Metastatic carcinoma in a 14th-19th century skeleton from Constância (Portugal)

International Journal of Osteoarchaeology Int. J. Osteoarchaeol. 20: 603–620 (2010) Published online 27 May 2009 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/oa.1084

SHORT REPORT

Metastatic Carcinoma in a 14th–19th Century Skeleton from Constaˆncia (Portugal) S. ASSIS* AND S. CODINHA Centro de Investigac¸a˜o em Antropologia e Sau´de, Department of Anthropology, University of Coimbra, 3000-056 Coimbra, Portugal

ABSTRACT

During 2002, the extensive archaeological excavations of the ancient Constaˆncia necropolis (Centre of Portugal), dated from 14th–19th centuries, resulted in the exhumation of 151 individuals. Among the several paleopathological cases, a middle-aged female skeleton with osteolytic lesions in her skull, axial skeleton, upper limbs and femurs was observed. These pathological findings are characterised by an asymmetric pattern with osteolytic focus of distinct size and irregular shape. Some skeletal elements display both osteolytic and osteoblastic lesions. The latter exhibit deposition of fine layers of woven bone. Lesions were observed macroscopically and radiology was used as a complementary method of scrutiny, especially in cases of unclear observation. The case was diagnosed as that of a probable metastatic carcinoma due to the multifocal distribution of the lesions in areas of intense haematopoietic activity, their morphology and some osteoblastic responses, as well as the presence of pathological fractures in the ribs. The skeleton’s sex and age at death are in agreement with the proposed diagnostic, constituting the first case of malignant carcinoma detected in non-identified Portuguese human skeletal remains. Copyright ß 2009 John Wiley & Sons, Ltd. Key words: paleopathology; malignant tumour; metastases; osteolytic-osteosclerotic abnormalities; pathological fractures; constaˆncia

Introduction According to the World Health Organization (2006), 7.6 million people died of cancer in 2005 and 84 million will die in the next decade if no measures are taken. Presently, malignant neoplasms are one of the main causes of death in developed countries. Several factors are associated with this high incidence, namely the profound changes introduced in the human environment, alterations in the traditional dietary patterns, and the increase

* Correspondence to: Department of Anthropology, University of Coimbra, 3000-056 Coimbra, Portugal. e-mail: [email protected]

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of population lifespan (Wakely et al., 1998). These factors, associated with some eventual genetic predisposition, have been invoked to clarify the age-specific prevalence of malignant disease in different areas of the modern world (De La Ru´a et al., 1995). A wide range of disciplines have focussed their attention on the study of neoplasms in search of the molecular, biochemical and genetic principles that may underlie its expression. The study of ancient human remains recovered from archaeological sites and housed in museums and/or anthropological collections has indirectly enriched this field of research. In agreement with Rothschild and Rothschild (1995), the study of skeletal populations can unlock an important source of Received 24 June 2008 Revised 31 January 2009 Accepted 19 February 2009

604 knowledge about the presence of tumours in ancient populations. Epidemiologically, it contributes valuable observations to medical sciences that are of great help in the difficult task of understanding the origin and evolution of these diseases. The past population’s pathological record is characterised by a relatively low frequency of malignant conditions, when compared with the high incidence observed in clinics. This distinct pattern of prevalence may be related to factors such as the correlation of malignant neoplasms with the elderly, a situation incompatible with the shorter lifespan of ancient populations; the influence of the body’s condition prior to death, and the velocity at which the lesions spread through the skeleton (e.g. Aufderheide & Rodrı´guez-Martı´n, 1998; Weiss, 2000; Ortner, 2003; Thillaud, 2006). In addition, we can also be confronted with the constraints of an accurate diagnosis of malignant disease in past populations due to the cost and the time factors associated with the application of certain diagnostic methods, such as radiology and histology (Ortner, 2003). The influence of taphonomic alterations, with the possibility of total disruption of human remains, plays its part in the low frequency of malignant neoplasm registered in the paleopathological record (Weiss, 2000; Steckel & Rose, 2002; Capasso, 2005; Marks & Hamilton, 2007 after Cohen & Armelagos, 1984). Nevertheless, we must always consider that the absence of diagnoses does not necessarily mean the absence of these conditions in ancient human populations. Several types of tumours can leave their manifestation in the human skeleton. However, and considering only the malignant ones, the metastatic carcinoma constitutes one of the most frequent manifestations observed in osteoarchaeological contexts (Steinbock, 1976). Etymologically, the word metastasis can be defined as the transfer mechanism of a disease from one organ (or part of an organ) to another structure not directly associated to it (Resnick & Kransdorf, 2005). Metastatic carcinomas primarily develop on the epithelial tissue (Ortner, 2003). Due to their invasive nature, they are characterised by an uncontrolled proliferation of tumorous cells whose dissemination through blood flow and/or lymphatic nodes can produce Copyright # 2009 John Wiley & Sons, Ltd.

