic and preferentially affect non-contiguous vertebrae and the sacroiliac joint. Chronic fungal infections such as coccidoidomycosis or paracoccidoidomycosis are associated with vertebral abnormalities (Long and Merbs, 1981; Ortner, 2003) but are characterized by well-defined lytic foci often coupled with sclerotic margins on non-contiguous vertebrae, the clavicles, ribs, and long bones (Temple, 2006).

These cases demonstrate a pathological process or processes involving mostly abnormal bone formation accompanied by some abnormal bone loss. Due to the completeness of the remains, a

5.1.3. Sclerosing bone disorders Multiple disorders generating abnormal sclerotic bone formation can affect the skeleton (Whyte, 2013). Hypertrophic

Fig. 14. Probable taphonomic damage mimicking pathological bone destruction related to postdepositional salt crystal invasion of bone (compare with patterns and forms of bone loss in Figs. 5, 8, 9, and 12), Case 4 (Colonial Eten Burial CNS U4-60). Photo by Haagen Klaus.

tent with postmortem breakage and degradation and not in vivo pathological bone loss, further contrasting it with Cases 1 through 4. Large marginal degenerative osteophytes were also present on the right superior and left anteroinferior margins of the affected vertebral body. Given their fairly well organized appearance consistent with well-remodeled bone, the osteophytes were morphologically distinct from the new bone formation observed on the anterior vertebral body. They appear unrelated in their pathogenesis such that marginal osteophyte formation represents pre-existing degenerative changes pre-dating the more rapidly forming and disorganized areas of abnormal new bone. The only other pathological conditions observed in this skeleton were moderate to severe marginal osteophytes in the superior lumbar and inferior thoracic vertebrae. 5. Discussion

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(pulmonary) osteoarthropathy (HOA, or Marie-Bamberger Syndrome) is associated with a neurocirculatory mechanism that triggers osteoblasts to produce periosteal new bone in response to pulmonary inflammation or secondary to cancer (Aufderheide and Rodríguez-Martin, 1998; Resnick, 2002). However, these lesions lacked ‘candle-wax’ bone formation on tubular long bone diaphysis and clubbing of the distal phalanges. Paget’s disease originates with a virus that subsequently induces pathological bone formation. Macroscopic characteristics of this disorder (abnormal cranial vault thickness, pumice bone formation (Ortner, 2003)) are absent in both cases. Fluorosis is produced by long-term intake of excessive fluorine (usually via groundwater) to induce periosteal new bone formation but preferentially involves bony hypertrophy of intervertebral disks and muscle attachment sites (Ortner, 2003). Melorheostosis is a developmental anomaly involving sclerotic bony dysplasia (Aufderheide and Rodríguez-Martin, 1998; Revell, 1986). This disorder is likewise ruled out since melorheostosis tends towards unilateral lesion formation and thickening of the cranial vault and mandible. 5.1.4. Metastatic bone disease Multiple cancers including meningiomas, myelomas, carcinomas, and sarcomas usually affect bone. Such disorders can produce lesions that are osteolytic, osteoblastic, or combinations thereof (Johnson and Sterling, 2013; Ortner, 2003; Resnick 2002; also Luna et al., 2008; Strouhal, 1991; Lieverse et al., 2014). Most metastases, such as metastasized breast cancer, are highly osteolytic (Resnick, 2002) and involve clusters of smaller lesions on contiguous skeletal elements that may coalesce into larger destructive foci originating deep within cancellous tissue that progressively removes bone from within. Given the extensive blastic component in these cases, diagnostic options such as multiple myeloma, leukemia, and Hodgkin’s and non-Hodgkin’s lymphomas can be confidently rejected (cf. Resnick and Haghighi, 2002). A minority of metastatic processes produces exuberant abnormal new bone formation such as meningiomas, hemanagiomas, sclerosing osteosacromas, chondrosarcomas, and adrenal neuroblastomas (Resnick, 2002). Blastic lesions, typified by radiating bony spicules or nodular formations (Ortner, 2003), involve a slower disease progression as osteolytic metastases are more aggressive and acute. Of all metastatic diseases, prostate cancer is by far the most likely to produce osteoblastic lesions (Resnick, 2002). Such metastases are nearly always osteoblastic and contrast strongly with lytic lesions associated with kidney, lung or breast cancer. In modern contexts, prognosis is usually measured in more than a year, and almost all patients who die of prostate cancer have some kind of skeletal involvement (Coleman, 2006). The distribution of metastatic prostate cancer is distinct from the majority of hematogenous metastases, in that the condition has a clear anatomical preference for the lumbar vertebrae, bony sacrum, and ossa coxae (Resnick, 2002; Ortner, 2003; Coleman, 2006). Related osteosclerotic new bone formation may possess radial, sunburst-like formations. Single or multiple vertebrae may be involved, and when lesions become confluent over multiple vertebrae, intervertebral disk spaces may be invaded by cancer cells and subsequently narrow (Resnick, 2002: 4304). Clinical findings of abnormal new sclerosing bone formation on vertebral bodies of older adult men are nearly always correlated to metastasized prostate cancer (Resnick, 2002: 4293). New bone proliferation on the os coxae is highly unique though not quite pathognomonic for disseminated prostate cancer (Ortner, 2003), and diagnosis does not oblige pelvic involvement. Despite clinical and paleopathological focus on the osteoblastic nature of prostate metastases, it is more accurate to character-

