Large lytic cranial lesions: A differential diagnosis from pre-Angkorian Cambodia

International Journal of Osteoarchaeology Int. J. Osteoarchaeol. 22: 731–739 (2012)

Published online 29 December 2010 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/oa.1234

Large Lytic Cranial Lesions: A Differential Diagnosis from Pre-Angkorian Cambodia K.M. DOMETT a* AND H.R. BUCKLEY b a Discipline of Anatomy and Pathology, School of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia b Department of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand

ABSTRACT

A late pre-Angkorian period, c. 350 BC - 200 AD, cemetery has been excavated in the village of Phum Snay, in northwestern Cambodia. In addition to the cemetery sample, a large sample of stratigraphically unprovenanced human skeletal material was uncovered in the village through extensive looting over the last 5–10 years. Both sample sets were available for study but the latter is comprised of only isolated bone elements. The differential diagnosis of the cause of lesions in one isolated cranial vault from this sample is presented here. Widespread, primarily lytic, lesions are concentrated on the frontal and anterior parietal bones, with an additional large lesion on the occipital bone. Lesions vary in size ranging from approximately 5–30 mm in diameter. A detailed description of these lesions is given and a differential diagnosis is presented that includes infectious disease, such as osteomyelitis, tuberculosis and treponemal disease, and also several forms of cancer including metastatic carcinoma, meningioma and multiple myeloma, and finally Langerhans Cell Histiocytosis. The diagnosis is difficult, given the lack of material, but it is suggested that one of the forms of Langerhans Cell Histiocytosis is the most likely candidate. The presence of such large and diffuse lesions is unusual in prehistoric Southeast Asia so the significance of this is also discussed. Copyright ß 2010 John Wiley & Sons, Ltd. Key words: Cambodia; cranium; Pre-Angkor; Langerhans’ cell histiocytosis; lytic lesions; metastatic carcinoma

Introduction Excavations in northwestern Cambodia have uncovered a rich burial ground at the village of Phum Snay, Banteay Meanchey, dated to the late pre-Angkorian period, c. 350 BC - 200 AD (O’Reilly & Pheng, 2001; O’Reilly et al., 2006; Domett & O’Reilly, 2009). In addition, extensive modern-day looting of the prehistoric site of Phum Snay has exposed a large sample of stratigraphically unprovenanced human skeletal material. Both sample sets were available for study but the latter is comprised of only isolated bone elements. During the analysis of the isolated crania a single specimen (WLC74) was observed with diffuse osteolytic lesions for which a differential diagnosis is presented here. To our knowledge no such striking * Correspondence to: Discipline of Anatomy and Pathology, School of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia. e-mail: [email protected] y Senior Lecturer.

Copyright # 2010 John Wiley & Sons, Ltd.

lesions have been observed in prehistoric remains from mainland Southeast Asia before.

Materials The cranium was incomplete with only a near complete cranial vault preserved. No facial bones were present. Based on cranial morphology the vault was estimated as female. No age-at-death could be accurately estimated but the spheno-occipital synchondrosis and the ectocranial frontal suture were fused and the sagittal suture was in an advanced state of fusion ectocranially, thus this vault was probably not from a young adult. Observations were made while temporary access to the stratigraphically unprovenanced collection was allowed at the E´cole franc¸aise d’Extreˆme-Orient in Siem Reap. Radiographic analysis was attempted but was not successful based on the limited nature of radiographic facilities in Siem Reap, Cambodia and post-depositional soil in the bone. After analysis, the material was Received 10 November 2009 Revised 31 October 2010 Accepted 5 November 2010

732 returned to a small mortuary temple at Phum Snay and to Wat Rajabo in Siem Reap.

Pathology description

K. M. Domett and H. R. Buckley All visible lesions were characterised by significant bone destruction through all cranial layers: outer table, diploe¨ and inner table. Lesions could then be collectively divided into two categories. Type 1 lesions (Figures 2 and 3) showed signs of considerable osteoblastic activity with remodelling and some

Widespread, primarily lytic, lesions were concentrated on the frontal (n ¼ 4) and parietal bones (n ¼ 6) (Figure 1), with an additional large lesion on the occipital bone (Figure 5). The left side of the vault (n ¼ 7) was more affected than the right (n ¼ 2) and two lesions were located centrally (occipital and frontal). No lesions were observed on the temporal or sphenoid bones or on the base of the cranial vault. Lesions were mostly circular and varied in size from approximately 5–31 mm in diameter.