S. Assis and S. Codinha secondary neoplasm focus in other physiological systems, namely the skeleton (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003). The cerebrospinal fluid represents another pathway for the dissemination of tumour cells, particularly in patients with intracranial neoplasms, such as medulloblastoma, ependymoma, pineal neoplasm or lymphoma (Resnick & Kransdorf, 2005). Bone tissue is one of the three most preferred sites for the development of solid tumour metastasis after lungs and liver (Mundy, 1997; Ka¨ko¨nen & Mundy, 2003). This incidence indicates that bone tissue ensures a good microenvironment for the growth of many human tumours totalising 15% of all carcinomas diagnosed in the clinical practice (Mundy, 1997; Campanacci, 1999). With an enormous impact on the well-being of people, tumour metastases are responsible for a great morbidity due to pain, body weight loss, osteolysis, pathologic fractures, hypercalcemia, lymphadenopathy and anaemia (Campanacci, 1999; Domchek et al., 2000; Orr et al., 2000 after Rubens, 1998; Saad et al., 2007). The malignant diseases that show higher incidence of bone metastases are cancer of the prostate (84%), breast cancer (72%), thyroid cancer (50%) and kidney cancer (37%) (Berna´ et al., 1991; Alcalay et al., 1995 after Rosenthal, 1997; Brage & Simon, 1992 after Rosenthal, 1997). These are followed by cancer of the lung, pancreas, bladder and uterus (Mundy, 1997; Campanacci, 1999). This higher bone incidence of certain types of malignant neoplasms, suggests that these possess intrinsic properties that facilitate the development of metastasising focusses in the bone. Mundy (1997: p. 1549) proposed four major factors underlying the correlation between certain types of malignant neoplasms and bones. These reasons are: (1) synthesis of proteolytic enzymes necessary for tumour cell detachment from the primary site, invasion to nearby soft tissues, intravasion to bloodstream or lymphatic pathway, extravasion, and bone matrix destruction; (2) expression or loss of cell adhesion molecules, necessary for the cell’s cleavage from the primary neoplasm and subsequent accumulation at the metastatic site; (3) migratory activity in order to spread throughout body, and (4) enhanced capacity to escape from host immune system. Int. J. Osteoarchaeol. 20: 603–620 (2010)

Metastatic Carcinoma in a Portuguese Skeleton In addition to these general principles, several studies have pointed out that the development of bone metastatic lesions is a multistep process involving complex interactions between malignant cells, the tumour-bearing host and its surrounding environment (Mundy, 1997; Orr et al., 2000; Ka¨ko¨nen & Mundy, 2003; Steeg, 2006). Bone metastases are particularly frequent in individuals above 50, and can affect several bone elements, amongst them the skull, the vertebrae, the pelvis, the ribs, the sternum, and the metaphyseal portions of the humerus and the femur (Steinbock, 1976; Waldron, 1996; Mundy, 1997; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; No¨bauer & Uffmann, 2005; Resnick & Kransdorf, 2005). Metastatic lesions distal to the elbow and knee are rare (Steinbock, 1976; Waldron, 1996; Thillaud, 1996; Campanacci, 1999; Ortner, 2003; Resnick & Kransdorf, 2005). Tumour cells commonly metastasise to the most vascularised parts of the skeleton due to haematological spread (Thillaud, 1996; Mundy, 1997; Smith, 2002; No¨bauer & Uffmann, 2005). The metastases may reach the skeleton by direct invasion from the primary tumours or from a secondary site, such as a lymph node. However, haematogenous dissemination is far more frequent than lymphatic spread or direct invasion (Rosenthal, 1997; Orr et al., 2000). It is still unclear why certain malignant diseases have this predilection for the vascular framework. However, recent studies have pointed out that the venous route, particularly the Batson paravertebral plexus, plays a major role in the haematogenous spread of tumour cells, rather than the arterial route (Rosenthal, 1997; Coleman, 2001). Metastatic carcinoma can generate a variety of alterations in bone cell function that are lytic, osteoblastic or a combination of both (Steinbock, 1976; Waldron, 1996; Coleman, 1997; Mundy, 1997; Rosenthal, 1997; Aufderheide & Rodrı´guezMartı´n, 1998; Coleman, 2001; Ortner, 2003; Resnick & Kransdorf, 2005). In the case of kidney, lung, thyroid and digestive tract carcinoma, the main alterations are predominantly osteolytic. Moreover, those of the prostate are characterised by osteoblastic activity. In breast carcinoma, both the destruction and the production of new bone can be found (Coleman, 1997; Copyright # 2009 John Wiley & Sons, Ltd.

605 Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick & Kransdorf, 2005).

Malignancy in paleopathological record In the last two decades, some cases of metastatic carcinoma have been described in the paleopathological literature. The reviewed literature reveals a transcontinental distribution of metastasising conditions, not only in Identified Human Collections (e.g. Marks & Hamilton, 2007), but also in the archaeological context from North America (e.g. Hanson et al., 1999; Jolly & Klepinger, 1999; Smith, 2002), Central and South America (e.g. Baraybar & Shimada, 1993; Luna et al., 2007) and in Africa/Egypt (e.g. Strouhal, 1991b; Bachmeier et al., 1999; Nerlich et al., 2006). In Europe, malignant conditions have been identified in the United Kingdom (e.g. Ortner et al., 1991; Anderson et al., 1992; Duhig et al., 1996; Mays et al., 1996; Waldron, 1997; Melikian, 2006); Hungary (e.g. Marcsik et al., 2002); the Czech Republic (e.g. Strouhal et al., 1996); Russia (e.g. Schultz et al., 2007); Slovakia (e.g. Sˇefcˇa´kova´ et al., 2001), Italy (e.g. Ricci et al., 1994; Tempestini et al., 1999) and Spain (e.g. De la Ru´a et al., 1995; Campillo, 2005). In Portugal, Marques and Matos (2002) described four cases in the Human Identified Skeletal Collection housed at the Bocage Museum (National Museum of Natural History—Lisbon). The four skeletons, all of them female, date from the first decades of the 20th century and present breast carcinoma as the cause of death. In addition, a case of prostate carcinoma in an individual from the Coimbra Identified Skeletal Collection (Department of Anthropology, University of Coimbra) was also described by Santos (2000). In this paper, the pathological lesions observed in an elder female skeleton exhumed from the ancient necropolis of Constaˆncia (14th–19th centuries) are presented and discussed. The main goals of the paper are: (1) to describe the patterns of bone lesions found; (2) to analyse their nature and distribution throughout the skeleton; and (3) to discuss the aetiological factors underlying their expression, revealing the difficulties and limitations that characterise its paleopathological analysis. Int. J. Osteoarchaeol. 20: 603–620 (2010)