ize it as a disease process dominated by new bone formation, as bone destruction can and does occur in disseminated prostate cancer (Resnick, 2002; Johnson and Sterling 2013). Lytic lesions may range from well circumscribed to poorly defined, highly irregular areas of penetrating bone destruction. Most critically, experimental work and therapeutic applications using bisphosphonates have supported the notion that osteoblastic metastases such as prostate cancer probably begin with a strong bone resorption component, and as the disease progresses, switches to predominately florid bone formation (Johnson and Sterling, 2013). The bone loss in Cases 1–3 thus could represent the earliest stages of bone involvement, and in Case 2, the extent of bone loss points to a comparatively more aggressive initial disease state. The lesions described here are each highly consistent with the anatomical specificity and known characteristics observed in prostate cancer in both clinical and paleopathological perspectives. Metastasized prostate cancer is the remaining differential diagnosis for both cases and cannot be rejected. This conclusion must be tempered somewhat, as a primary carcinoma of the bladder that invades the prostate, pancreatic cancer, and carcinoid tumors (primarily of the bronchus) may also produce similar blastic lesions on vertebrae (Resnick, 2002). These may not be differentiated from prostate metastases on visual or radiographic appearance alone. However, when compared to bone involvement in prostate cancer, bladder, pancreatic, and carcinoid tumors are far less common, making each a probabilistically far weaker differential diagnoses. This is particularly the case for carcinoid and pancreatic malignancies, as the former tends to be predominantly lytic while the latter preferentially involves both thoracic and lumbar vertebrae (see extensive comparative discussion in Resnick, 2002). 6. Discussion The identification of probable prostate cancer in these four cases is not based solely upon comparisons with clinical and bioarchaeological literature, but it also finds independent support in the innate factors that underscore lesion distribution and progression in this disease. Specially, the lesions in these cases are additionally consistent with both the anatomical basis of prostate cancer metastases as well as a variety of even more fundamental molecular signaling mechanisms that are known to drive osteoblast activity in this specific malignancy. 6.1. Anatomical basis for vertebral involvement in metastasized prostate cancer As noted earlier, the skeleton is commonly affected by tumor metastases. While some metastases are direct extensions of a primary malignancy, the transfer of cancer cells from the site of a primary tumor to unaffected and distant skeletal tissue is both common and complex. Tumors constantly shed cells, but only a fraction of them are ever capable of establishing themselves elsewhere. An elaborate sequence of events must progress, from tumor emboli gaining access to the lymphatic or circulatory system, surviving transport to a distant capillary bed, binding to the endothelium via specific cell tumor receptors, exiting the vessel, and finally instigating angiogenesis and developing its own blood supply (Resnick, 2002). The lymphatic and circulatory systems provide routes for metastatic dissemination. Tumors typically lack extensive interfaces with the lymphatic network and rarely infiltrate the lymphatic system beyond the immediate margins of a tumor (Morgan-Parks, 1995). The circulatory system is the route for metastatic spread to the skeleton. In particular, the paravertebral venous plexus of Baston (1940) holds a fundamental role in

