Circulatory, Reticuloendothelial, and Hematopoietic Disorders

Chapter 14

Circulatory, Reticuloendothelial, and Hematopoietic Disorders Anne L. Grauer Loyola University Chicago, Chicago, IL, United States

CIRCULATORY DISORDERS This chapter reviews a wide array of diseases linked loosely by the structure, function, and constituents of the circulatory and immune systems. As with many diseases, but especially with those classified as vascular (see Ragsdale and Lehmer, 2012), the causes of disruption vary appreciably, extending from genetic to infectious etiologies. Hence, while a wide range of conditions are included within this chapter, some, such as osteochondritis dissecans or hypertrophic osteoarthropathy (HOA), could comfortably fit within other disease categories. Furthermore, because of the circulatory link between most of the disorders in this chapter, determining the exact etiology of a particular lesion is often difficult, if not impossible. In paleopathological contexts, rigorous differential diagnosis must be employed, as careful attention to the location and anatomical details of the pathological bone and nearby tissue will be crucial in formulating a diagnosis. The following discussion is intended to highlight the diversity of circulatory, reticuloendothelial, and hematopoietic disorders, and call attention to some of their most common manifestations, or manifestations more likely to be encountered in human archeological remains.

Blood Supply of Bones The human skeletal system is heavily reliant on the circulatory system to supply oxygen, nutrients, minerals, and regulatory factors to cells, and to eliminate carbon dioxide, acid, and other metabolic waste products (Marenzana and Arnett, 2013). Experiments on animals suggest that between 5% and 15% of cardiac output is received directly by bone tissue, varying by animal, bone type, and method of detection (Ray et al., 1967; Gross et al., 1979). In spite of these variances, the vascularization of bone is

relatively consistent (Ramasamy, 2017), and adequate blood supply is an indispensable basis of bone growth and maintenance (Brooks and Revell, 1998: 3). Clinical studies of the arterial anatomy of bones have begun to identify patterns of vascularization that may lead to a higher risk for circulatory disturbance and eventually necrosis (Johnson et al., 2004). Most circulatory disturbances in archeological skeletal remains appear on long bones. For these bones, there are four separate arterial inlets: a nutrient artery of the diaphysis, periosteal arteries, metaphyseal arteries, and arteries for the epiphysis. In the diaphysis, one or more nutrient arteries enter the cortex through a grossly visible nutrient canal and divide into ascending and descending branches in the medullary cavity, supplying blood to the cortex and marrow. Periosteal arteries, themselves reliant on surrounding tissues, supply blood to the periosteum and shallowly penetrate the cortex. In the metaphysis, several smaller nutrient vessels enter through the cortex around the circumference of the bone, supplying blood to the metaphyseal cortex and marrow. Epiphyses have several small arteries, which branch from a vessel that also supplies the joint capsule and the synovium. During the growing period, the growth plate completely isolates the vascular supply of the metaphysis and the epiphysis. This structure explains why many diseases that occur during growth and development do not cross the growth plate (physis). After closure of the growth plate, some connections between the two systems are established, but the circulation, to a large extent, remains separate. The intraosseous arteries, which are enclosed in rigid compartments shielded from external pressure, are usually thin walled. This is particularly true of the arterioles. The diaphyseal cortex is, in part, supplied by ramifications of the nutrient vessels and partially by the periosteal vessels. The relative contribution of each of these two systems

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varies in different portions of the same bone. The epiphyseal vessels, which form a system of arcades beneath the articular cartilage, contribute to the nutrition of the cartilage during the growing period, before formation of a more or less solid subchondral bony plate. Cortical bone also has vascular supply through the Haversian and Volkmann canals, which connect Haversian canals and also enter directly from the periosteum. Cancellous bone trabeculae are usually avascular and depend on the vasculature of the marrow spaces for nutrition. The sinusoidal veins of the marrow are numerous, thin walled, and in hematopoietic marrow, wide. They collect into a large, thin-walled vein running lengthwise in the medullary canal. The venous return in part follows the nutrient artery, but also exits through multiple, circumferentially located venous outlets in the metaphyseal area. The epiphyseal venous return drains into that of the adjacent joint capsule. In smaller and cancellous bone, the blood supply is less complicated, except for bones that have growth plates, which always lead to separate epiphyseal and apophyseal vascular territories, at least during the growing period. The vertebral bodies show a radiant arrangement of larger veins, which converge medially and pass through two foramina close to the midline of the posterior surface of the vertebral body. These segmental veins join the longitudinal vertebral plexus in the spinal canal, which is significant in the predilection of spinal elements in infection and malignancy. The diploe¨ of the cranial vault likewise shows large interconnecting venous channels, which drain through the parietal and mastoid emissary foramina, but also have some connection with the large intracranial venous sinuses through small openings in the inner table.

Osteonecrosis Osteonecrosis (osteo 5 bone, necrosis 5 death) is a general and widely used term referring to the irreversible death of bone cells due to reduction or loss of blood supply, leading to the destruction of bone architecture. While synonyms such as avascular, aseptic, or ischemic necrosis can lead to confusion, current usage of the term avascular necrosis (AVN) tends to refer more specifically to lesions affecting the epiphyses and subchondral bone, while bone infarct is used when the metaphysis or diaphysis is affected (Fotiadou and Karantanas, 2013). Loss of blood supply, regardless of anatomical area, reduces (hypoxia) or eliminates (anoxia) tissue and cellular access to oxygen. The length of survival of bone cells following reduced oxygenation varies relative to the severity of the circulatory deficiency, but complete loss of oxygen results in bone cell death after about 12 48 hours (Sweet and Madewell, 1995: 3447).

The etiology and pathogenesis of osteonecrosis is complex and varied. For instance, osteonecrosis can be the result of trauma (Bachiller et al., 2002; Kain and Tornetta, 2015; Keating, 2015), but has also been associated with hemoglobinopathies such as sickle cell disease (Hernigou and Daltro, 2014), alcoholism (Jacobs, 1992; Takatori et al., 1993), infections such as osteomyelitis, and a long list of other conditions (Assouline-Dayan et al., 2002). Table 14.1 offers conditions that are clinically associated with osteonecrosis and are relevant to paleopathology. The clinical recognition of idiopathic osteonecrosis suggests that impairment of blood supply need not be due to a single disruption event, but rather may be associated with a repeated interruption of revascularization (Takashi and Yoshikatsu, 1992).

TABLE 14.1 Conditions Associated With the Onset of Osteonecrosis Relevant to Paleopathology Congenital Congenital hip dislocation Hereditary dysostosis Legg Calve´ Perthes disease Environmental/behavioral Alcoholism Obesity Hematological Sickle cell disease Thalassemias Hemophilia Infectious Osteomyelitis Meningococcemia Septic arthritis Septic emboli Inflammatory Pancreatitis Idiopathic Metabolic/endocrinological Chronic renal failure Cushing disease Gaucher disease Gout Hyperparathyroidism Rheumatological Rheumatoid arthritis Ankylosing spondylitis Systemic lupus erythematosus Traumatic Fracture/dislocation Burns Frostbite Keinbo¨ck disease Ko¨hler disease

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In spite of our growing knowledge of bone vascularity and microstructure, the pathogenesis of osteonecrosis remains unclear (Ma et al., 2017). In part, this is due to the multifactorial etiology of reduced flow to bone tissue. Pathogenic contributors to osteonecrosis include arteriopathy and intramedullary hemorrhage, fat embolism, intravascular coagulation, intraosseous hypertension, and fat-cell hypertrophy (Abraham and Malkani, 2004). Current research tends to focus on the association between necrosis and modern treatments, such as surgical intervention and the use of corticosteroids and bisphosphonates. However, it appears that irrespective of the etiology of osteonecrosis, hypoxia activates mature osteoclasts and inhibits the function of mature osteoblasts (Arnett, 2010), and that apoptosis of osteoblasts and osteocytes is a key constituent of the pathogenic pathway to osteonecrosis (Kaushik et al., 2012). Skeletal morphology and biomechanics factors are also correlated with the presence of the condition, as microcracks and fatigue fractures develop alongside bone remodeling, compromising bone integrity (McFarland and Frost, 1961; Yang et al., 2002). Trauma, or fracture-induced osteonecrosis may provide the most straightforward pathogenic process, as direct interruption of blood flow due to arterial damage or hemorrhage directly compromises the oxygenation of bone tissue. In infarction, larger areas of fatty bone marrow and the intervening bone trabeculae undergo necrosis, presumably due to interruption of blood circulation. The lesion is most frequently observed in the long bones of the extremities. The areas involved are principally the diaphyseal and metaphyseal marrow of the femur, tibia, and humerus. An infarction in the medullary space of a long bone undergoes mineralization at the interface between living and dead marrow. The living fat tissue at the margins of the infarct forms a mineralized margin surrounding it (Milgram, 1990: 963). Newly formed bone margins are radiographically visible as a circumscribed lesion, often up to 10 cm in length, showing a radiodense shell around the whole lesion and between its individual components (Fig. 14.1). There is little or no change in the overlying cortex. It is unknown whether mineral deposits of this type can be preserved and macroscopically identified in archeological material. Further complicating recognition and diagnosis in human archeological remains is the infiltration of soil particles into the marrow cavities of interred bones, creating areas of radiodensity that may mimic marrow infarction radiographically. Trauma-induced avascular (ischemic) necrosis of the epiphyses commonly affects the head of the femur, humerus, and talus. Importantly, however, the presence of traumatic injury and its subsequent blood flow interruption does not invariably lead to osteonecrosis (Hertel et al., 2004). Ma et al. (2017) point out that clinically,

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FIGURE 14.1 Histological preparation demonstrating a bone infarct in the distal femur. Note the central lesion surrounded by a darker-staining margin (arrow) where mineralization has occurred at the boundary with living tissue. Adult; courtesy of Dr. Bruce Ragsdale, M.D., Central Coast Pathology Associates, San Luis Obispo, California.

1 3 years can pass before postsurgical symptoms of trauma-induced osteonecrosis develop in patients, calling into question the singular role that blood flow disturbance plays in the pathogenesis of the condition.