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Material and methods In 2002 and 2003, during an extensive archaeological excavation in the historical centre of Constaˆncia (Santare´m, Portugal), 151 skeletons (106 adults and 45 non adults) were recovered from the ancient necropolis and the associated Church of Sa˜o Julia˜o, both dated from the 14th– 19th centuries (Garcia, 2004; Assis, 2006). The skeleton with the reference PAH/C.02 SG19 E7, depicted in this paper, was found buried in a sand grave without evidence of coffin inhumation (Figure 1). The body was exhumed in extended supine, following a West–East orientation, with the head to the West, in accordance to the Christian belief in the resurrection of the soul (Barroca, 1987). The skull was positioned on

the occipital with a slight rotation to the left. The upper limbs were flexed over the chest and the lower limbs semi-flexed. Above the skeleton’s feet, a small ossuary was detected, probably resulting from a previous inhumation in the same area. Finally, a copper coin was recovered over the right hand bones. This occurrence may be related with the Roman tradition of Caronte’s payment (Tranoy, 2000). The skeleton was fairly well preserved, showing partial destruction of the skull, scapula, pelvis, ribs and spine. Of the latter, it was only possible to recover some fragments of the apophyseal processes from the thoracic and lumbar vertebrae and several fragments from the vertebral bodies and sacrum. Most of the available bones are incomplete and fragmentary, especially the joint surfaces. The long bones are the best preserved elements. The morphological and morphometric analysis revealed that the skeleton probably belonged to a 50 year old female. Sex determination was made based on the morphology of the skull (Ferembach et al., 1980) and the morphometric analysis of the long bones, talus and calcaneus (Wasterlain, 2000). The age at death was assessed according to the appearance of the auricular surface of the ilium (Lovejoy et al., 1985) and with the degree of closure of the cranial sutures (Masset, 1982). The stature was estimated in 161, 2  3, 53 cm (Olivier et al., 1978). The skeleton was examined macroscopically and the affected bones radiographed through digital mammography (Mamograph General Electrics, senographe DMR, voltage: 28 Kv; Exposition: 20 mAs; DOI: 660), using the facilities of the Clı´nica Universita´ria de Imagiologia from Hospitais da Universidade de Coimbra (HUC). The previous analysis complemented the detailed description of the bony lesions according to their anatomical location and severity. This procedure was concluded with the differential diagnosis.

Results

Figure 1. Skeleton PAH/C.02 SG19 E7 in situ.

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An asymmetric pattern of osteolytic foci with varied sizes and an irregular shape, located on the skull, axial skeleton, upper limbs and pelvis, Int. J. Osteoarchaeol. 20: 603–620 (2010)

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characterise the lesions observed. Both osteoclastic and osteoblastic lesions were found in the scapula, hip bones, ribs and humerus. The details of the lesions observed, as well as their radiological appreciation, are described in the next sections.

poorly delineated lytic lesions distributed through the cranial vault. These lesions are associated with some decrease in bone density, mainly in the parietals, and by a demarcation in the vascular etching of the inner lamina. These lesions are predominantly erosive without sclerotic signs.

Skull

Scapula

The macroscopic analysis of the skull reveals a fine porosity on the extra cranial surface, namely in the parietal, frontal and occipital bones. This porosity is interluded by small holes apparently produced by post-mortem damage. In some areas, the outer table of skull displays a tiny taphonomical discolouration of the bone surface. The most conspicuous alteration is present in the left zygomatic bone (Figure 2). The lytic lesion, a circular medium-sized perforation (8 mm), is located near the zygomaticomaxillary suture and appears to have perforated the spongy bone towards the outer surface, creating a roundshaped capsule. The mandible does not show any pathological involvement. The discrete alterations observed on the skull and on the facial bones were confirmed by radiological study (Figure 3a,b) which revealed a complex mesh of multiple, different sized and

On the left scapula (Figure 4a,b) there are two discrete lytic lesions: one close to the superior border of the glenoid fossa (from a ventral view), and the second, minimally enlarged by postmortem damage, in the infraglenoid tubercle. Larger lytic areas are situated in the superomedial surface of the scapula cortex, mainly at the base of the acromial process, spine and subscapular fossa. In the latter, the large destructive focus (21  18 mm) is only visible on the ventral side of scapula. The radiological spectrum shows, however, an anteroposterior perforation, and an irregular, reactive bone proliferation in some areas is concomitantly noted (Figure 4c). These are more pronounced at the base of the acromion process. This osteoblastic activity attributed to the affected zone an irregular appearance aided by small deposits of woven bone (Figure 4d). Radiologically, the scapula displays a great densification of the body, with increased radiopacity in the supraspinous process. The areas of well-delineated lytic lesions exhibit a ‘blotchy’ appearance (Ortner, 2003: 535) due the marginal sclerosis of their edges. On the right scapula, it was impossible to conduct the paleopathological evaluation due to post-mortem destruction.