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the hematogenous spread of breast, prostate, lung, and other neoplasms. The paravertebral plexus of Baston is a unique intercommunicating network of thin-walled vessels. This vascular structure generally lacks valves and is characterized by a low intraluminal pressure, especially as they are outside of the throacoabdominal cavity and not subject to the pressure induced by the thoracoabdominal muscular press (Galasko, 1981). Venous blood within the plexus can reverse in flow direction owing to pressure shifts related to routine and daily actions such as coughing, straining, or other kinds of physical activities (Resnick, 2002). The paravertebral plexus of Baston extensively communicates with the veins of the spinal canal, breast, head, and neck to form an extensive reservoir of blood where tumor emboli encounter an ideal transportation hub to multiple parts of the body. In the case of a primary prostate cancer tumor, a straightforward anatomical expectation might expect shed tumor cells to pass directly from the prostatic venous plexus to the inferior vena cava, but the pressure dynamics unique to the paravertebral plexus of Baston make it the more likely vascular intake point for prostate cancer cells that take them rather directly to the inferior axial skeleton (Resnick, 2002). Further, the rich hematopoietic marrow, large capillary networks, and sluggish blood flow in lumbar vertebrae represent an attractive environment for tumor metastases development (Harrington, 1986). Another route of tumor spread from the paravertebral plexus of Baston involve the basivertebral veins into the vertebral body itself. Within lumbar vertebrae, the major venous channels possess a V- or Y-shaped configuration with associated cortical fenestrations (Resnick, 2002: Fig. 78-3). The lytic metastatic foci observed in the inferior body of the L3 and superior L4 vertebral bodies in Case 1 and somewhat so in Case 2 map onto the location of these channels and suggest either direct hematogenous seeding via the basivertebral veins or direct superior and inferior extension via invasion of tumor cells into the intervertebral disk itself as might be suggested by endplate involvement in Cases 1–3.

6.2. Molecular mechanisms of osteoblast activity in disseminated prostate cancer In addition to anatomical considerations, even more fundamental molecular signaling mechanisms between cancer cells and bone cells drive pathological new bone formation in metastasized prostate cancer. These mechanisms also help explain the lesion appearance and progression in these four archaeological cases. While still incompletely understood processes, current work into the molecular signaling of abnormal new bone in prostate cancer holds immense clinical and therapeutic interest. In bioarchaeology and paleopathology, consideration of molecular signaling mechanisms is beginning to better contextualize the fundamental pathophysiological mechanisms that create and sustain pathological bone phenotypes (Gosman, 2012; Klaus, 2014b). In normal bone remodeling, a tightly integrated system maintains the balance between osteoblastic and osteoclastic activity. Osteoblasts operate a master switch over osteoclast activity via production of cytokines such as RANKL (receptor activator of nuclear factor ␹b ligand). The receptor molecules on the surface of osteoclast precursor cells are called RANK, which is activated by RANKL to differentiate and activate osteoclasts. The effects of RANKL are inhibited by osteoprotegerin (OPG), which is a decoy receptor for RANKL. Should bone resorption need to be slowed or overtaken by osteoblastic activity, OPG production increases. With more OPG molecules in circulation, more RANKL molecules will be intercepted before they can reach their target cells. Thus, all bone resorption is coordinated by this fundamental RANKL/RANK/OPG regulatory axis