Paleopathology Given the multifactorial causes and diverse etiology of osteonecrosis, it is not surprising that its presence is noted in the paleopathological record. With or without clear knowledge of the etiology, osteonecrosis may have occurred as early as the Mesozoic in marine reptiles (Surmik et al., 2017) and has been reported in a Late Cretaceous dinosaur (Anne´ et al., 2016). Its presence in humans reaches deep into antiquity, associated with a wide range of etiologies. The mummified remains of Tutankhamun (KV62), dating from 1333 to 1324 BC, display necrosis of the left second and third metatarsals,

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which has been associated with Ko¨hler disease and perhaps malaria (Hawass et al., 2010). A male skeleton from 1st- to 3rd-century Kazakhstan displays ankylosed carpals suggestive of traumatic AVN (Schwarz and Gresky, 2016). In North America, skeletal remains recovered from a prehistoric Late Mississippian site (AD 1540 1650) present multiple joints affected by AVN, the etiology of which remains unknown (Johnston et al., 2015). Careful consideration of the clinical literature provides important insight into the recognition and interpretation of osteonecrosis in the paleopathological record: 1. It is clear from the clinical literature that osteonecrosis develops from both extraosseous and intraosseous abnormalities (Assouline-Dayan et al., 2002; Seamon et al., 2012). 2. Paleopathological comparisons to modern studies must be made cautiously. Clinically reported frequency rates are influenced by modern surgical procedures and pharmacological intervention (Kaushik et al., 2012), type of imaging techniques employed (Steinberg and Steinberg, 2004), and the patient sample (Mont et al., 2010). 3. Sole reliance on macroscopic evaluation can compromise paleopathological diagnosis. Initial stages of the disease process are first recognizable histologically and radiographically, with macroscopically recognizable cystic and/or sclerotic changes occurring later in the disease process (Steinberg et al., 1989). 4. Predicting the behavioral effects (pain, change of gait, etc.) of osteonecrosis on the individual warrants caution. Radiographic signs of necrotic fibrovascular change, including porosis, sclerosis, or cysts (which might be macroscopically recognizable), can be clinically asymptomatic (Marcus et al., 1973; Enneking, 1997), and at times are unexpectedly identified contralateral to the area presenting pain (Mont et al., 2010). 5. For all conditions linked with circulatory disturbance, clinically derived epidemiological data must be evaluated carefully (Mays, 2017). Clinical samples, like all samples, are skewed; being based on selected patient records. For necrotic conditions, with its multifactorial etiologies, isolating an environmental cause (such as socioeconomic) from genetic, developmental, or infectious causes can be impossible.

Necrosis of the Femoral Head Necrosis of the femoral head is differentiated frequently as traumatic or nontraumatic in origin (Assouline-Dayan et al., 2002). In cases of traumatic untreated subcapital or transcervical fracture of the neck of the femur, the progression to aseptic necrosis of part or all of the femoral head can be expected (Fig. 14.2). Fielding (1980), in a

FIGURE 14.2 Aseptic necrosis of the femoral head. (A) Proximal right femur, anterior view, showing collapse and cavitation of the femoral head with a sequestrum of necrotic bone (arrow). (B) Radiograph showing reactive osteosclerosis on the border of living and dead bone. Sixtynine-year-old male with bilateral aseptic necrosis of the femoral head for several years; USPHS surgical specimen 2427, 1975; courtesy of Dr. Bruce Ragsdale, M.D., Central Coast Pathology Associates, San Luis Obispo, California.

review of the efficacy of the telescoping Pugh nail in mitigating the onset of necrosis, reported that prior to 1935, 78% of patients with femoral head fractures developed necrosis in spite of the use of manipulation and spica casts. As osteopenic or osteoporotic femoral bone is vulnerable to fracture, adult women of advanced age are particularly susceptible to femoral head necrosis (Fondi and Franchi, 2007). The femoral head is vulnerable to necrosis due to the arrangement of the blood supply. The medial and lateral femoral circumflex arteries, which rest inferiorly, branch into multiple ascending cervical arteries supplying the inferior aspect of the head. The foveal artery within the ligamentum teres vascularizes the femoral head superiorly. In cases where femoral head fracture is survived for a considerable period of time, inactivity osteoporosis is characteristically present in the surviving part of the

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femoral head and neck, whereas the necrotic portion maintains the trabecular pattern present at the time of fracture if no revascularization and new bone deposition has occurred. The necrotic portion appears dense in radiographs due to inactivity atrophy and osteoporosis in the adjacent surviving bone, the deposition of calcium into the necrotic tissue of the fatty marrow, the compression of dead bone trabeculae into a smaller area during collapse, and the deposition of new bone on dead bone in the process of repair. Traumatic AVN of the femoral head is also associated with hip dislocation. This is especially true in cases of posterior dislocation (Kain and Tornetta, 2015). In these instances, the ligamentum teres is often torn, compromising the blood supply to the medial third of the femoral head. The femoral head may become necrotic and demarcated as a sequestrum surrounded by a sclerotic rim on its base, resembling a focus of osteochondritis dissecans. Atraumatic osteonecrosis is a perplexing condition affecting any joint, but most commonly found in the hip (Johnson et al., 2014). Its presence was rarely reported prior to 1960, but has increased appreciably, associated with the growing use of corticosteroid and bisphosphonate treatment and the clinical recognition of alcoholism (Mont et al., 2010). Unlike necrosis associated with trauma, atraumatic necrosis of the femoral head is more commonly found in younger male patients between the ages of 30 50 years old (Patrascu et al., 2017; Liu et al., 2017). The necrotic bone usually appears asymptomatically in the weight-bearing area of the femoral head, beneath the articular cartilage. Joint shape plays a considerable role in the distribution of lesions. Divergent forces of concave surfaces (such as the acetabulum) lead to increased thickness of subchondral bone, and convergent forces of convex surfaces (such as the head of the femur) lead to collapse of the necrotic region due to subchondral fatigue (Simkin, 1980; Abraham and Malkani, 2004). The macroscopic and gross radiologic appearances of atraumatic necrosis are similar regardless of the etiology, known or unknown. Sickle cell anemia, Gaucher’s disease, and systemic lupus erythematosus, a disease of the connective tissue of the body, for instance, appear as unilateral or bilateral necrosis of the femoral head (Mont et al., 2010).

Paleopathology Reports of femoral head necrosis are infrequent in the paleopathological literature. This may be, in part, due to taphonomic complications, which compromise our ability to recognize the condition in skeletal remains. However, an example of a possible case is seen in a proximal fragment of a left femur (Fig. 14.3) excavated in a Native American site in Arkansas (NMNH 255142). The

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archeological age is uncertain. Most of the superior portion of the femoral head was destroyed antemortem, creating two large confluent depressions. The smallest of these is superior, lateral, and continuous with the femoral neck. The largest depression involves about one-half the area of the femoral head. There has been considerable bony reaction in the depressions, in which the exposed trabeculae have become greatly thickened, indicating a long-standing condition. On the anteroinferior margin of the articular surface there is a bony projection about 1 cm that extends inferiorly. There is noticeable periosteal bone deposition on the femoral neck that is suggestive of a low-grade inflammatory condition. This raises the possibility of a septic condition that contributed to the necrosis of the femoral head. However, periosteal reaction to an aseptic inflammation arising from trauma is also possible.

Legg Calve´ Perthes Disease and Slipped Femoral Capital Epiphysis Legg Calve´ Perthes disease is an idiopathic condition characterized by aseptic necrosis of the femoral head, resulting from disruption of blood supply to the epiphysis. While the etiology remains unknown, delayed bone age in children 4 9 years old, might lead to reduced size of the ossific secondary growth center in comparison to the cartilaginous component of the epiphysis, rendering traversing blood vessels more vulnerable to mechanical compression and damage (Little and Kim, 2011). Boys are diagnosed 5 times more often than girls, with equatorial countries exhibiting the highest incidence of the disease (Chaudhry et al., 2014). A socioeconomic correlation, with “underprivileged” populations displaying higher frequency rates, suggests a strong environmental component to this condition, rather than a genetic predisposition (Hall et al., 1983) In the course of the disease, the relative radiodensity of the necrotic epiphysis increases when contrasted with focal radiolucency of the area of the femoral neck that borders the growth plate. Later, the head flattens due to a combination of compression fracture and lack of endochondral growth. The basal bulge of the flattened head leads to subperiosteal and endochondral bone formation as well as thickening of the femoral neck. The end result, after revascularization, is a mushroom-shaped femoral head with a flared margin but with no significant shift in the center of the femoral head relative to the axis of the femoral neck. Early severe degenerative arthritis modifies the appearance and can make differentiation from the end stage of slipped capital femoral epiphysis difficult or impossible. In the acute stage, differentiation from tuberculous coxitis and from aseptic necrosis in Gaucher’s disease may be uncertain in dry bone.

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FIGURE 14.3 Necrosis of the femoral head of a left femur fragment. (A) Anterior view. (B) Radiograph of anteroposterior view. Note the radiodense sclerosis inferior to the necrotic defect. (C) Anterosuperior view of reactive bone. (D) Detailed view of reactive bone that shows the thickened trabeculae. (NMNH 255142.)

Slipped femoral capital epiphysis has a different pathogenesis than Legg Calve´ Perthes disease, although trauma is a common contributing factor. The condition presents as a stress fracture between the metaphyseal side of the growth plate and the neck of the femur. This allows medial posterior and downward displacement of the head of the femur and, not uncommonly, leads to some degree of aseptic necrosis in the epiphyseal bone. Because the growth plate remains with the epiphysis, the bone of the epiphysis is minimally altered, except in cases with extensive aseptic necrosis. The proximal end of the femoral neck, however, shows irregularities due to the fracture as well as subsequent abrasion and resorption. In dry bone, because the joint capsule and the cartilage are missing, the appearance of the proximal surface of the femoral neck is the main clue. With healing, the head, united with the neck in the slipped position, shows some dislocation of the center of the head toward the axis of the neck. In contrast, in Legg Calve´ Perthes disease, the neck is always short and thick, reflecting both attrition in the fracture area and loss of endochondral growth for varying

lengths of time. Occasionally, upward dislocation of the femur is observed to stimulate a new “acetabulum” on the lateral aspect of the ilium, while the head is held in the anatomical acetabulum by the ligamentum teres (Schinz et al., 1951 1952(1): 450 454). Similar to Legg Calve´ Perthes disease, in slipped capital femoral epiphysis early and severe degenerative arthritis complicates diagnosis. Slipped capital femoral epiphysis most commonly occurs in adolescents between the ages of 9 and 16 years old and is significantly more common in boys than in girls (Lehmann et al., 2006). The condition frequently (B20% 35%) occurs bilaterally (Loder, 1996; Loder et al., 1993). While there might be evidence of an underlying genetic factor, given that African-American and Hispanic children in the United States have been reported to suffer from the condition more frequently than those of European descent (Lehmann et al., 2006), a large international multicenter study found children of European decent with the highest rate of occurrence (Loder, 1996). The message here is that prevalence rates within and

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between populations, for virtually all pathological conditions, are contingent upon statistical sampling and the parameters of the study. Regardless of ancestry, it appears that trauma, the adolescent growth spurt, and obesity are contributing factors to the development of the condition (Murray and Wilson, 2007).

Paleopathology A right femur recovered from the Valley of Chicama in Peru provides a possible example of Legg Calve´ Perthes disease. This case is from a miscellaneous group of femora all accessioned as NMNH 265331 at the National Museum of Natural History, Washington, DC. Both the age of the individual and the antiquity of the bone are unknown. The diaphysis, distal metaphysis, and subchondral bone are normal. Part of the femoral head was damaged postmortem, although enough remains to indicate the nature of the pathology. There is a large circumscribed porous lesion covering more than half of the remaining joint surface of the femoral head (Fig. 14.4). This porosity has completely obliterated the depression for the ligamentum teres. There is a depressed groove at the boundary with normal bone. The margins of the joint surface are characterized by exuberant bony overgrowth that creates a mushroom-like appearance. This overgrowth extends well over the femoral neck. There are some bony outgrowths on the superior portion of the neck, but otherwise the neck appears normal.