Ribs

Figure 2. Osteolytic foci on the left zygomatic bone (8 mm in diameter).

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Most ribs show lytic foci of distinct sizes and severity, accompanied, in some cases, by the perforation of the cortical bone. This type of alteration shows a symmetrical occurrence that has affected several rib fragments (Figure 5a). In the shaft of a left rib fragment there is a massive destruction of the visceral surface (15  3 mm), increased by post-mortem breakage. Another left rib fragment displays a lytic lesion (5  3 mm) between the dorsal and the Int. J. Osteoarchaeol. 20: 603–620 (2010)

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Figure 3. (a) Post-mortem damage of the outer table of the cranial vault. (b) Radiograph showing multiple osteolytic foci with different size and shape without evidence of osteoblastic formation.

visceral surfaces of the ‘heart’ of the rib. The lesions can be described as possessing cavitations, or a ‘space-occupying’ mass appearance (Rothschild et al., 1998: 244). Lining the osteolytic foci new bone deposition was observed (Figure 5b). There is a bone callus resulting from a healing fracture on one of the left ribs. This traumatic event seems to indicate a possible case of pathological fracture, eventually secondary to the neoplasm disease. In addition to the traumatic lesion, there are two lytic foci, one on the dorsal view of the body (15  5 mm), and the second on the visceral surface (12  4 mm). Likewise, this case shows a proliferation of new bone deposits, particularly on the surfaces affected by destructive defects. Another traumatic lesion on one of the right ribs shows an incorrect alignment of the shaft and by the degree of remodelling it occurred before death (Figure 5c). Copyright # 2009 John Wiley & Sons, Ltd.

Radiological analyses reveal several lytic foci of discrete dimensions, not visualised through macroscopic scrutiny. Moreover, an intense radiopacity can be observed on the rib shafts. This may be due to loss of bone mass. The bone densification noted in the lytic edges indicates the existence of osteosblastic activity near to the reabsorptive areas.

Vertebral column The spine is only represented by some apophyseal processes of vertebrae and sacrum, and by fragments of the vertebral bodies, whose postmortem destruction discarded any paleopathological analysis. The apophyseal processes showed several osteolytic foci without new bone deposition (Figure 6a). These were found in the transverse processes of the lower thoracic and Int. J. Osteoarchaeol. 20: 603–620 (2010)

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Figure 4. (a) Ventral view of the left scapula with two discrete osteolytic foci on the superior border of the glenoid fossa and on the infraglenoid neck. (b) Osteolytic lesion on the supraglenoid fossa of the left scapula. Dorsal view. (c) Radiograph showing an anteroposterior perforation on the ventral side of the left scapula. (d) Superior view of the acromial process showing massive bone destruction followed by osteoblastic activity, with irregular layers of new bone deposition.

lumbar vertebrae. The lesions on one thoracic fragment were perceived in the superior articular facets. Radiologically, these features were increased numerically, showing a great rarefaction of bone tissue (Figure 6b). Copyright # 2009 John Wiley & Sons, Ltd.

Hip bones The great post-mortem destruction of the hip bones conditioned the paleopathological assertion of bone lesions. However, one fragment of Int. J. Osteoarchaeol. 20: 603–620 (2010)

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Figure 5. (a) Radiograph of ribs showing several osteolytic foci. (b) Dorsal view of a left rib showing severe lytic foci, with osteoblastic response in its contours. (c) Right rib with an incorrectly aligned bone callus resulting from a possible pathological fracture.

the left ischium displays a large osteolytic focus (16  10 mm) with irregular shape and demarked perforation of the entire fragment (Figure 7a). There are several layers of new bone deposition with smooth surfaces lining the lytic lesions. The radiological examination has confirmed this reactive bone response through an increase in radiopacity (Figure 7b). Additionally, discrete osteolytic lesions with irregular edges in the acetabular fossa were observed. In one fragment of the ilium blade an intense erosion of their surface is noted and confirmed radiologically by multiple and discrete perforating lesions.

Humerus The gross observation of the long bones only detected a lytic lesion in the lower extremity of the left humerus. The lesion, in the anterolateral portion of the bone, exhibits 22  17 mm in diameter (Figure 8). With its sharp edges, the lytic perforation created an enormous cavity in the medullar channel, affecting both aspects of the diaphysis. The adjacent surface (in an Copyright # 2009 John Wiley & Sons, Ltd.

anterosuperior view) is eroded, showing a large area of destruction with a rugged-like appearance. Discrete patches of new bone deposition accompanied this bone resorption. The radiological study shows two–three additional foci affecting the medullar cavity. These lytic lesions are located in the upper quarter of the shaft, close to the metaphyseal neck. The rich supply of haematogenous tissue of these anatomical areas may have dictated the development of new metastatic foci in progress at death, not detected under gross inspection. The right humerus has only revealed a possible focus in the lower extremity after radiological inspection. The radius, ulna and the bones of the lower limbs do not exhibit paleopathological alterations. This absence of pathological lesions is also true to the bones of the hands and feet, including the existing phalanges.

Discussion The pattern and distribution of the skeleton’s bone lesions are consistent with a diagnosis of metastatic carcinoma (Table 1). Int. J. Osteoarchaeol. 20: 603–620 (2010)

Metastatic Carcinoma in a Portuguese Skeleton

Figure 6. (a) Dorsal view of a thoracic vertebra with roughly circular foci of different size. Note the two major perforations in the upper apophyseal joints. (b) Radiograph showing several osteolytic foci with no signs of osteoblastic activity.