Figure 1. Cranial vault (WLC74). (A) Left lateral view indicating the predominance of lesions on the left frontal and parietal bones; (B) Superior view showing the large midfrontal lesion and a number of smaller lesions scattered over the frontal and parietal bones.

Copyright # 2010 John Wiley & Sons, Ltd.

Figure 2. A. superior view of frontal bone (anterior to the right hand side of image). This superior midfrontal lesion of Type 1 was the largest with a maximum diameter of 31 mm across the widest opening on the outer table. The inner table opening is much narrower and there is some sclerotic remodelling (‘smoothing’) of the trabeculae within the diploe¨ (white arrowhead). There is moderate new bone formation around the rim of the lesion with elevation of the margins (white arrows) but there is also some postmortem damage. (B) The rim of the lesion on the outer table is elevated (white arrow). Trabeculae remodelling can again be seen (white arrowhead).

Int. J. Osteoarchaeol. 22: 731–739 (2012)

Large Lytic Cranial Lesions

733

Figure 3. Lateral view of left aspect of the frontal bone, superior to temporal suture. This Type 1 lesion has a larger opening on the outer table with bevelling of the diploe¨ inwards. The margins are only slightly elevated compared to the lesion in Figure 2. There is smoothing of the diploe¨ with some remodelling external to the margins on outer table.

smoothing of the scalloped out diploic bone. The clearly demarcated borders of the two lesions belonging to this type were elevated on the outer table and the outer table opening was larger than the inner table opening. One of these lesions (Figure 2), a large superior midfrontal lesion, was the largest of all the lesions measuring approximately 31 mm across at its widest point. It is likely that this was the primary or longest existing lesion. The other lesion (Figure 3) in this category was approximately half the size of the larger lesion. Type 2 lesions also showed signs of osteoblastic activity but remodelling was confined to the outer table margins of the lesion (Figure 4). The borders of all lesions were quite clear with some sclerosis circumscribing the lesion, indicating that the disease process was moderately slow (Ortner, 2003). The amount of remodelling did vary between lesions indicating the disease process was active at the time of death. Most of these lesions had more extensive resorption of the inner table compared to the outer table (e.g. Figure 5) in contrast to the Type 1 lesions. Type 2 lesions had reasonably widespread porosity and subperiosteal activity which was remodelled or remodelling around the margins of the lesions outer table (Figures 4 and 5). This would indicate that the formation of lesions was causing associated inflammation. Copyright # 2010 John Wiley & Sons, Ltd.

Figure 4. Lesion of Type 2 on the superior-lateral aspect of the left parietal bone. This lesion measures approximately 13 mm at its widest point. Note the presence of new bone around the margins of the lesion on the outer table (black arrows). This image also shows the ‘overhang’ of the outer table over the diploic bone (if somewhat blurry) (white arrow).

In nearly all cases of both types of lesions, the diploe¨ was ‘scalloped’ out to some extent so that the inner or outer table ‘overhung’ the diploe¨, but this was not remodelled in Type 2 lesions. This would tend to imply that the lesions had possibly developed initially from within the diploic bone.

Differential diagnosis These types of primarily lytic and diffuse lesions have not been reported within remains from prehistoric Southeast Asia before. The lesions have been compared with paleopathological and clinical evidence from a wide range of diseases, particularly those of an infectious and neoplastic nature, but the presence of polytypic lesions has made the diagnosis difficult. A number of features of the lesions support a diagnosis of osteomyelitis. Firstly, many of the lesions have a larger area of lysis in the diploic bone rather than the tables. This may indicate that the disease Int. J. Osteoarchaeol. 22: 731–739 (2012)

734

Figure 5. Lesion of Type 2 on the occipital bone. (A) Ectocranial view. Note the extensive porosity around the lesion. This lesion has quite sharp margins and what appears to be a large nutrient foramen on the superior-lateral aspect of the lesion. (B) Endocranial view through the foramen magnum. While the entire outer table opening is not visible, the inner table opening is considerably larger (17 mm at widest). Note the smoothing of the diploic bone and the large nutrient foramen (white arrow).

originated from a haematogenous source. Osteomyelitis is an infection in the marrow space that frequently also involves the outer table (Ortner, 2003). Osteomyelitis can spread through the marrow space in the diploic bone to other sites including across sutures, although the occipital bone is often not affected (Ortner, 2003). One of the frequent causes of osteomyelitis is as a consequence of traumatic injury, however, this type tends to remain localised, involves a sequestrum and does not necessarily involve the diploe¨ (Ortner, 2003). While osteomyelitis as a result of trauma is unlikely in WLC74 given the nature of the lesions (widespread and involving all three layers of the cranial bone), it is worth noting that in an investigation of the entire skeletal collection from Phum Snay as many as 20% of the crania had evidence of trauma, particularly in the form of well healed depression fractures but also some healed and unhealed Copyright # 2010 John Wiley & Sons, Ltd.