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and the RANKL: OPG ratio (Porth, 2011; Gosman, 2012; Burr and Allen, 2014). At the other end of the spectrum, osteoblast-mediated bone production is controlled by a group of proteins called Wnt (named after the wingless gene in Drosophila). The Wnt/␤-catenin pathway is commonly called the canonical pathway as it activates gene expression in cell nuclei to incite osteoblasts to form new bone. Bone could theoretically proliferate without end if not for the downregulating effects of molecules in the Dickkopf protein family (Dkk1 and 2) and the glycoprotein sclerostin that is produced by the SOST gene to serve as an antagonist to Wnt (Datta et al., 2008). Additional bone-forming factors involve bone morphogenic proteins (BMPs), transforming growth factor-␤1 and ␤2 (TGF␤1 and TGF␤2), insulinlike growth factor 1 (IGF1) and IGF2, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and more indirectly, vascular endothelial growth factor (VEGF) (Mundy et al., 2001). New bone formation in prostate cancer metastases appears to reveal an intertwined relationship between prostate cancer cells and osteoblasts such that tumor progression is dependent on the induction of new bone formation via soluble stimulatory factors produced by the prostate cancer cells themselves (Logothetis and Lin, 2005). In other words, sustained metastasized prostate tumor growth probably requires secretion of osteoblast-derived growth factors. Prostate cancer cells appear to secrete multiple Wnt ligands to activate the canonical Wnt pathway in osteoblasts within prostate cancer bone lesion microenvironments (Chen et al., 2004; also Johnson and Sterling, 2013). Other key signaling pathways such as RUNX2 and increased osteocalcin production has also been found (Yang et al., 2001). Elevated levels of multiple BMPs have been documented in prostate carcinoma bone metastases where TGF␤2 is also abundantly expressed (Autzen et al., 1998; Marquardt et al., 1987). Additional elevated expressions of osteoblast-stimulating factors IGF1 and related binding proteins and receptor signals, endothelin-1 (ET1), urokinase-type plasminogen activator (uPA) and prostate-specific antigen (Baserga, 1995; Logothetis and Lin, 2005; Mundy et al., 2001; Nelson et al., 2003; Rabinni et al., 1990). In a circuitous way, osteoblasts appear to be “master switches” for the progression of prostate cancer in skeletal tissue as fundamental upregulation of OPG has been documented in cases of advanced prostate cancer (Brown et al., 2001). Of course, early metastasis progression involving an intense resorptive component would mean that the bone formation/resorption control axis evidently, at that point, favors exclusively osteoyltic signaling factors. How and why the balance appears to flip so dramatically in favor of osteblastic activity as a prostate metastasis progresses represents an immensely important question (Johnson and Sterling, 2013). The co-existence of lytic and blastic lesions in the same bone (Cases 1–3) probably represent the persistence of lesions in an earlier rather than later state of progression, but the lack of reparative new bone associated with the lytic lesions probably indicates that highly localized microenvironmental signaling differences may still persist on the level of bone and periosteal microenvironments. While anatomical bases for lesion distribution are clear, other studies appear to indicate additional molecular mechanisms directly assist cancer emboli. That is, disseminated cancer cells not only home in towards specific organs (such as bone) that provide the most ideal microenvironments for tumor development, but the evolving theoretical concept of the pre-metastatic niche holds that parts of the skeleton may be further pre-selected and groomed for the arrival of cancer metastases by factors such as osteopontin, VEGF 1, and hepranase (Clines, 2013). Thus, the anatomical specificity for lumbar, sacral, or pelvic lesions associated with prostate carcinomas may most deeply relate to the existence of unique and pre-existing molecular “addresses” in these bones for prostate metastases, and the intervertebral venous plexus of Baston con-

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spires in the process to make transport of prostate tumor emboli just that more effective.

explanation in paleopathology and specifically metastasized bone disease.