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Figure 7. a. Left ischium with a large and irregular osteolytic lesion (16  10 mm), with new bone deposition on its edges. b. Radiograph showing a major destructive lesion with marked radioluscence contours.

Figure 8. Distal portion of the left humerus showing a large destructive lesion with cortical erosion of the nearby area.

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Int. J. Osteoarchaeol. 20: 603–620 (2010)

Copyright # 2009 John Wiley & Sons, Ltd. Sex

Bones affected

Location and morphology of the bone lesions

yes yes yes yes yes yes yes

yes yes yes yes no

yes yes

yes yes yes yes

yes yes yes yes yes yes yes

no no yes yes no no yes

yes yes yes yes yes

yes yes

yes yes

yes yes no no yes no yes

yes no no no yes

no yes

yes yes

yes no no no yes yes yes

yes no no yes yes

yes yes

yes yes

yes no no no yes yes yes

yes yes no no no

no no

yes no

no no no no no no yes

yes yes no yes yes

no no

yes no

no yes yes yes yes yes yes

yes no no yes no

yes no

yes no

no no no yes yes yes yes

no yes yes yes yes

yes yes

yes yes

yes yes yes yes yes yes yes

yes no yes yes yes

no yes

no no

no no no yes yes yes yes

no rarely yes no yes

rarely no

no rarely

rarely yes rarely rarely rarely yes yes

yes — — — yes

— yes

yes —

— yes yes yes — yes yes

Osteolytic/ Pathological  50 Female Skull Ribs Vertebrae Scapula Humerus Hip Diaphyses Multiple, bones Metaphyses asymmetric Osteoblastic fractures lytic lesions mixed pattern with variable size and shape

Age

Biological and paleopathological profile of Skeleton PAH/C.02 SG19 E7

Adapted from Steinboch (1976); Zimmerman and Kelley (1982); Aufderheı´de and Rodrı´guez-Martı´n (1998); Campanacci (1999); Ortner (2003); Resnick et al. (2005); Resnick and Kransdorf (2005); Roberts and Manchester (2005).

1

Primary tumours Osteoblastoma Osteosarcoma Fibrosarcoma Fibrous histiocytoma Angiosarcoma Ewing’s sarcoma Metastatic carcinoma Haematological disorders Multiple myeloma Leukaemia Fungal diseases Cryptococcosis Sporotrichosis Infectious conditions Tuberculosis Syphilis Osteomyelitis Echinococcosis Histiocytosis - X

Differential diagnosis

Table 1. Differential diagnosis for the presenting pathological case1

612 S. Assis and S. Codinha

Int. J. Osteoarchaeol. 20: 603–620 (2010)

Metastatic Carcinoma in a Portuguese Skeleton In paleopathology, there is some grade of difficulty in differentiating between secondary tumours, like metastatic carcinoma, and other pathological abnormalities such as primary tumours, haematological disorders, fungal diseases, infectious conditions and Hitiocytosis-X (De la Ru´a et al., 1995; Rothschild & Rothschild, 1995). Several primary bone tumours such as osteosarcoma or osteogenic sarcoma are able to mimic the response induced by metastasising carcinoma. This malignant bone-forming tumour can arise on the cortical surface of bones, constituting one of the most frequent bone neoplasms (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick et al., 2005). The traditional concept of osteogenic sarcoma implies the production of osteoid. It does not represent however, an exclusive feature, seeing as it can affect either the cartilage or the fibroid matrix (Steinbock, 1976; Aufderheide & Rodrı´guezMartı´n, 1998). The aggressiveness of the tumour may create a distinct pattern in the bone ranging from purely osteolytic or osteoblastic forms, to those with a mixed response, which are more typical (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick et al., 2005). When bone reaction is extensive, several layers of new bone are produced creating a radiant alignment of tumour tissue called ‘sunburst’ (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; No¨bauer & Uffmann, 2005; Resnick et al., 2005). In all cases, lesions may increase in size, but it is almost always a single lesion and rarely metastasises to other bones (Steinbock, 1976; Ortner, 2003). With a high incidence in younger adults, especially males, this primary tumour is more frequent in the long bones, particularly in the distal portion of the femur and in the upper ends of the humerus and tibia (Steinbock, 1976; No¨bauer & Uffmann, 2005). The age and the acute spreading of bone lesions, predominantly at the axial skeleton and skull, observed in the female skeleton, are incompatible with a case of osteosarcoma. Equal inference can be obtained to the aggressive form of osteoblastoma, a bone neoplasm that has a major expression in young adults, particularly in the femur, humerus and vertebrae (Resnick et al., 2005). Copyright # 2009 John Wiley & Sons, Ltd.