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The radiographs show considerable thickening of the trabeculae under the porous lesion. This is indicated by a radiodense zone on the medial aspect of the femoral head. There are small radiolucent areas in the lateral head region and in the femoral neck. There has been considerable reduction in the mediolateral diameter of the head. Added to the marked overgrowth at the joint margins, this observation creates the false impression that the head was forced into the femoral neck. However, the normal length of the neck and the overgrowth of the joint margins make it clear that the pathological process involves collapse of the superior medial portions of the femoral head, followed by bony overgrowth on the articular margins. A possible case of bilateral Legg Calve´ Perthes disease is seen in the skeleton of an adult male from the site of the medieval hospital of St. James and St. Mary Magdalene, Chichester, England (Fig. 14.5). The skeleton is incomplete, but there is no evidence of significant osteoarthritis on any of the other bones that are present, including most of the bones of the lower extremity. The femoral neck appears to be shorter than normal, which is a feature that favors a diagnosis of slipped capital femoral epiphysis. However, both femoral heads seem to be in the correct anatomical position, which favors a diagnosis of Legg Calve´ Perthes disease. This case illustrates the diagnostic problems that can be encountered in differential diagnosis of disease in archeological human remains. Helpful criteria for differentiating Legg Calve´ Perthes disease and slipped capital femoral

FIGURE 14.4 Legg Calve´ Perthes disease in a right femur. (A) Posterior view. Notice extensive development of periarticular lipping. (B) Radiograph of anteroposterior view. Note the relatively normal length of the femoral neck. (C) Medial view of the femoral head. Note the enlargement in diameter and extensive porous degeneration. (Chicama, Peru; NMNH 265331.)

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FIGURE 14.5 Bilateral Legg Calve´ Perthes disease in a skeleton from the site of the medieval hospital of St. James and St. Mary Magdalene, Chichester, England. (A) Anterior view of the right and left proximal femur. (B) Anterior view of the pelvis. Note the extensive marginal bone formation of the right and left acetabulum. (C) Detail of the right acetabulum showing subchondral bone remodeling in response to the destruction of articular cartilage and marginal bone formation. (Adult male; UB C-13.)

epiphysis can be seen in a right femur from the miscellaneous femora from Chicama, Peru (NMNH 265331). The maximum length of this femur is 370 mm, although this value is misleading due to the inferior displacement of the femoral head. The diaphysis, distal metaphysis, and the joint surface are normal except for a moderate degree of mid-diaphyseal, anteroposterior flattening, which is due in part to the abnormal gait induced by the defective femoral head. The femoral head is displaced inferiorly (Fig. 14.6) so that the superior margin is about 15 mm lower than the greater trochanter. There is no evidence of porosity. Indeed, the joint surface is smooth and intact. The depression for the ligamentum teres is well defined, unlike that of the head in Legg Calve´ Perthes disease. Its position relative to the joint surface is much nearer the inferior, posterior margin of the joint surface than normal. The ligament attachment was maintained after the epiphysis slipped. Growth continued in the epiphysis, but occurred predominantly on the anterior and superior aspects. Ultimately, the head reunited with the neck. The femoral neck is abnormally short and thick due to the loss of growth plate activity when the epiphysis slipped. The radiograph shows an even, well-organized, trabecular

structure. It is possible to identify the growth plate of the femoral head in the film and determine that the mediolateral diameter of the head is relatively normal. In marked contrast with Legg Calve´ Perthes disease, the femoral neck is almost nonexistent on the superior aspect and greatly shortened inferiorly. Another example of slipped epiphysis is seen in a left femur of a specimen from the Historical Museum in Chur, Switzerland (HMCS GR 1582). The specimen is from the archeological site at Bonaduz in Canton Grisons, Switzerland. The epiphysis has slipped inferiorly and the femoral neck is shortened (Fig. 14.7).

OTHER DISORDERS ASSOCIATED WITH OSTEONECROSIS The following two diseases illustrate the variation in pathogenesis that is associated with a deficiency of vascular supply. Trauma seems to be a common link, but the sequence of events that lead to the diseases and the relationship between trauma and vascular insufficiency remain uncertain.

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FIGURE 14.6 Slipped capital femoral epiphysis in a right femur. (A) Anterior view displays inferior displacement of the capital epiphysis. (B) Radiograph of the anteroposterior view demonstrating the shortened femoral neck. (Adult male, NMNH 265331.)

FIGURE 14.7 Slipped capital femoral epiphysis in a left femur. (A) Anterior view. Note that the superior articular surface is below the level of the greater trochanter. (B) Posterior view. (HMCS GR 1582.)

Ko¨hler’s Disease of the Tarsal Navicular The navicular bone is in a key position in the vault of the foot. Disruption of the blood supply to the ossification center may be impaired in the growing child, leading to aseptic necrosis. This is usually expressed as flattening of the bony center, reduced size, and increased density in radiographs. Flattening may be due to compression of the

necrotic bone and/or an effect of arrested endochondral ossification in the necrotic area (Fig. 14.8). Skeletal repair can occur secondary to revascularization. The disease is uncommon, usually presents unilaterally, and occurs more often in males than in females. The onset of the disease is often noted between 4 and 5 years of age, first detected by a noticeable limp (Khoury et al., 2007; Shastri et al., 2012).

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FIGURE 14.9 Radiograph of Kienbo¨ck’s disease of the carpal lunate bone showing areas of alternating density and lucency. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

FIGURE 14.8 Radiograph of Ko¨hler disease of the left pedal navicular showing flattening, reduction in size, and increased density associated with necrosis. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

Freiberg’s Disease of a Metatarsal Head The gross manifestation of this disease is an irregular depression in the subchondral bone of the distal second metatarsal, although other metatarsal heads can be affected. The metatarsal is somewhat shortened, the head is broadened transversely, and the distal portion of the metaphysis and diaphysis is abnormally enlarged due to the necrotic collapse of the cartilage and subchondral bone (Ko¨hler, 1923). The margins of the lesion tend to be sclerotic. Lesions are often unilateral rather than bilateral. Associated with the condition is a corresponding enlargement of the articular surface of the associated basal phalanx. Although the second metatarsal is usually the longest and bears the burden of pressure against the ground, perhaps leading to trauma, impaired vascularization and systemic disorders are also etiological factors (Carmont et al., 2009; Stanley et al., 1990). Importantly, other diseases, including erosive arthropathies, may produce similar bone abnormalities, but localization to the

second metatarsal, the presence of sclerotic margins, and bone remodeling, known to occur in Freiberg’s disease, can be cautiously used to eliminate diagnostic alternatives. The carpal lunate is the center of the proximal carpal chain, and thus tends to bear the brunt of mechanical impact transmitted to the radius. Repeated trauma results in disrupted vascular supply, subsequent necrosis, and fragmentation of the lunate. Radiologically, areas of increased density and lucency alternate, and in dry bone areas may actually be fragmented after the disappearance of interposed fibrous and cartilaginous tissue (Fig. 14.9).

OTHER DISEASES ASSOCIATED WITH TRAUMA AND VASCULAR DEFICIENCY Osteochondritis Dissecans Osteochondritis dissecans involves fragmentation of cartilage and, possibly, the underlying subchondral bone (Resnick et al., 1995: 2611), although subchondral bone may not participate in the abnormality in some cases. The prevailing consensus is that trauma is a major etiologic factor, although other factors including a defect in the development of the subchondral bone, depending on the joint affected, appear etiologically important (Schenck and Goodnight, 1996; Waldron, 2009). Classic osteochondritis dissecans is associated with true separation of a

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small sequestrum, typically triangular in profile view, consisting of articular cartilage and necrotic subchondral compact and cancellous bone. The onset of disease often occurs in adolescents and young adults, and appears more commonly in the lateral portion of the articular surface of the medial femoral condyle, and more commonly in males than in females (Kessler et al., 2013). Familial occurrence has been observed (Stougaard, 1964). In the course of the disease, the necrotic fragment may pass into the joint cavity and become a loose osteocartilaginous body, which often enlarges due to continuing growth of the surviving cartilage. The cartilage may calcify, but the bone fragment remains dead and unaltered in size and shape. The subchondral osseous defect of the condyle may close over with a thin layer of bone, but always remains a depression on the bony articular surface.

Paleopathology A number of cases of osteochondritis dissecans have been reported in archeological populations. Wells (1962, 1974) and Aufderheide and Rodriguez-Martin (1998: 81 82) provide a brief review of cases. A classic case of osteochondritis dissecans, however, is found in the skeleton of an adolescent from the medieval site of St. George’s Church (burial no. 81), Canterbury, England. This burial is curated at the Canterbury Archaeological Trust. The lesion occurs on the medial condyle of the right femur and includes both the subchondral bone fragment and the depression in the condylar surface that remained when the fragment was created (Fig. 14.10). Although the shape of the fragment corresponds generally to the defect on the condyle, it is larger, which indicates continued growth after its avulsion. More recent cases of the lesion in the archeological record are reported in an analysis of 140 skeletons from The Netherlands, dated to the early to mid-19th century, where 12.9% of the adults displayed pedal osteochondritis dissecans potentially associated with repetitive trauma caused by footwear (Vikatou et al., 2017).

Osgood Schlatter Disease The tibial tubercle is the site of the insertion of the patellar tendon. It develops from one or more apophyseal ossification centers that, during the growth period, are separated from the proximal tibial metaphysis by a cartilage plate. There is considerable variation in this process, but the powerful pull of the quadriceps may lead to partial avulsion of the tendon insertion accompanied by fragmentation of the apophyseal center (Gholve et al., 2007). The avulsed fragment may eventually fuse with the epiphysis and/or tibial metaphysis. However, the fragment may remain free and result in an abnormal flattened or

FIGURE 14.10 Osteochondritis dissecans in the distal right femur in a burial from the medieval site of St. George’s Church, Canterbury, England. (A) Inferior view with bone fragment in place. (B) Inferior view with bone fragment reflected. Note that the bone fragment diameter is greater than the diameter of the residual defect in the subchondral bone. This indicates possible continuing growth of the fragment and/or healing with partial closure of the defect in the subchondral bone. (14years-old; CAT burial no. 81.)

depressed surface of the anterior, proximal tibial metaphysis. The etiology of the disease includes mechanical, growth, and/or traumatic factors (Demirag et al., 2004).