7. Conclusion and directions for future research

Acknowledgements

These four cases of probable disseminated prostate cancer on north coast of Peru adds to a small but increasing number of pre-modern individuals affected by neoplasms in the Lambayeque region of northern Peru, from the Middle Sicán to the Early Colonial era (A.D. 100–1530s). These findings also provide a foundation to consider wider issues regarding the paleopathology of cancer in Peru and beyond. Skeletal remains of more than 2500 individuals have been studied to date in Lambayeque, most generated via regional and representative archaeological sampling strategies. Current findings indicate all forms of skeletal neoplasms were rare in the late preHispanic and Colonial eras, that cancer crude prevalence currently shows no relation to major biocultural transitions, and cancer was not necessarily exclusive to any one social or ethnic group. Taking a step further back, we know now that various cancers were present in Andean peoples, and of all the neoplastic disorders documented in Lambayeque, probable prostate metastases are the most commonly observed (n = 5). While this may reflect a measure of crude prevalence based on the current evidence, ascertaining true prevalence presents far greater challenge. A broader paleopathological understanding of this and other cancers in Andean populations is still quite limited. Beyond a case of probable acute childhood leukemia (Klaus, 2016), Hrdliˇcka (1914) collected pathological skeletal specimens that included metastatic phenomena from the devastated landscapes of looted cemeteries on the central and north coasts of Peru during the early 20th century. Ortner (2003) highlighted these very cases as exemplars of osteoblastic meningioma, metastatic carcinoma, and multiple myeloma. Other examples among Hrdliˇcka’s disembodied and decontextualized skeletal specimens contain tantalizing prostate cancer-like abnormalities (Tyson and Dyer Alcauskas, 1980), but their isolated nature prevents differential diagnosis. Similarly, Cabieses (1974) illustrated similarly decontextualized Peruvian crania with metastatic and meningioma-like lesions. cemeteries in the early 20th century. Beyond this, little can be said. While no doubt a multi-decade effort, a more complete paleopathological assessment of cancer in ancient South America is both advisable and possible, especially with increasing emphases on burial context excavation and scientific studies of human remains. Future research may seek to explore (1) the antiquity and diversity of neoplasms in the Andes; (2) biocultural correlates and predisposing factors of ancient cancer (i.e., social organization, diet, and comorbid factors); and (3) potential deviations of Andean cancer phenotypes from those of modern Western populations or clinical perspectives. Related to this last point, a number of paleopathological and clinical descriptions of skeletal prostate involvement demonstrate the relative frequency in which the os coxae is involved. Every suspected case in Lambayeque is restricted to the axial skeleton. Is this due to a small and possibly skewed sample involving only a handful of cases, or could there be a different progression of prostate carcinomas in this population? Though it will probably always be among the most rarely documented skeletal lesions, a more complete understanding of cancer represents and important component of ancient human biology. In Andean South America, further development of bioarchaeology, regional and diachronic sampling of mortuary contexts, and a rigorous approach to lesion description and differential diagnosis will advance this aim. The combination of systematic differential diagnoses, applied anatomy, and molecular processes hopefully demonstrates the utility of a holistic and multi-level framework for

Grants from the National Science Foundation (Grant BCS 1026169), the Wenner-Gren Foundation for Anthropological Research (Grants 7302, 8009, 8132, and 8838), George Mason University’s Office of Research, and Utah Valley University’s College of Humanities and Social Sciences, The Center for Engaged Learning, SCOP program, Presidential Scholar Award, Department of Behavioral Science, and the International Center funded this work from 2005 to 2016. Ignacio Alva co-directed the 2016 lab season that included the Zarpán skeletal material, and Rosabella Alvarez-Calderón (Pontífica Universidad Católica del Perú) was the co-director of the excavations in Eten. Additional thanks are owed to Walter Alva, Edgar Bracamonte, Carlos Elera, Marco Fernández, Raul Saavedra, and Carlos Wester, and all the members of the Lambayeque Valley Biohistory Project for their countless contributions to this work. Allison Ham provided the initial observations in Cases 1 and 2. I am grateful to Katie Hunt for the invitation to contribute to this special issue of IJPP. Jane Buikstra, the associate editor, Jenny Peterson-Klaus, and the anonymous reviewers provided constructive critiques and thoughtful corrections to an earlier version of this work. Any remaining errors are my own.

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Please cite this article in press as: Klaus, H.D., Possible prostate cancer in northern Peru: Differential diagnosis, vascular anatomy, and molecular signaling in the paleopathology of metastatic bone disease. Int. J. Paleopathol. (2017), http://dx.doi.org/10.1016/j.ijpp.2016.11.004