K. M. Domett and H. R. Buckley (perimortem) cut marks (Domett et al., in press). None of the calvaria with healed lesions (cuts or fractures) had any severe complications such as infection, however, it would not be uncommon for the subsequent infection, if prolific enough, to obscure the evidence for the original injury. Other infectious diseases that were briefly considered include tuberculosis, leprosy and treponemal disease. No cases of treponemal disease and very few cases of tuberculosis and leprosy have been reported from mainland Southeast Asia (Douglas, 1996; Tayles & Buckley, 2004). Tuberculosis is an unlikely candidate as skull lesions are rare in adults (Ortner, 2003). When tuberculoid lesions in the skull are present in adults, the resorption of the inner table is larger than the outer table opening, like in many of the WLC74 lesions, but the lesions tend to be solitary (Ortner, 2003), unlike in WLC74. However, Hackett (1976) believes that the tuberculosis and metastatic neoplasm sequences are very similar by the end stage making differential diagnosis difficult. Leprosy was considered unlikely as lesions of the skull prevail within the face, not the vault (but there was no face preserved) (Ortner, 2003). Treponemal disease (syphilis, yaws, etc.) has characteristic lesions of the cranial vault, caries sicca. Caries sicca tends to spare the inner table, although full thickness damage can occur but inner table changes will be small (Hackett, 1976; Aufderheide & RodriguezMartin, 1998; Ortner, 2003). There tends to be little bone regeneration in treponemal lesions (Aufderheide & Rodriguez-Martin, 1998). The lesions in WLC74 do not appear to be similar in any way to ‘classic’ caries sicca, however, early changes of syphilis might be confused with other bone lesions such as the early changes in metastatic carcinoma such as clustered pits and confluent clustered pits on the outer table (Hackett, 1976). WLC74 does not have any lytic lesions that are solely confined to the outer table which would imply that the lesions did not start on the outer table. The inner table is difficult to fully observe given the near completeness of the vault and that radiography was not successful. Given the size and extent of the lesions in WLC74, they are likely to be advanced lesions of some standing. Late stages of syphilis have circumvallate cavitation (rounded raised margins) (Hackett, 1976) and these are not seen in WLC74. With an infectious origin ruled out, three main types of neoplasms are considered as candidates for the cause of the lesions in WLC74: meningioma, multiple myeloma and metastatic carcinoma. Cranial meningioma is known to penetrate the cranial vault through the inner table but this often results in the formation of radiant spicules outwardly Int. J. Osteoarchaeol. 22: 731–739 (2012)

Large Lytic Cranial Lesions projecting from the destroyed outer table (Ortner, 2003). The aggressive destruction can give the appearance of metastatic carcinoma (Ortner, 2003) but meningiomas are often slow growing; they may start out as a lytic lesion but soon form significant amounts of new bone (Jo´nsdo´ttir et al., 2003). WLC74 does show new bone development in most Type 2 lesions and more so in Type 1 lesions, but does not show any of the typical features such as inner table origin, hyperostosis or the formation of spicules. Multiple myeloma is a possibility for the lesions observed in WLC74. This disease arises in the marrow at a primary site but quickly results in multiple lesions. The typical appearance of lesions is sharply defined as small ‘punched out’ holes (5–20 mm) that penetrate all cranial tables. Lesions also often show scalloped margins but will rarely show sclerotic remodelled margins as osteoblastic activity is inhibited (Ortner, 2003). This particular aspect of multiple myeloma does not favour it’s diagnosis in WLC74 as does the large size of some lesions. Some of the lesions in WLC74 are much larger than what is typically seen in multiple myeloma (Zimmerman and Kelley, 1982, cited in Marks & Hamilton 2007). Zimmerman and Kelley (1982, cited in Marks & Hamilton, 2007) also mention that multiple myeloma lesions tend to be more consistent in size compared to other neoplastic diseases. They tend to be small, approximately 3– 10 mm although up to 30 mm is possible. Most cases in the literature (e.g. Morse et al., 1974; Suzuki, 1981; Strouhal, 1991; Haidle, 1995) that have arrived at a diagnosis of multiple myeloma do not resemble WLC74. Apart from the actual form of the lesions, multiple myeloma also tends to have a predominance in males (Strouhal, 1991; Ortner, 2003; Melikian, 2006), although this would not preclude it forming in this woman. Metastatic carcinoma is also known as secondary cancer and bone is not an uncommon secondary site from breast, prostate, kidney and lung cancer (Chambers et al., 2002; Ortner, 2003). Determining the origin of the primary tumour based on skeletal lesions can be difficult as skeletal lesions tend to be similar no matter where the original tumour arose (Ortner, 2003). Three quarters of active metastatic skeletal tumours in the cranium are osteolytic with destruction of the diploic bone, internal scalloping and destruction of the compact bone. Slower lesions will show some osteoblastic activity with new bone produced often covering the trabeculae (Ortner, 2003). The diploic bone will show the most marked destruction. These features all share similarities with WLC74. Copyright # 2010 John Wiley & Sons, Ltd.