Paleopathology A possible case of Osgood Schlatter disease is found in the miscellaneous long bones from Chicama, Peru (NMNH 265330-661). This specimen is a right tibia (Fig. 14.11) from a small adult. The archeological age is unknown. The diaphysis, distal metaphysis, and distal joint surface are normal. In the region superior to the tibial tubercle there is a flattened surface. Inferior to this abnormal surface is a large irregular spur that projects toward the knee joint and is a partially ossified patellar tendon that probably reflects the trauma associated with the abnormal flattened surface. Both medial and lateral to the spur are zones of periosteal reactive bone. These are

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FIGURE 14.11 Possible Osgood Schlatter disease of the tibial tubercle in a right tibia. (A) Anterolateral view displays the bony spur. Note the defect (arrow) inferior to the joint surface possibly the result of a crushing injury. (B) Radiograph of the mediolateral view of the proximal tibia. (NMNH 265330-661.)

well healed, indicating that the condition was not active at the time of death. The proximal joint surface of the tibia is abnormal. The bony surface for the attachments of the cruciate ligaments is poorly defined. The lateral and medial joint surfaces are poorly delimited. The medial joint surface extends posteriorly, creating an irregular surface. There is a sharply defined narrow depression 11 mm long, by 3 mm wide, and 4 mm deep on the anterior lateral edge of the lateral joint surface. Grossly, this defect appears to have resulted from a crushing injury to this portion of the joint. Reactive bony spurs in the region of the tibial tubercle and reactive bone deposition are compatible with Osgood Schlatter disease. DiGangi et al. (2010) have rigorously discussed the presence of extensive cartilaginous dysplasia in an individual from Mississippian period Tennessee. Here, avulsion of both the left and right tibial tuberosities is recognized as indicators of Osgood Schlatter disease.

cartilaginous and osseous endplates and its correlation with the adolescent growth spurt. Radiographic and skeletal signatures include narrowing of intervertebral disk space, endplate irregularity, kyphosis greater than 45 degrees of three or more vertebrae angled greater than 5 degrees, lengthening of the vertebral body, and the presence of Schmorl’s nodes (Fig. 14.12) (Ali et al., 2000). Histological studies note the disorganized endochondral ossification of the endplates (Lowe and Line, 2007). The etiology of the disease remains controversial (Palazzo et al., 2014). While Scheuermann believed that AVN led to endplate disruption and growth disturbance, recent research does not corroborate this assertion (Ippolito and Ponseti, 1981). The presence of a genetic link or predisposition has been noted (Damborg et al., 2011), but mechanical stress, both repetitive and acute, are consistently recognized as essential etiological factors (Palazzo et al., 2014).

Scheuermann’s Disease

Paleopathology

Scheuermann’s disease is a perplexing condition. Unlike many vascular disruptions affecting long and sesamoid bones, this condition impacts the growth plates and secondary ossification centers (annular epiphyses) of thoracic and lumbar vertebrae, often leading to kyphosis (Scheuermann, 1920, 1921). The disease is classified as a form of juvenile osteochondrosis due to alterations to the

A few cases of Scheuermann’s disease appear in the paleopathological literature. Early occurrences have been reported by Cook et al. (1983) on a Pliocene Australopithecine skeleton from Hadar, known colloquially as “Lucy” (AL-288), by Wells (1961) on a case from 1600 BCE Bronze Age England, by Anderson and Carter (1994) reporting on a case from Iron Age England, and

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the classic expression is a dense, “lumpy” surface (Fig. 14.13B and C). The new bone is usually thickest mid-diaphysis, tapering toward the metaphysis (Fig. 14.13A) and spares the epiphyses and tendon insertions. The new bone is first fibrous and later is remodeled into lamellar bone. The new bone may be separated from the original cortex by a thin, fibrous layer, and when fully developed, several millimeters thick at mid-diaphysis. In the late stages, the underlying cortex shows resorption, widening of the Haversian canals, and at times, endosteal resorption leading to widening of the medullary cavity (Fig. 14.13C). A considerable number of conditions lead secondarily to HOA (Yap et al., 2017). Pulmonary conditions, such as cancer of the lungs and pleura, cystic fibrosis, injury, and parenchyma, as well as compromised lung circulation stemming from cyanotic heart disease, have a recognized association with the presence of HOA. Nonpulmonary associations include gastrointestinal cancers, infections such as tuberculosis and irritable bowel disease, and cirrhosis of the liver. In children, bacterial and congenital heart diseases, along with chronic lung diseases, more commonly lead to HOA (Yap et al., 2017).

FIGURE 14.12 Scheuermann’s disease recognizable in a radiograph of thoracic vertebrae displaying narrowed and lengthened anterior bodies, and substantial endplate disruption appearing as undulating, interrupted endplate borders. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

most recently by Viciano et al. (2017) on a case from 3rd- to 4th-century Spain. The paucity of reported incidence is more likely due to the difficulty of diagnosing the condition in skeletal remains, rather than it being a reflection of the frequency of the disease in past populations. Vertebral bodies are often recovered with substantial taphonomic damage, which would be exacerbated, no doubt, by the effects of Scheuermann’s disease.

Hypertrophic (Pulmonary) Osteoarthropathy Hypertrophic (pulmonary) osteoarthropathy (HOA) is an uncommon secondary condition characterized by skin and periosteal proliferation. Clinically, three features are diagnostically key: periostosis of long bones, digital clubbing, and synovial effusion (Pineda and Martin-Lavin, 2013). For paleopathologists, the presence of periostosis serves as the only persistent indicator, as the other two manifest in soft tissues. In skeletal HOA, symmetrical diaphyseal periostitis appears commonly in the tibiae, fibulae, radii, and ulnae, and less commonly in other major long bones or tubular bones of the hands and feet (Fig. 14.13). The morphology of the periosteal bone formation varies, but

Paleopathology Given the osteoblastic nature of HOA, it is likely that bony remnants of the condition will be recovered from archeological populations. However, differential diagnosis of HOA is challenging. Periosteal reaction is one of the most common pathological conditions encountered in the archeological record and several pathological conditions cause these lesions. Careful attention to the type and distribution pattern of periosteal lesions is thus critical. In leprosy, for example, the lesions of the tibia and fibula usually are limited to the distal diaphysis, metaphysis, and epiphysis in contrast with the mid-diaphyseal distribution in HOA. The fact that HOA is a secondary condition further complicates attempts to diagnose the primary disease. Yap et al. (2017) and Flohr et al. (2018) warn against prematurely associating HOA with a pulmonary disorder. HOA is reported in prehistoric and historic archeological populations across a broad geographic range, and even in faunal remains (Lawler et al., 2015). Its etiology is frequently associated with pulmonary tuberculosis (Mays and Taylor, 2002; Masson et al., 2013), perhaps due to the rare skeletal involvement of other disorders. However, Assis et al. (2011) report from their sample of 125 identified individuals from the Coimbra skeletal collection that HOA was 3.41 times more common in individuals with recorded tuberculosis, suggesting a true association between the primary disease and the secondary condition.

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FIGURE 14.13 Hypertrophic osteoarthropathy. (A) Anterior view of the right tibia and fibula. (B) Detail of diaphyseal pathological bone formation demonstrating the “candle wax” morphology. (C) Cross-section of the fibula, enlarged to show periosteal bone deposition and cortical bone resorption. (D) Right radius and ulna displaying diffuse periosteal hyperostosis with pronounced vascular grooving. (E) Right foot, dorsal view. Note periosteal hyperostosis of metatarsals and phalanges. (58-year-old female with large, solitary metastasis of breast cancer in lung; IPAZ 6649, autopsy 1259, 1961.)

Aneurysmal Erosion An aneurysm is the abnormal dilation of a blood vessel caused by hereditary and acquired conditions. It commonly occurs in the aorta, brain, posterior knee joint, intestine, and spleen. The aorta, in particular, appears vulnerable to this abnormality, with rupture of the aorta, whether thoracic or abdominal, being fatal. Blood vessels, regardless of location in the body, produce pulsating

pressure on closely adjacent bones, leading to normal and abnormal vascular grooves on bony surfaces. An extreme case in point is the long-term effect of a large saccular dilatation of an artery (aneurysm) to bone. For instance, the ascending portion of the aortic artery is located immediately behind the manubrium of the sternum. Aneurysms in this area can cause defects of varying depths on the posterior surface of the manubrium. Complete round perforation of the manubrium can occur. Posteriorly, the

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FIGURE 14.14 Erosion of vertebral bodies by aortic aneurysm, probably arteriosclerotic. Note the multiple deep scalloping defects that partly show a thin layer of reactive bone. (A) Lateral view. (B) Anterior view. Note the resistance to erosion of the areas adjacent to disks. (FPAM, Jubila¨umspital 593.)

descending aorta is closely attached to the left side of the vertebral column. Aneurysms of this portion of the artery may erode impact several vertebral bodies with an emphasis on the left lateral portion of the vertebral body. Because cartilage does not resorb as readily as bone in response to pulsating pressure, deeply scalloped resorption defects occur on several adjacent vertebral bodies, while the endplates adjacent to the intervertebral disks are better preserved (Fig. 14.14). The predilection for the left side of the mid-thoracic vertebral bodies is clearly apparent in another modern case from the skeleton of a 68year-old male (Fig. 14.15). The left-sided focus and the marginal sclerosis in this condition provide some help in differential diagnosis from the many other diseases that can result in destructive lesions of the vertebrae. Although not creating as dramatic a bony response, internal mammary arteries are closely attached to the posterior surface of the ribs near the osteochondral junction. In congenital extreme narrowing of the aorta below the left subclavian artery (coarctation), the internal mammary arteries show marked compensatory dilatation. In this condition, deep pressure grooves are produced on the ribs near the osteochondral junctions. Aneurysms have been linked to heritable and/or spontaneous genetic mutations, such as those responsible for Marfan and Loeys Dietz syndromes (Gelb, 2006; Loeys et al., 2007). More commonly, they are associated with acquired conditions. Abdominal aortic aneurysms, for instance, are clinically associated with the presence of atherosclerosis, as older males display the condition more frequently than females (Norman and Powell, 2007). However, a recent epidemiological study, finding little association between individuals with atherosclerosis and abdominal aortic aneurysm, calls this etiology into

FIGURE 14.15 Scalloping defects Erosion of the central thoracic vertebral bodies on the left side by an aortic aneurysm. Note the reactive bone formation at the costovertebral joint margins. (65-year-old male; IPAZ 1006/56.)

question (Blanchard et al., 2000). Thoracic aortic aneurysms have been clinically associated with syphilis (Kunz, 1980; Jackman and Radolf, 1989).

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Paleopathology Convincing evidence of the presence of aortic aneurysm is well established in the paleopathological literature (Aufderheide and Rodriguez-Martin, 1998: 81) based carefully on the presence of relatively smooth-walled erosive lesions with minimal reactive bone located in anatomical areas in close proximity to arteries. Rigorous differential diagnosis is crucial in the evaluation of aneurysms, as cysts and diseases producing a lytic bony response must be considered. Ascribing a cause for this secondary condition is even more difficult. Taphonomic processes and incomplete recovery of skeletal material can greatly impede diagnosis. In spite of these obstacles, the antiquity of aneurysm has been associated with the presence of syphilis by Walker (1983) and Kelley (1979). More recently, a pre-Columbian skeleton dated to 210 BC, has been reported to display lesions associated with aneurysm and syphilis, offering implications for the origins of syphilis in the New World (Castro et al., 2016).