613 Fibrosarcoma and fibrous histiocytoma are primary tumours that arise from the fibrous connective tissue (Resnick et al., 2005). These malignant conditions are characterised by osteolytic focus with poor bone remodelling (Resnick et al., 2005). Like the metastatic conditions, they are more frequent in middle–old age adults and may produce pathological fractures (Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick et al., 2005). However, these osteolytic lesions contrast with those of metastatic cancer in their reduced number and configuration. Additionally, they exhibit localised pattern with large foci, especially in the metaphyseal portion of long bones (Resnick et al., 2005), a requirement not observed in our case. Angiosarcoma is another rare condition that may mimic metastatic carcinoma. This malignant tumour apparently arises from the vascular components of bone (or from a pre-existing benign angioma) producing a pattern of osteolysis, uncommonly followed by osteoblastic activity (Copeland & Geschickter, 1963; Aufderheide & Rodrı´guez-Martı´n, 1998; Roessner & Boehling, 2002; Resnick et al., 2005). The lesions are quite variable in size and do not possess uniform contours. Like the metastatic carcinoma, the multifocal involvement is frequent, although with an anatomical pattern of distribution (Roessner & Boehling, 2002; Resnick et al., 2005). Multiple lesions may occur in a single bone, in the same extremity, or several pieces may be affected by one or more foci (Resnick et al., 2005). The distinguishing pattern of bone involvement is the clustering of multifocal lesions in a single limb or anatomic location (Balicki et al., 1996; Roessner & Boehling, 2002). This malignant condition tends to affect the long bones, such as the tibia and the femur, and the axial skeleton, namely the spine. Pathological fractures may be present (Roessner and Boehling, 2002; Resnick et al., 2005). Angiosarcoma is more frequent between the second and third decade of life (Roessner & Boehling, 2002). None of these pathological lesions nor the age are congruent with skeleton PAH/C.02 SG19 E7. Malignant neoplasms such as Ewing’s sarcoma are known to produce severe osteolysis in the cortical and trabecular bone. This acute destruction may be followed by the elevation of the Int. J. Osteoarchaeol. 20: 603–620 (2010)

614 periosteum, due to new bone deposition and/or irregular calcification, creating an onion-like appearance (Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick et al., 2005). Neither gross inspection nor radiological analysis of the skeleton showed a pattern of lesions consistent with this description. The skeletal distribution of Ewing’s sarcoma shows a predilection for the metaphyseal portion of long bones, especially in the lower extremities (25% in the femur) (No¨bauer & Uffmann, 2005). Nevertheless, lesions can also be found in the hip bones, vertebrae and ribs (Steinbock, 1976; Resnick et al., 2005; Ortner, 2003). Although the multifocal distribution of Ewing’s sarcoma is consistent with our case, it occurs at a younger age, which excludes it from the present diagnostic (Copeland & Geschickter, 1963; Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; No¨bauer & Uffmann, 2005). Haematological disorders such as leukaemia and multiple myeloma may produce pathological alterations in bone tissue. Leukaemia, a malignant condition of the myeloid and lymphoid blood cells, can develop a pattern of diffuse osteopenia, followed by marked pitting in the metaphyseal surface of bones (Zimmerman & Kelley, 1982; Rothschild & Rothschild, 1995; Rothschild et al., 1997; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003). In acute leukaemia, the tumour cells can penetrate the periosteum throughout vascular foramina, producing an abnormal proliferation of grooves and pitting in the cortex (Zimmerman & Kelley, 1982). This particular manifestation can be distinguished from metastatic carcinoma by their massive number, that may vary between isolated, multiple or coalescent holes, with an elliptical and/or an irregular shape (Rothschild & Rothschild, 1995; Rothschild et al., 1997; Rothschild et al., 1998). Occasionally, it can produce new bone deposition in the ribs and long bones (Ortner, 2003). The osteolytic lesions observed in the female skeleton are less numerous and exhibit a reticulated appearance with irregular contours. The age of the individual is not in much accordance with leukaemia either, which is more frequent at younger ages, whereas metastatic carcinoma is particularly common in older individuals (Zimmerman & Kelley, 1982; Rothschild et al., 1997; Ortner, 2003). Moreover, the Copyright # 2009 John Wiley & Sons, Ltd.

S. Assis and S. Codinha radiological analysis of our specimen showed absence of radiolucent and sclerotic bands in the metaphyses, a feature related to leukaemia (Steinbock, 1976; Zimmerman & Kelley, 1982; Rothschild et al., 1997). The differential diagnosis between multiple myeloma and metastatic carcinoma is one of the most difficult in the study of bone neoplasms from archaeological contexts. The main factors that make this differential diagnosis so challenging is their equal pattern of skeletal involvement and a correspondent biological profile, when considering the individual’s age. In any case, it is possible to note several particularities in the morphology of the lesions useful to their differentiation. Multiple myelomas are typically described as producing lytic lesions with spheroid morphology and relative uniform diameter (0.5–2 mm) (Rothschild & Rothschild, 1995; Rothschild et al., 1998; Aufderheide & Rodrı´guez-Martı´n, 1998). The osteolytic lesions are sharply defined with an effaced or ‘punched-out’ appearance and the internal relives are smooth without signs of osteoblastic activity (Rothschild et al., 1998: p. 242). In general, myeloma presents a further dispersion than metastatic cancer and affects males more frequently (Strouhal, 1991a). The most diagnostisizing lesions for myeloma are observed in the glenoid fossa of the scapula, in the lateral portion of the clavicle, and in the radius and ulna (Ortner, 2003). As myeloma, the metastatic carcinoma exhibits a multifocal distribution, with particular incidence in the vertebrae, ribs, pelvis and skull (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003). Even so, the metastasising lesions possess a distinct pattern that may diverge between lytic, osteoblastic or a mixed combination (Zimmerman & Kelley, 1982; Aufderheide & Rodrı´guezMartı´n, 1998; Ortner, 2003). The osteolytic lesions are characterised by an asymmetrical shape, with rough edges and variable size (Rothschild et al., 1998). These destructive alterations progressively consume the cancerous bone and erode the cortex of long bones (Ortner, 2003). In the vertebrae, the bone involvement follows a descendent route, starting in the lower thoracic vertebra and progressing to the lumbar segments and the sacrum (Ortner, 2003). Both body and apophyseal processes are equally affected. In the Int. J. Osteoarchaeol. 20: 603–620 (2010)