735 Lesions of the cranial vault described in Smith (2002) and attributed to metastatic carcinoma share some similarities with the present case study of WLC74. Three large lesions (up to 34 mm) on the superior parietal and frontal bone have slightly elevated and pitted margins on the outer table and the diploic margin is larger in diameter. Smith’s (2002) lesions though do not appear to show remodelled diploic bone, a key point of difference. Other publications of possible metastatic carcinoma in the paleopathology literature also resemble WLC74 (e.g. Manchester, 1983; Sˇefcˇa´kova´ et al., 2001). Sˇefcˇa´kova´ et al. (2001: 226) based their diagnosis on the ‘‘multifocal character of the lesions (their large number, varying dimensions, and acute edges, a scarcity of new bone formation. . .’’. Again, the varying presence of new bone, some with quite well developed margins, do not support a diagnosis of metastatic carcinoma in WLC74 but other features are very similar. Hackett (1976) presents a number of cases reported as metastatic carcinoma that look very similar to WLC74 but without the clustered pits that are perhaps an earlier stage (e.g. Hackett’s (1976) Figure 2, 14 and 17a). Hackett’s (1976) case in Figure 17a has a single large lytic lesion and is very similar to the large frontal lesion in WLC74. Both lesions have raised margins on the outer table with a sharp outer edge falling smoothly and acutely to the inner opening. The diploic bone is slightly scalloped, with a bevelled wall that appears gouged out. The diploe¨ can still be recognised. There is some smoothing of the diploe¨ in WLC74 but this is not clear in Hackett’s (1976) example. Pitting surrounds the opening on the outer table in WLC74. Hackett (1976) believes some syphilitic lesions may appear similar to this but the diploe¨ would be smooth and sealed and small sequestra may be present. Hackett (1976) describes the diagnostic criteria of neoplasms as those with smooth ‘gouged out’, rather steeply inward sloping (bevelled) margins, in which the cancellous tissue of the diploe¨ is exposed and with no tissue reaction. WLC74 does have some remodelling and smoothing of the diploe¨ and these may be an indication of the long standing, slow progression of the lesions which again goes against a more aggressive malignant carcinoma as the cause. Marks & Hamilton (2007) presented the skeletal pathology of a modern, untreated case of metastatic carcinoma from the breast and the lytic lesions in the skull are very similar to that of WLC74 study although some are considerably larger in their specimen. Marks & Hamilton (2007) present the skull with lytic lesions ranging from small (60 mm) with some remodelling of the scalloped margins. The Int. J. Osteoarchaeol. 22: 731–739 (2012)