RETICULOENDOTHELIAL DISORDERS The reticuloendothelial system consists of the various cells of the body that primarily function to remove dead or abnormal cells, tissues, and foreign substances. Not surprisingly, the cells are highly phagocytic, and abnormalities either in the cells or in the biological mechanisms for controlling the cells result in disease. Reticuloendothelial diseases affect the human skeleton largely through abnormalities of the histiocytes, a type of macrophage. There are two general pathologic mechanisms involved in reticuloendothelial diseases. In one of these there is an abnormal accumulation of lipids within the histiocyte. The other mechanism involves a loss of control over the proliferation of histiocytes. Both can result in skeletal manifestations, although the primary pathology is in other tissues. There are very few reports of reticuloendothelial diseases in the paleopathological literature, in part because these diseases are uncommon, but also because some of the changes that occur in the skeleton resemble other diseases, making differential diagnosis challenging.

Lipid Storage Diseases Gaucher’s Disease Gaucher’s disease is the most common of the lipid storage diseases. It is, however, a relatively uncommon familial abnormality linked to multiple known autosomal recessive mutations that affect lipid metabolism. The presence of the mutations is associated with a deficiency of the enzyme glucocerebrosidase (Hruska et al., 2008). In this disorder, cerebrosides are accumulated in histiocytes (macrophages) of the reticuloendothelial system,

especially in the spleen, liver, lymph nodes, and bone marrow (Charrow et al., 2000). The disease is classified into three types: type 1, which is a chronic and nonneuronopathic form affecting all organs except the brain in adulthood (most frequently in Jews of Ashkenazi descent) (Grabowski, 1997); type 2, which is a fatal neuronopathic form affecting infants; and type 3, a chronic/subacute neuronopathic form affecting juveniles and young adults. Types 1 and 3 affect the skeletal system. Bone changes associated with the disease are due to the accumulation of cerebroside-laden histiocytes, called Gaucher cells, in bone marrow. The accumulation may be diffuse or in the form of nodular aggregates. The deposition, although widespread throughout the skeleton, does not involve all bones equally. Diffuse infiltration in hematopoietically active bones (vertebrae, sternum, ribs, pelvis, and cranial vault) is most common, but bone infarcts, AVN, lytic lesions, and fractures due to osteopenia or osteoporosis in other skeletal elements have also been associated with the disease (Mikosch and Hughes, 2010). The presence of Gaucher cells leads to a widening of marrow spaces and reduction of the number and diameter of bone trabeculae, giving a coarse, spongy appearance in radiographs and in dry bone. Focal concentrations of abnormal histiocytes may also result in cortical scalloping and thinning, with the periosteal surface remaining smooth. The long bones, most commonly the distal diaphysis and metaphysis of the femur, may become the seat of nodular and diffuse infiltration with Gaucher cells, resulting in a modeling defect and an abnormally enlarged bone diameter. Instead of the usual concave flare, the bone shows a straight contour or even a slightly bulging outline, giving rise to the descriptive term Erlenmeyer flask deformity (Fig. 14.16). This deformity can be due, in part, to inhibited modeling during the growth period or actual enlargement of the thin metaphyseal cortex in adult life. The nodular infiltration may also lead to complete trabecular resorption in the affected area, giving a lytic appearance in radiographs and a cystic defect in dry bone. Wenstrup et al. (2002) report that skeletal involvement appears as three processes: irreversible focal bone changes such as osteonecrosis and osteosclerosis, local bone change such as cortical thinning and long bone deformity, which appear adjacent to areas greatly affected by marrow involvement, and generalized osteopenia.

Niemann Pick Disease Niemann Pick disease is a rare, congenital, familial disorder of phospholipid metabolism that leads to progressive storage of phospholipids (mainly sphingomyelin) in the reticuloendothelial cells of the liver, spleen, lymph nodes, and bone marrow. Inheritance patterns suggest that multiple mutations are associated with the disease, all

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FIGURE 14.16 Radiograph of a juvenile distal femora displaying Gaucher’s disease with modeling during growth. Note the enlarged metaphyses. Courtesy of Dr. Morrie E. Kricun, M.D., Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA.

believed to be autosomal recessive (Simonaro et al., 2002). Three main types of Niemann Pick disease have been identified (A, B, and C), which vary in clinical manifestations, age of onset, and mutated gene. Type A appears more frequently in individuals of Ashkenazi Jewish decent, while type B is more common in individuals of Turkish, Arabic, and North African decent (Simonaro et al., 2002). Bone changes, including a reduction of the number and the size of trabeculae, cortical thinning of long bones, and the Erlenmeyer flask, appear in some long bones, rendering differential diagnosis from Gaucher’s disease difficult. However, the enlargement of the long bone metaphysis seems less severe than in Gaucher’s disease (Crocker and Farber, 1958: 82). Osteonecrosis is not associated with Niemann Pick disease. This means that collapse of the subchondral bone in long bone epiphyses does not occur. This, along with the absence of focal lytic lesions (Gildenhorn and Amromin, 1961), provides helpful distinctions in differential diagnosis. The generally poor health of affected infants may manifest itself in delayed appearance of secondary ossification centers. Superimposed deficiency in vitamins D and C may add features of rickets and scurvy to the picture.

Other Lipidoses Essential familial hypercholesteremia is a disorder of cholesterol metabolism linked to a genetic mutation. The condition is characterized by elevated blood cholesterol levels and often leads to tumor-like deposits of cholesterol in subcutaneous and periarticular connective tissues or

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tendons (xanthoma tuberosum). Observed erosive bone changes are believed to have an intraosseous origin (Bjersand, 1979). Lipid (cholesterol) granulomatosis (Erdheim Chester disease) is a rare disorder characterized by massive cholesterol deposition in the bone marrow and occasionally in other organs, but sparing the spleen. The condition remains asymptomatic into adult life. The reason for mentioning it here is that distinct bone changes have been demonstrated radiologically and anatomically (Dion et al., 2006). The most marked lesions were found symmetrically in the long bones of the forearms and lower legs. The changes consist of spotty and diffuse osteosclerosis, most pronounced in the metaphyseal area, but often involving the epiphysis. The diaphyseal cortex may be thickened, but shows widened Haversian canals. The changes extend into the bones of the hands and feet, most markedly so in the talus and calcaneus. The femur and humerus are less affected and the skull is normal. The sclerosis observed is due to both trabecular thickening and ossification of medullary cholesterol granulomas.

Langerhans Cell Histiocytosis (Histiocytosis X) Langerhans cell histiocytosis (LCH) was originally described as histiocytosis X (Lichtenstein, 1953). Recognition of the diagnostic significance of the abnormal histiocytes known as Langerhans cells has led to the more recent terminology for this disease. Langerhans cells are histiocytes that contain abnormal cytoplasmic granules. As macrophages, histiocytes are normally responsible for the removal of abnormal and dead cells. Recent studies using cell-specific gene expression profiling suggest that LCH arises from bone marrow-derived immature myeloid dendritic cells, rather than from epidermal Langerhans cells (Harmon and Brown, 2015). There are a number of classification systems used to categorize LCH. For paleopathological evaluation, however, the recognition of three clinical manifestations is germane: Letterer Siwe disease (disseminated multifocal multisystem LCH), Hand Schu¨ller Christian disease (multifocal unisystem LCH), and eosinophilic granuloma (unifocal LCH). Satter and High (2008) report a widely varying incidence of unifocal bone involvement in clinical reports ranging from 28% to 83% of patient cases, and multifocal involvement in 19% 28% of patients. Children display an overall higher incidence of bone involvement than adults. The common link between the three conditions is proliferation of histiocytes in various tissues and organs. Although bone lesions are similar in all three conditions, their distribution may vary. Bone lesions generally present as a central, purely lytic, lesion with or without sclerotic margins or reactive bone formation. The small

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lesions are round or oval and may coalesce, creating an undulating or “geographic” border (Fig. 14.17). In Letterer Siwe disease, multiple skull lesions are usually present, involving the cranial vault and base, especially the sphenoid. In some cases, facial bones are involved. In eosinophilic granuloma, the most common lesion is a solitary, purely lytic, round or oval defect in an area of the cranial vault, showing a beveled edge and, occasionally, a central sequestrum. In Hand Schu¨ller Christian disease, large, multiple, confluent cranial defects are often seen (Fig. 14.18). The lesions of the cranial vault, even after destruction of both tables, are usually devoid of periosteal reactive bone, although in some cases marginal sclerosis of a lytic focus may occur. In eosinophilic granuloma, destructive focal involvement of the mandible is not uncommon: the teeth become elevated, creating the appearance of “floating” teeth in radiographs. Lesions of the vertebral bodies, especially in small children, often lead to collapse, creating the appearance of flattened vertebral bodies (vertebra plana). The involvement of long bones is also primarily subcortical, mostly metaphyseal, less commonly mid-diaphyseal, and rarely epiphyseal. If the overlying cortex is destroyed, subperiosteal reactive bone formation does occur. Rib lesions may circumferentially erode the old cortex and expand the diameter, eliciting some sclerotic response in the new cortex. Pathological fractures can occur in long bones and ribs.

abnormalities seen in the Paleolithic Cro-Magnon Skeleton No. 1 to LCH, although he recognizes the challenges in differential diagnosis. Strouhal (1976 1977) describes Hand Schu¨ller Christian disease in two individuals (a young adult and an adolescent) from the Nagaed-Der cemetery dated to the 5th 6th Dynasties of the Old Kingdom in Upper Egypt, and Campillo (1977) describes three possible cases of eosinophilic granuloma from archeological sites in Spain. Lastly, Barnes and Ortner (1997) describe destructive lesions on an adolescent skeleton from a medieval cemetery in Corinth, Greece, with destructive lesions limited to the skull, possibly due to the incomplete preservation of the skeleton (Fig. 14.19).

HEMATOPOIETIC DISORDERS Anemias The term anemia describes pathological symptoms linked to a variety of abnormalities of red blood cells, which affect the circulatory system’s ability to exchange oxygen. The condition can be clinically linked to excessive red blood cell destruction caused by malaria (Ha˚kan, 2003), or to excessive red blood cell loss due to parasitic or bacterial infection, injury, menstruation, or childbirth. It can

Paleopathology In spite of the rarity of LCH, there are a few cases reported in the archeological record. Thillaud (1981 1982) attributes the largely destructive

FIGURE 14.17 Radiograph of humoral lesion associated with Langerhans cell histiocytosis. Note the coalescing oval lytic lesions with undulating borders, the absence of sclerotic margins, and in this case, reactive periosteal bone formation. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

FIGURE 14.18 Langerhans cell histiocytosis: cranial vault with multiple penetrating defects that show geographic contours and little reactive bone. Multiple destructive lesions were found in many bones. (31/2 years known duration; IPAZ autopsy 1328, 1955.)