Metastatic Carcinoma in a Portuguese Skeleton skull, the most conspicuous lesions are observed in the diploe¨ (Ortner, 2003). The radiological analysis of skeleton PAH/C.02 SG19 E7 revealed several unsuspected lytic lesions with irregular size and shape inconsistent with multiple myeloma. In spite of the mixed pathological pattern registered at the axial skeleton, hip bones and humerus, the diagnosis of multiple myeloma must not be completely ruled out. A group of fungal conditions may induce a pathological bony response that is somewhat identical to that observed in metastatic carcinoma. In the present discussion, only the diseases which have European distribution, namely the cryptococcosis (or European blastomycosis) and the sporotrichosis (Zimmerman & Kelley, 1982; Aufderheide & Rodrı´guez-Martı´n, 1998) are listed. These rare conditions are characterised by an osteolytic nature, with absent or rare periosteal deposition. The discrete lesions may affect several bones, namely the skull, the vertebrae and the long bones. Additionally, there is some joint involvement in long bones, a feature not observed in the present skeleton, or in metastatic cancer. In the differential diagnosis of metastatic carcinoma, it is equally important to consider certain types of infections, specific and non-specific, such as tuberculosis, syphilis and osteomyelitis. Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. In paleopathology, its diagnosis is centred on the search for vertebral lesions and acute joint destruction, particularly at the hip and knee (Aufderheide and Rodrı´guezMartı´n, 1998; Roberts and Manchester, 2005). In the vertebral segments the lesions are characterised by the erosion of cortical and trabecular bones, with abscess formation. Severe cases may induce body collapse (or Pott’s disease) and subsequent ankylosis (Roberts & Manchester, 2005). Unfortunately, skeleton PAH/C.02 SG19 E7 exhibits severe post-mortem damage of the vertebral column. This causality conditioned the accurate observation of vertebral bodies, in pursuing possible infectious signals. However, the reasonable preservation of apophyseal processes revealed lytic foci, unusual in tuberculosis, but frequent in metastatic carcinoma (Ortner, 2003). The involvement of the joints in tuberculosis may cause septic arthritis followed by the Copyright # 2009 John Wiley & Sons, Ltd.

615 destruction of the articular surfaces and ankylosis (Steinbock, 1976; Roberts & Manchester, 2005). No joint involvement was observed in our case a feature commonly seen in the distribution of metastatic lesions. In bone tuberculosis there is supremacy of destructive processes over proliferative reactions (Steinbock, 1976; Roberts & Manchester, 2005). An exception is noted at the visceral surface of ribs, where a correlation between new bone deposition and pulmonary tuberculosis seems to exist (Kelley & Micozzi, 1984; Roberts et al., 1994; Santos & Roberts, 2001; Matos & Santos, 2006; Santos & Roberts, 2006). The osteoblastic signature observed in the ribs of the female skeleton does not suggest an infectious process. Acquired syphilis is another infection that may produce serious damage to the bone surface. This disease is caused by Treponema pallidum, a bacterium that reaches the body through the skin or mucosa (Steinbock, 1976; White, 2000; Roberts & Manchester, 2005). In general, syphilis may affect the whole skeleton. However, the more conspicuous lesions are observed at the latter stages of the disease. With a symmetrical dispersion, it is more frequent in the tibia, nasal bones and skull (Ortner, 2003). Syphilitic lesions may be grouped in gummatous, a pathological variant characterised by localised thickness of bone, increased hypervascular activity and formation of irregular grooves, termed as snail tracks (Mann & Murphy, 1990). The nongummatous type, less suggestive, may occur through periosteal deposition, with the formation of plaque like exostoses and marked hypervascular bone build up (Ortner, 2003). In advanced cases, increased thickness is followed by the obliteration of the medullar cavity (Mays, 1998; Ortner, 2003; Roberts & Manchester, 2005). This focal distribution is different from the morphological pattern of the bone lesions observed in skeleton PAH/C.02 SG19 E7. Osteomyelitis is a bone infection with primary incidence in the medullar cavity of long bones, especially in the tibiae (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003). Additionally, it may cause an inflammation in the periosteum (periostitis) or in the endosteum (osteitis) (Steinbock, 1976). The lesions involve a mixed pattern with destructive Int. J. Osteoarchaeol. 20: 603–620 (2010)