736 inner table contour is retained in both cases and the outer table borders are elevated and remodelled. Remodelling has also filled the diploic bone at later stages. No mention is made of an outward bevelling of the diploe¨ like in the largest lesion of WLC74, however, the similarities are strong. Two other diseases considered by Marks & Hamilton (2007) were multiple myeloma (discussed above) and Langerhans’ cell histiocytosis. Langerhans’ cell histiocytosis (LCH) again leads to lytic lesions of the cranial vault (Ortner, 2003). Much of the modern clinical information regarding LCH is in regard to children as most LCH is diagnosed in those less than 15 years of age (Azouz et al., 2005), but diagnosis can be made in adulthood and childhood cases of LCH can persist into adulthood (Howarth et al., 1999). Eighty per cent of the lesions in children belong to the eosinophilic granuloma type which is the localised benign form, but there are forms that can resemble a malignant disease (Stockschlaeder & Sucker, 2006). Lesions of LCH in the skull are often sharply defined, ‘punched out’ holes (round or oval) with welldefined margins, although, because the inner and outer tables can be differentially affected, a bevelled appearance to lesions may occur (Azouz et al., 2005). Opinions differ as to the presence of reactive sclerosis and marked versus undefined margins (cf. Stull et al., 1992; Ortner, 2003; Azouz et al., 2005). The margins are quite well defined in WLC74 and Stull et al. (1992: 807) believe this would reflect lesions that were of a less aggressive form, perhaps more of a chronic nature, and in more well established lesions the margins become more ‘‘sharply circumscribed’’. There seems to be some agreement that no periosteal reaction is seen in skull lesions although there may be in other bones in LCH (Stull et al., 1992; Ortner, 2003; Azouz et al., 2005). There is some reactive bone in some WLC74 lesions that does indicate increased vascularity, particularly in Type 2 lesions (Figures 4 and 5) which goes against a diagnosis of LCH. Stull et al. (1992: 809) describe how ‘‘(t)he uneven destruction of the outer and inner cranial table results in a beveled-edge or double-contour appearance’’ which is evident in WLC74. Differential diagnosis between osteolytic metastatic carcinoma, multiple myeloma and Langerhans cell histiocytosis has long been recognised as difficult and many studies have presented this dilemma (e.g. Gregg et al., 1982; Strouhal, 1991; Haidle, 1995; Aufderheide & Rodriguez-Martin, 1998; Ortner, 2003; Melikian, 2006; Marks & Hamilton, 2007). In light of all the evidence, the lesions of WLC74 female cranium fit most comfortably with a diagnosis of either LangerCopyright # 2010 John Wiley & Sons, Ltd.

K. M. Domett and H. R. Buckley hans cell histiocytosis or metastatic carcinoma. Multiple myeloma can be eliminated as the lesions are much larger than is typically present in multiple myeloma and WLC74 does not have the typical moth eaten, punched out appearance. There are a number of features that are consistent with both LCH and metastatic carcinoma. Both diseases can have lesions of variable size with a varying degree of remodelling depending on the aggressiveness of the disease. Lesion edges of metastatic carcinoma are typically denticulated or craggy with scalloped margins as is seen in some of the WLC74 lesions (Figures 4 and 5) while chronic lesions in LCH have more defined margins, with or without sclerosis which is also seen in some of the WLC74 lesions (Figure 3). In favour of an LCH diagnosis, and in particular against a diagnosis of malignancy, is the presence of remodelling of some of the lesions, not commonly seen in metastatic carcinoma. If we accept a possible diagnosis of LCH, the question is then raised as to which type of LCH WLC74 might have suffered from: Letterer–Siwe disease, Hand–Schu¨ller–Christian disease and eosinophilic granuloma. While the clinical manifestation of each disease is clearly different, the bone lesions are typically quite similar, making a diagnosis from bone alone, quite challenging (Ortner, 2003), especially considering only the cranium has been preserved in this case. A tentative diagnosis may be possible by observing the distribution of lesions and the age of the individual. Letterer–Siwe disease is unlikely to be the cause in this case study as it typically affects very young children and is often fatal (Ortner, 2003). Hand–Schu¨ller–Christian disease is also most common in children but can occur in young adults and can have varying outcomes. Eosinophilic granuloma is the most common type affecting children and young adults and is most often not life threatening (Ortner, 2003). The cranial vault is the most commonly affected bone in all three LCH types. Ortner (2003) reports that Hand–Schu¨ller–Christian disease more often shows multiple, confluent cranial lesions (and has also been named multifocal eosinophilic granuloma (Mazabraud, 1998 cited in Oxenham et al., 2005)) while eosinophilic granuloma commonly leads to a solitary lytic lesion with a bevelled edge. Given the absence of the postcranial skeleton, it is deemed inappropriate to take this differential diagnosis any further than a tentative case of LCH. The aetiology of LCH is still elusive and ranges from inflammatory, viral or neoplastic aetiologies and immune system disorders (Kilpatrick et al., 1995; Howarth et al., 1999; Azouz et al., 2005). Int. J. Osteoarchaeol. 22: 731–739 (2012)

Large Lytic Cranial Lesions It is also possible that both LCH and metastatic carcinoma coexisted in this individual. Sufferers of LCH in the modern literature have been noted to also have various other neoplasms (Howarth et al., 1999).

Discussion The presence of such large and diffuse lesions has not previously been reported in late prehistoric mainland Southeast Asian skeletal remains. In fact, studies detailing any non-trauma related pathology in the region make a short list (Douglas, 1996; Tayles, 1996; Tayles et al., 1998; Pietrusewsky & Douglas, 2002; Tayles & Buckley, 2004; Oxenham et al., 2005). This is a reflection of the rarity of pathological specimens and the relatively small number of skeletons excavated (