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FIGURE 14.19 Probable multifocal eosinophilic granuloma in an adolescent skeleton from a medieval cemetery in Corinth, Greece. (A) Top view of the right and left parietal bones with multifocal lytic lesions. (B) Scalloped edges of a large lytic lesion in the occipital bone. (C) Sclerotic margins of the occipital lesion. Adolescent ca. 13 years; courtesy Dr. C. K. Williams II and the American School of Classical Studies in Athens.

also be caused by insufficient or abnormal red blood cell production caused by poor dietary intake or absorption of iron and essential vitamins (e.g., A, B12, folic acid), increased need for nutrients due to growth or disease (such as diarrheal diseases), infectious disease, and hereditary (genetic) hemolytic disorders (Camaschella, 2015). Importantly, parsing a single cause is often impossible, as a suite of conditions, leading to compromised health, are often concomitantly found in human populations (Verhagen et al., 2013) (Fig. 14.20).

Thalassemia Thalassemia is a pathological condition linked to deficient synthesis of hemoglobin due to alterations in genes creating alpha and beta globin protein chains; both needed for the production of a healthy hemoglobin molecule. Four genes on homologous chromosome 16 are responsible for the production of alpha globin, while two genes on homologous chromosome 11 contribute to the production of beta globin. The two main categories of thalassemia are based on whether the abnormality results from deficient synthesis of the alpha or the beta hemoglobin chain. In alpha thalassemia, if one of the four genes contains one or more of the 100 known allelic variants (often deletions) (Piel and Weatherall, 2014), the carrier is usually asymptomatic. However, if two or three of the four genes contain deletions (manifestations of three genetic mutations is known as HbH disease), the individual displays mild to

moderate microcytic red blood cells and hemolytic anemia (Galanello, 2011). If all four alpha globin genes are affected, the result is a fatal condition known as hemoglobin Bart’s hydrops fetalis. In beta thalassemia, an inherited mutation of one gene on chromosome 11, responsible for the production of beta globin, may result in a condition referred to as thalassemia minor, which is asymptomatic, or thalassemia intermedia, with a range of clinical symptoms. When two genes on the homologous loci carry one of the 200 known mutations at this locus, the resulting condition is classified as thalassemia major (Cao and Galanello, 2010). Predicting the systemic, let alone the skeletal effects of many of the globin mutations is difficult, as wide genotypic variation leads to even greater variation in phenotypic responses (Taher et al., 2006), and environmental factors impact the presence of symptoms (Weatherall, 2001). Both alpha and beta thalassemia have wide geographic distributions, likely associated with genetic selection by the presence of malaria. Both alpha and beta thalassemia appear in elevated frequency in tropical and subtropical regions such as Southeast Asia, the Mediterranean area, the Indian subcontinent, the Middle East, and Africa, with alpha thalassemia extending more widely into southeast Asia and continental Africa (Piel and Weatherall, 2014). A detailed discussion of the geographic, ethnic, and genetic problems of this disease complex has been offered by Rucknagel (1966). Although helpful in understanding the genetic factors that contribute to the disease, the

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Hereditary

Thalassemia

Compromised hemoglobin molecules

Infection

Sickle cell anemia

Microbial and parasitic

Compromised RBC formation

Hemolysis

Inflammation

↓ Eurethropoeisis

Diet

Vitamin deficiency A,K,B12

Blood loss

Phagocytosis

Iron deficiency

Blunted villi

↓ Micronutrient absorption

Anemia FIGURE 14.20 Multiple pathways of clinically recognized anemia. Numerous etiological factors contribute to the complexity of diagnosis and the unlikelihood of attributing a single cause of anemia in archeological populations. Although variables contributing to anemia are represented here as unidirectional, the interrelationship between the variables is far more complex. Adapted from Foote et al. (2013).

skeletal manifestations of all types of thalassemia are the same, so differentiating between them in archeological human remains on the basis of anatomical features is impossible. Skeletal changes have been associated with HbH and intermediate thalassemia. Bone lesions are entirely due to compensatory hyperplasia of bone marrow leading to expansion of the marrow cavity (Helmi et al., 2017). In keeping with the general distribution of hematopoietic marrow, the entire skeleton of the child is usually affected, more or less uniformly, whereas in the adult, characteristic bone changes remain only in areas of permanent hematopoietic activity. Baldini et al. (2014) report that bone disease was observed in 76% of their sample, osteoporosis in 49%, and osteopenia in 51%. The most severe changes associated with thalassemia are in the skull. In children, the diploe¨ of the cranial vault enlarges, leading to marked thickening of the cranial vault, usually beginning in the upper portion of the frontal bone (Fig. 14.21A C). The trabeculae of the diploe¨ are reduced in number and accompanied by thickening, and later radial rearrangement of the remaining trabeculae. The external table is progressively impacted and subsequently completely destroyed. This is accompanied by honeycombed compartments of subperiosteal new bone that harbor hyperplastic marrow. The destruction of the inner table comes much later and is always much more limited than that of the outer table. In radiographs of severe cases, the honeycombed compartments create the appearance of “hair-on-end” rays perpendicular to the normal bone surface (Fig. 14.22). The external dimensions of the facial bones, especially the maxilla and

zygoma, are enlarged, and show thin cortices and loose spongiosa producing prominent cheek bones, referred to as chipmunk facies. Development of maxillary and sphenoid sinuses, as well as the mastoid cells, is inhibited and delayed (Caffey, 1957, 1972[1]: 89). Ethmoid sinuses are better developed because there is little marrow in these bones. The involvement of the maxilla and, to a lesser extent, of the mandible leads to disorderly eruption of the teeth and malocclusion of the jaws. In general, the reduction of the total mass of trabecular and cortical bone throughout the skeleton leads to arrangement of the remaining trabeculae along stress lines to give maximum mechanical stability with minimum encroachment on marrow space. This is most pronounced in ribs, where the cortex can be completely missing and the trabeculae show diagonal arrangement with occasional buttressing trabeculae approximately perpendicular to the main trabeculae (Fig. 14.21D and E). Linear reinforcement occurs on the concave surface in response to respiratory bending stresses. The diameter of the ribs is enlarged. Similar enlargement and alteration of the trabecular pattern are seen in flat bones (pelvis and scapulae), and show a fan-like pattern in radiographs. In addition to porosis, the vertebrae show decreased height, increased width, and cupping of the endplates. Actual compression fractures occur, especially in the lower thoracic and lumbar vertebrae. In children, metacarpals, metatarsals, and phalanges show enlargement with diagonally crossing trabeculae and reticulated thin cortices. Long bones of the extremities show marked widening of the medullary cavity accompanied by thinning of the cortex, most pronounced in the femur. In the metaphyseal

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FIGURE 14.21 Thalassemia major involving multiple bones in a child. (A) External view of the frontoparietal segment of the cranial vault. (B) Endocranial view. (C) Cross-section that shows widening of the diploic spaces and honeycombed buildup of subperiosteal bone replacing the outer and inner tables. (D) Longitudinal cut (left) of the proximal tibia that shows widening of the epiphyseal and metaphyseal marrow spaces and of the medullary cavity, marked thinning of the cortex, and lines of arrested growth. External view (right) of the distal radius that shows lace-like reduction of the metaphyseal cortex. (E) Rib plural surface that shows extreme lacy cancellization of the cortex. (8-year-old Thai studied by Dr. W. J. G. Putschar, M.D. in 1962, Department of Pathology, Medical School, Chiengmai, Thailand.)

area, the cortex may become reticulated and have markedly enlarged vascular foramina, containing hyperplastic marrow. There is often inhibited remodeling of the distal femoral metaphysis, leading to a widened contour that does not have the usual concave flair and closely resembles the Erlenmeyer flask deformity seen in Gaucher’s disease. Multiple “lines of arrested growth” are frequently present and indicate growth initiation after a period of inhibited growth due to severe illness. Delayed

epiphyseal closure is also observed in this disease. In some cases, premature and irregular fusion of the growth plate occurs, especially of the proximal humerus, leading to an abnormal medial angulation of the humeral head. In the series published by Currarino and Erlandson (1964), 12 of 79 thalassemia patients showed premature fusion of growth plates beginning after 10 years of age that produced shortening and deformity. Of these, nine involved the proximal humerus (three bilateral) and three involved

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FIGURE 14.22 Thalassemia major involving the cranium of a child. Note the extensive hair-on-end ectocranial surface created by subperiosteal new bone. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

the distal femur (one bilateral). Generalized growth stunting in children has also been noted (Foote et al., 2013). In adults, the tubular bones of the hands and feet resume normal contours and may develop some osteosclerosis subsequent to the replacement of erythropoietic marrow by fatty marrow (Caffey, 1972 [2]: 1284). The widening and reticulation of the ribs remains mostly in the posterior portions and, rarely, may lead to a tumorlike expansion of erythropoietic marrow covered by a thin, enlarged, cortical shell that projects into the thoracic cavity. Changes in the vertebrae and, to a lesser extent, in the cranium remain. Pathological fractures, especially of the femur, occur in adults more frequently than in children. In the differential diagnosis of dry skeletal elements, other hemoglobinopathies, congenital spherocytic anemia, and iron-deficiency anemia (IDA) must be considered. The cranial changes of thalassemia occasionally resemble those in sickle cell anemia, but the extensive lesions of the rest of the skeleton do not. Cyanotic congenital heart disease (Ascenzi and Marinozzi, 1958) and, rarely, polycythemia (Dykstra and Halbertsma, 1940) can mimic the skull changes in thalassemia. In congenital hemolytic anemia and IDA the bone changes are less severe and do not affect the facial bones.