616 and remodelative processes including necrosis, increase in bone density and reactive sclerosis (Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003). Nevertheless, the most conspicuous traits include the formation of sequestra, hypervascular porous periostitis and a draining cloaca (Ortner, 2003). This ‘diagnostic evidence’ (Ortner, 2003: 199) was not identified in the skeleton. Echinococcosis, a worldwide parasitic infection, is identified in the archaeological context by the formation of hydatid cysts (Aufderheide & Rodrı´guez-Martı´n, 1998). More uncommon is the occurrence of osteolytic lesions in the vertebrae, pelvis or long bones such as the tibia, the humerus and the femur. These abnormalities are usually limited to a single bone or region (Aufderheide & Rodrı´guez-Martı´n, 1998). The nature and distribution of this parasitic infection contrasts with the widespread lesions observed in the female skeleton. Histiocytosis-X corresponds to a major pathological group that includes eosinophilic granuloma, Letterer-Siwe disease and Schu¨ller-Christian syndrome (Steinbock, 1976). Bone response to this rare condition includes osteolytic foci, associated with periosteal remodelation and marginal sclerosis (Aufderheide & Rodrı´guezMartı´n, 1998; Ortner, 2003). The lytic lesions are of variable size and present a punched-out configuration that contrasts with the irregular contours of a metastasising tumour (Resnick & Kransdorf, 2005). Although Histiocytosis-X presents a pattern of distribution similar to malignant carcinoma, it affects individuals in the first decade of life, which is inconsistent with the age at the death of the analysed individual. The pattern of multiple bone lesions on skeleton PAH/C.02 SG19 E7, characterised by lytic and osteosclerotic foci in the skull, the axial skeleton, the hip bones and left humerus, in addition to its biological profile, are compatible with a possible case of metastatic carcinoma. However, the type of malignant condition we are dealing with is undetermined The knowledge of tumour lesions constitutes an important pathway to identify the primary origin of metastatic lesions in bone. Unfortunately, and in spite of new medical efforts and advanced techniques, the application of these criterion diagnostics in the study of dry bone is Copyright # 2009 John Wiley & Sons, Ltd.

S. Assis and S. Codinha somewhat difficult and perhaps impossible, particularly when the lesions exhibit a great spread throughout the body (Rothschild & Rothschild, 1995). Skeletal lesions associated with carcinoma of the bladder, pancreas, esophagus and melanoma are uncommon (Resnick & Kransdorf, 2005). When present, they follow an axial distribution through thoracic lumbar segments and ribs, with production of lytic foci (Coleman, 1997; Resnick & Kransdorf, 2005). Melanoma can also affect the hip bones (Resnick & Kransdorf, 2005). This occurrence is distinct from the mixed pattern observed in skeleton PAH/C.02 SG19 E7. Equal assumption can be obtained for carcinoma of the kidney and uterine cervix and thyroid carcinoma (Steinbock, 1976; Coleman, 1997; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick & Kransdorf, 2005). In the case of the latter, the lesions have a tendency to extend across articulations (Resnick & Kransdorf, 2005), a feature not identified in the female skeleton. Carcinoma of the colon and rectum produce lytic or mixed osteolytic-osteosclerotic lesions such as those observed in the present skeleton. Another condition to be considered is lung cancer (Rosenthal, 1997; Resnick & Kransdorf, 2005). This tumour is mainly osteolytic, evincing, however, sporadic osteoblastic activity (Resnick & Kransdorf, 2005). It is characterised by an acute involvement of the axial skeleton, with rib erosion and vertebral destruction (Resnick & Kransdorf, 2005). An identical pattern was observed in the present skeleton, namely on the visceral surface of preserved ribs and apophyseal processes. Finally, we must consider breast carcinoma. In the medical practice, large retrospective studies revealed enormous skeletal involvement in women with breast carcinoma, exceeding 50% of all analysed cases (Domchek et al., 2000). As in the case of lung malignancy, this disease is characterised by osteolytic foci and/or a mixed osteolytic/osteoblastic pattern (Steinbock, 1976; Aufderheide & Rodrı´guez-Martı´n, 1998; Ortner, 2003; Resnick & Kransdorf, 2005). The axial skeleton is the most affected element (Body, 2001). Pathological fractures, such as those noted in PAH/C.02 SG19 E7, are frequent (Resnick & Kransdorf, 2005). Int. J. Osteoarchaeol. 20: 603–620 (2010)

Metastatic Carcinoma in a Portuguese Skeleton Several studies have been conducted fully to appreciate the frequency of pathological fractures in malignant diseases. Saad et al. (2007), searching through a sample of 3049 individuals has revealed a major incidence of fractures in multiple myeloma (43%), followed by breast carcinoma (35%), prostate carcinoma (19%) and lung carcinoma (14%). In what concerns skeletal distribution, the ribs and the vertebrae are the most affected bones, followed by the long tubular bones (Coleman, 1997). In this matter Scheid et al. (1986) describes an incidence of rib fractures in 29% of the patients with breast carcinoma. Vertebral trauma appears in minor frequency, occurring in only 9% of the cases.

Conclusion The biological profile and the multiple patterns of the bone lesions of skeleton PAH/C.02 SG19 E7, characterised by lytic and osteosclerotic foci concentrated in the skull, axial skeleton, hip bones and left humerus, are compatible with a probable case of metastatic carcinoma. Although the primary cause of these bone abnormalities is uncertain due the widely disseminated metastases along the skeleton, this case is of extreme relevance, not only because it involves a relatively well preserved skeleton, but particularly by the fact that it represents the first case of malignant carcinoma registered in the Portuguese archaeological record. Furthermore, considering the low number of similar cases in the Iberian Peninsula (De La Ru´a et al., 1995; Campillo, 2005), this case is also extremely valuable to the understanding of the incidence of this disease among past Iberian populations.

Acknowledgements The authors thank Fundac¸a˜o para a Cieˆncia e Tecnologia (SFRH/BD/36739/2007), Centro de Investigac¸a˜o em Antropologia e Sau´de (CIAS), and Clı´nica Universita´ria de Imagiologia (HUC). Authors also thank anonymous reviewers for their comments. Copyright # 2009 John Wiley & Sons, Ltd.

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