Sickle Cell Anemia and Its Genetic Variants Sickle cell anemia is a genetic anemia that occurs when the autosomal recessive gene (hemoglobin S) is present in the homozygous condition (HbSS). Individuals with one

sickle cell gene and the normal hemoglobin A gene (SA) have the sickle cell trait. The abnormality in the hemoglobin occurs on the seventh codon of the beta chain and involves the substitution of the amino acid valine for glutamic acid. In spite of the disease being associated with a single gene Mendelian disorder (homozygosity for HBB glu6val), the noted phenotypic variations are great, suggesting that environmental and epigenetic factors are critical to symptomology (Steinberg, 2009). The gene for hemoglobin S is predominantly found in people of African descent, with instances in Mediterranean populations (southern Italy, Greece, and Armenia). Gene frequencies exhibit a strong geographical link with areas of high malaria endemicity (Piel et al., 2010). There are three other genetic variants associated with sickle cell disease. Hemoglobin SC disease is the second most common type of sickle cell disease. It is a heterozygous form of the disease, where HbS is inherited from one parent and the variant HbC gene from the other. Individuals with HbSC have similar but less severe symptoms than individuals with HbSS. Hemoglobin SB 1 (beta) thalassemia is another variant, which affects beta globin gene production. If this gene is inherited with the HbS gene, the size of the red blood cell is reduced due to reduced production of beta protein. Symptoms are not as severe. Sickle beta-zero thalassemia is the third type of sickle cell disease, displaying symptoms similar, but at times more severe than HbSS anemia. Individuals with this disease have a particularly poorer prognosis. Individuals with homozygous SS develop hypoxemic stress when tissue oxygen needs exceed availability, usually met through exchanges between red blood cells and body tissues. In this hypoxemic state, the erythrocytes will assume a sickle shape due to crystallization of the abnormal hemoglobin within the cell. The abnormal red blood cells have a shorter lifespan and are less effective in transferring oxygen, creating an increased demand for red cell production to compensate for increased cell turnover and decreased oxygen exchange. Additionally, during hypoxemic crises, the misshapen red blood cells conglutinate and cause vascular obstructions, leading to areas of ischemic necrosis and infarction. Although the genetic abnormality is present at birth, clinical manifestation is prevented before 6 months of age due to the protective effect of the high concentration of fetal hemoglobin F. The mortality rate of infants and children with sickle cell anemia is high. In persons with sickle cell trait (SA), only extreme hypoxemic stress can produce hemolysis and infarctions. Persons with the genetic combination of sickle cell trait and persistent fetal hemoglobin (SF) are usually free of anemia. Sickle cell disease manifests in the skeleton in three different ways: (1) changes secondary to increased demand of space for hematopoietic marrow; (2) sequelae

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of vascular obstruction of smaller and larger blood vessels; (3) secondary infections superimposed on ischemic areas. Although a variety of bone changes have been described in sickle cell anemia, it should be emphasized that, as a rule, they are not common, obvious, or specific. A careful and detailed study of bone changes in this disease was published by Diggs et al. (1937) in a series of their own cases. Their series comprised 39 patients of African descent who had active severe sickle cell anemia and ranged in age from 1 to 51 years old. The data included eight autopsies at which special attention was paid to bone changes. The frequency and degree of bone involvement increased with age beginning in children past 5 years of age. The bones most likely to reveal alterations were the skull, vertebrae, tibia, and fibula; the cranial changes appear the earliest. Diggs et al. found that the majority of patients showed no alteration in bone size, shape, and density in radiographs. There is general agreement among all observers that bone changes are not related to the severity of the disease. The first and most conspicuous changes are observed in the skull. The diploe¨ may be enlarged and there may be diminished definition of the outer table in radiographs. The radiation density is diminished, sometimes with coarsened trabeculation arranged perpendicular to the inner table. Complete destruction of the outer table with hair-on-end orientation of bony septa is uncommon: it was present in only 1 of 39 cases cited by Diggs et al. (1937). They also found diploic enlargement to be bilateral, symmetrical, and usually limited to the parietal bones, less often involving the frontal and occipital bones. The maximal enlargement occurs in the vertex, tapering to normal toward the temporal area. Cranial changes are most often observed in older children and in young adults. Occasionally osteoporosis may lead to small focal lytic lesions that resemble myeloma. The facial bones showed normal appearance in radiographs. Sarjeant (1974: 166) stated that the zygoma may be enlarged and the orbital roof thickened, but the frontal sinuses develop normally, although the other sinuses may be delayed and hypoplastic. The finding of enlarged orbital roof plates also has been identified in radiographs of clinical patients with various anemias (Stuart-Macadam, 1987a). In the mandible, reduction and coarsening of trabeculae is observed, accompanied by prominence of the lamina dura of the alveoli and thinning of the cortex. The vertebrae show rarefaction of the spongiosa in the vertebral bodies, at times leading to collapse (Emodi and Okoye, 2001). In adults, depression of the central portion of the endplate results in the fish vertebra appearance also seen in postmenopausal osteoporosis. A virtually pathognomonic radiographic change in the vertebral bodies is squared-off indentations (Resnick, 1995: 2110), often referred to as “H”-shaped vertebrae (Williams et al.,

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2004). The scapula, sternum, pelvic bones, and ribs (flat bones) may show increased lucency and coarsening of the trabeculation. In long bones, the most marked changes occur in the tibia and fibula. Hematopoietic marrow may occupy Haversian resorption spaces in the cortex, especially near the medullary canal. In adults with advanced disease, endosteal reactive lamellar bone and occasional bony plugging of segments of the marrow cavity can occur. In these cases, neither the medullary cavity nor the diameter of the shaft is widened. On the contrary, the cortex is thickened and the medullary cavity actually narrowed. Diggs et al. (1937) found 11 cases out of 39, mostly adults, with marked changes to long bones. The hyperplastic marrow also may produce multifocal spotty radiolucency in the metaphyseal areas. The medullary cavities of metacarpals may be widened and vascular foramina may be enlarged. Dactylitis of the fingers and toes is also seen in radiographs of children (Resnick, 1995: 2110; Kim and Miller, 2002), at times with extensive infarction of the marrow, medullary trabeculae and inner layer of the cortical bone, and subperiosteal new bone formation (Weinberg and Currarino, 1972). The changes produced by sickling and blocking of blood vessels are essentially ischemic infarctions, which may be large and located in the medullary cavity, small and spotty in the metaphysis, or involve portions of shaft cortex due to blockage of Haversian vessels. Generally, the large medullary infarcts are indistinguishable from those produced by other causes. As in those other causes, the infarcts also tend to collect calcium salts around the necrotic focus, which is readily visible in radiographs. The metaphyseal foci may appear as focal increased densities that alternate with spotty lucencies of hyperplastic marrow. In fact, some of the bony plugging of the medullary cavity, as described by Diggs et al. (1937), may well represent healed infarctions. The cortical infarcts may reveal a lytic intracortical separation in radiographs. Infarctions of the cortex of short tubular bones of the hands and feet are not uncommon in infants and small children. These may elicit moderate periosteal reactive bone formation, and spotty densities and lucencies in the course of repair. Of special significance is the occurrence of aseptic necrosis in the head of the femur in sickle cell anemia and its genetic variants. It resembles Legg Calve´ Perthes disease, but with two differences: the lesion occurs several years later and it lacks metaphyseal changes adjacent to the growth plate. If the necrotic focus is small, hugging the base of the articular cartilage, it may simulate an unusually large osteochondritis dissecans or Legg Calve´ Perthes disease. Secondary infections are not uncommonly superimposed on ischemic necrotic foci, which permit colonization of bacteria

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occurred in infancy or early childhood may show the most marked changes (Moseley, 1963: 10 11).

Iron-Deficiency Anemia IDA, or acquired anemia, is the most common type of anemia found globally. It is associated with the presence of microcytic and hypochromic RBC, along with depressed levels of total body iron (Camaschella, 2015). Bone changes in IDA tend to be clinically mild. Changes in the skull vault resemble those described for other anemias, i.e., radiographically recognizable enlargement of the diploe¨ with vertical orientation of the trabeculae. Aksoy et al. (1966) report that generalized granular osteoporosis of the skull and long bones might also appear in some patients. IDA has received the greatest attention as a diagnostic option for porous hypertrophic lesions of the skull in the paleopathological record. However, the tendency for this anemia to produce only limited skeletal involvement has raised questions about the legitimacy of the diagnosis. Importantly, a wide range of conditions invoke an anemic response by the body, rendering the isolation of the cause of hypertrophic lesions extremely difficult (Table 14.2).

Erythroblastosis Fetalis

FIGURE 14.23 Radiograph of the right humerus in sickle cell anemia with Salmonella osteomyelitis. Nigerian case; courtesy of Dr. Stanley Bohrer, Ibadan, Nigeria.

circulating in the bloodstream in only small numbers. In these infections, intestinal pathogens, especially strains of Salmonella, make up an unusually large percentage (Fig. 14.23). As in ordinary types of osteomyelitis, the metaphyses of growing long bones are predilected. In contrast to purulent osteomyelitis, there is often destruction of the growth plate, which may lead to abnormal angulation of the hip joint. Pathological fracture through the osteoporotic bone also occurs.

In some infants with erythroblastosis fetalis, which is usually based on Rh incompatibility between an Rh-negative sensitized mother and an Rh-positive fetus, bone changes have been described. These changes consist of alternating band-like areas of increased and decreased radiodensity, especially in the metaphysis of the most rapidly growing bones (distal femur and proximal tibia). Such changes were present in 20 of 110 cases (Brenner and Allen, 1963), but are not specific. They reflect disturbances of late fetal endochondral ossification with delayed resorption of calcified cartilage cores in primary trabeculae (Follis et al., 1942). The condition may be confused with congenital syphilis and scurvy. However, the absence of periostitis in patients with erythroblastosis fetalis provides a useful skeletal feature in differential diagnosis (Resnick, 1995: 2139).

Paleopathology of Anemia Hereditary Spherocytosis (Congenital Hemolytic Anemia) Hereditary spherocytosis is a genetically determined hemolytic disorder characterized by the globular shape of the erythrocytes. It is the most common inherited anemia in individuals of European decent (Perrotta, 2008). The disease manifests itself at various ages. Bone changes are uncommon and slight, usually limited to the cranial diploe¨, and rarely affect long bones. Cases where onset

The presence of anemia in the archeological record is complex and controversial. Porous and hypertrophic lesions (porotic hyperostosis (PH)) of the skull are frequently recorded by paleopathologists (Jatautis et al., 2011). However, despite evidence that infection, cancer, and metabolic disease can produce porous and hypertrophic lesions in bone, PH is consistently attributed to anemia, to the extent that the presence of the lesion in bone has been treated synonymously with the presence of

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TABLE 14.2 Causes of Iron Deficiency and IronDeficiency Anemia Environmental Insufficient dietary intake Dietary restrictions or predilection (grain intensive, vegetarian, vegan, etc.) Genetic Iron-refractory iron-deficiency anemia Pathologic Decreased absorption Atrophic gastritis Celiac sprue Helicobacter pylori infection Inflammatory bowel diseases Parasitic infestation Chronic blood loss Gastrointestinal tract Benign and malignant tumors Diverticulitis Erosive gastritis Esophagitis Hookworm infestation Peptic ulcer Genitourinary system Intravascular hemolysis Heavy mensis or menorrhagia Systemic bleeding Chronic schistosomiasis Hemorrhagic telangiectasia Physiologic Increased demand for iron Infancy Rapid growth (adolescence) Menstruation Pregnancy Source: After Camaschella (2015).

anemia, especially IDA (Stodder, 2006). This is unacceptable. Without careful analysis of cranial and postcranial remains and rigorous differential diagnosis, researchers must avoid simplistically assuming that porous lesions of the skull, even when hypotrophic, are caused by anemia. In general, inferences made about the presence of anemia in paleopathological specimens are based on the presence of porous, periosteal bone lesions on the skull vault, primarily affecting the outer table of the frontal and parietal bones, and the orbital roof (Fig. 14.24A and B). Several descriptive terms have been used for this condition, including cribra crania, symmetrical osteoporosis, and spongy hyperostosis. However, the term PH, which was introduced by Angel (1966), has become the term used by most researchers to describe this condition in human archeological skeletal remains, with cribra orbitalia (CO) being used to describe lesions of the orbital roof.

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Given the tendencies by many researchers to assume that PH and CO are manifestations of the same condition that simply occur in different anatomical locations, and to assume that the presence of the lesions are indicative of anemia, it is imperative that two questions are explored. First, what is the relationship between PH and CO? A variety of hypotheses for the relationship between the calvarial and orbital lesions have been proposed. StuartMacadam (1987a,b) offered clinical radiographic data, alongside macroscopic data to support a link between orbital and calvarial lesions. The radiographs used in the study included documented cases of genetic and acquired anemia. More recently, Rivera and Lahr (2017) have explored the relationship between orbital and calvarial lesions, and conclude that cribrotic lesions can be associated with PH under conditions invoking compensatory bone marrow expansion due to increased hematopoiesis, such as genetically based anemias and IDA. However, in CO cases where bone marrow expansion of the orbit is absent, the lesions are more likely related to anemias producing localized diploic atrophy or hypoplasia, such as anemia of chronic disease. The second question to evaluate is whether all lesions recorded as CO and PH are etiologically linked with anemia. Many early researchers were careful in their description of lesions classified as CO or PH, and most descriptions included hyperostotic ectocranial porosity accompanied by diploic thickening (hence the early term hyperostosis spongiosa). I would argue, however, that terminology and concomitant diagnosis changed inadvertently with the widespread adoption of Buikstra and Ubelaker’s (1994) Standards for Data Collection From Human Skeletal Remains. Here, under the purely descriptive pathological term “porotic hyperostosis” were codes for varying skeletal manifestations including pinpoint porosity, coalescing foramina, and diploic thickening. This led to an unfortunate trend towards researchers conflating description with diagnosis. The presence of pinpoint porosity, since categorized by Buikstra and Ubelaker as a descriptive form of PH, became treated as an indicator of anemia, most commonly, IDA. However, the clinical and much of the early paleopathological literature was clear: only in instances where hyperporotic changes were evident, triggering compensatory bone marrow expansion, was anemia invoked as the cause. Tiny pinpoint lesions of the calvarium and orbits were not diagnostic. A number of recent studies draw attention to the need for careful lesion description, analysis, and differential diagnosis. Wapler et al. (2004), for instance, identify multiple alternative etiologies for CO, such as localized inflammation and the presence of rickets, based on histological evidence. Walker et al. (2009) argue that IDA is an unlikely contributor to the diploic thickening of PH, as

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FIGURE 14.24 Child with severe porotic hyperostosis with marrow hyperplasia. (A) Orbital roof with cribra orbitalia. (B) Broken section through the left orbital lesion that shows enlargement of the marrow space. (C) Anterior view. (D) Porous hypertrophic lesions of the skull vault. (E) Lateral view of the skull. (F) Radiograph of the skull, lateral view. (1- to 2-year-old child from pre-Columbian site of Pueblo Bonito, New Mexico; NMNH 327074.)

the disease suppresses rather than triggers marrow and red blood cell formation. Megaloblastic and hemolytic anemia, linked to B12 and B9 deficiency, is a more likely etiology. Although Oxenham and Cavill (2010) take issue with Walker et al.’s assessment, they emphasize that differential diagnosis is critical in all analyses of lesions, while Gowland and Western (2012) and Smith-Guzma´n (2015) emphasize the role that malaria can play in the development of anemia. One distinction that might assist differential diagnosis is the geographical distributions of genetic anemias. Sickle cell anemia and thalassemia have been associated with the geographical distribution of malaria, while acquired anemia is a response to several variables, including nutrition and debilitating diseases, and thus occurs in any human population irrespective of the presence of malaria. Carefully evaluating the archeological context from which the individuals are recovered

thus becomes an essential component of differential diagnosis. DNA analyses might also prove beneficial, as Filon et al. (1995) successfully identified the beta thalassemia mutation in an archeological specimen displaying marked PH. Faerman et al. (2000) positively identified the homozygous mutation of adenine to thymine at codon 6 of chromosome 11, associated directly with sickle cell anemia, in a skeleton with clinically diagnosed sickle cell disease, highlighting the promise of genetic analyses accompanied by stringent controls and differential diagnosis. Interpreting the presence of PH and CO in the paleopathological record is also confounding. By far the most common diagnosis associated with the presence of these lesions is that of IDA. In 1965, Moseley added acquired anemia to the list of possible morbid conditions that produce PH. On the basis of his clinical experience as a

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radiologist, he proposed to differentiate thalassemia major from other genetic and acquired anemias because of involvement of the face and long bones. He expressed the opinion (1965: 141) that PH seen in skulls from Peru and Yucatan was due to IDA. This diagnosis was also applied to a Bronze Age (1650 1550 BC) skull of a 6-year-old child from Wales that had PH, as described by Cule and Evans (1968). Sir Arthur Keith, however, who also saw the skull, attributed the lesions to rickets (Wheeler, 1923: 21). El-Najjar (1976) and El-Najjar et al. (1975, 1976) offered hallmark studies on the presence of PH in archeological samples from the southwestern United States. Here the authors found an association between presumed dietary factors (maize consumption) and the frequency of skeletons displaying PH. They concluded that acquired anemia due to inadequate iron absorption caused by a maize-intensive diet was the most likely causative factor for PH. A few years later, however, Mensforth et al. (1978:38) reported a more complex association between evidence of infectious disease and the occurrence of PH in prehistoric skeletons from Ohio. They suggest that illness and nutritional stress were important factors stimulating IDA. Today it is clear that enthusiasm for the hypothesis that the human diet plays a predominant role in provoking IDA may be warranted in some contexts, but can only be concluded after thorough evaluation of both the skeletal lesions and the archeological context. A number of unresolved issues exacerbate the complexity surrounding the determination of causes and interpretation of PH and CO in the archeological record: 1. There are no known associations between the severity of lesions found within skeletal remains and the severity of the condition in vivo. Greater skeletal involvement does not necessarily correlate with greater severity during the life of the individual, since other variables such as the age of the individual and the presence of other conditions/diseases influences the body’s response. 2. The duration of the condition cannot be determined by the types or extent of the skeletal lesions due to the changing plasticity of the human skeletal system throughout childhood and adolescence, and changes to the hematopoietic processes of the human body. 3. Interpreting the presence of active (unremodeled) and “healed” (remodeled) lesions is complicated by unknown associations between these lesion types and clinical measures of anemia. 4. The interrelationship between variables associated with IDA is complex, with a cascade effect obscuring primary causes of the disease. For instance, the presence of infection (affecting nutrient absorption or leading to malaise or culturally defined behavioral

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responses) can alter dietary consumption (reduced volume or selection for particular food types) leading to IDA. Alternatively, dietary consumption (choice or availability of food) can lead to infection (e.g., pathogenic contamination), which can lead to IDA. Importantly, the role of human agency, choice, and cultural constructs impacts the variables contributing to IDA. A further development is the hypothesis that a reduction in available iron within the body may be part of the arsenal of the immune system in response to exposure to infectious agents, as pathogen proliferation is compromised by low iron/oxygen levels (Stuart-Macadam, 1992; Weinberg, 1984). In this scenario evidence of PH is a reflection of the infectious disease load of a skeletal sample rather than a specific indication of anemia. Known as the optimal iron hypothesis, Wander et al. (2009) have suggested that serum iron levels are mediated, in part, by external ecological demands. Moderate iron deficiency might therefore be prophylactic in environments of high pathogenic loads. Recent tests of this hypothesis, however, call for care in adopting this premise. Hadley and DeCaro (2015) found in their study of 1164 Tanzanian children that those with IDA had very similar levels of elevated C-reactive protein (a marker of infection) to those without clinical manifestations of IDA. Further research is needed in order to determine whether reduced iron levels is, in fact, protective or produced as an adaptive response by the body once infection is present.

THALASSEMIA AND SICKLE CELL ANEMIA The presence and antiquity of thalassemia have been reported by a number of researchers, primarily using macroscopic and radiographic analysis. Zaino (1964: 403) proposed that PH, which he reported in pre-Columbian skulls from Peru, is due to thalassemia, while Jarcho et al. (1965) reported a case of PH from a Pueblo Indian site in the American Southwest. The problem with inferring the presence of thalassemia in the New World before the arrival of Europeans is that there is no evidence of this genetic expression of anemia in post-Columbian Native American populations. The case for archeological evidence of thalassemia in the Old World is much more convincing. Angel (1964, 1966) proposed that PH found in ancient Greek skulls was evidence for the presence of thalassemia in antiquity. He made this argument largely on the basis of skeletal lesions. However, he combined these data with a reconstruction of the ecology in ancient Greece, in which the conditions would have favored the presence of anopheline mosquitoes as carriers of malaria. Because the evidence for the genetic variant in modern ethnic groups is

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unquestioned, this inference is certainly plausible. At issue here, however, is that both thalassemia and malaria can result in anemia, with thalassemia compromising the production of hemoglobin, and Plasmodium falciparum, a protozoan parasite transmitted by the female Anopheles mosquito, provoking excessive removal of nonparasitized erythrocytes and immune destruction of parasitized red cells. Hence, using the presence of PH without rigorous evaluation of other skeletal modifications and archeological context cannot directly lead to conclusions regarding either the presence of thalassemia or malaria within an individual or population. A number of studies have sought to tackle these obstacles. Lagia et al. (2007), for instance, provide a macroscopic and radiographic evaluation of an individual with clinically diagnosed thalassemia as a means to improve our ability to differentially diagnose the disease. Likewise, a careful evaluation utilizing multiple diagnostic criteria in an archeological context has been offered by Lewis (2012), who evaluated 364 juvenile skeletons from Roman-era Britain, finding skeletal lesions on two individuals more consistent with thalassemia than acquired anemia. The successful isolation of the beta globin mutation itself in bone, rather than its secondary effects on the human skeleton, further improves our ability to assess thalassemia in antiquity (see Filon et al., 1995 and Vigano´ et al., 2017). In spite of the fact that millions of people carry the sickle cell gene today, there are few reports of the disease in the archeological record. This is likely due to the shared primary and secondary changes macroscopically and radiographically evident in the human skeleton associated with genetic and acquired anemias. Means toward differential diagnosis are offered by Hershkovitz et al. (1997:220), but highlight the fact that key differences between the anemias are subtle (e.g., statistically affecting an anatomical area more or less frequently, rather than present/absent), and that there are few diagnostically unique manifestations of sickle cell anemia. According to the authors, of the 62 anatomical characteristics offered for differential diagnosis between thalassemia, sickle cell anemia, and primary and secondary iron deficiency, only diffuse calcification of the skull, increased radiolucency and coarsened trabeculae of the mandible, patchy sclerosis of the pelvis, enlarged basivertebral foraminae, vertebral sclerosis (dense bands), retarded bone age and delayed closure of growth plate, growth deformity of the proximal femoral epiphyses after the age of 10, bone infarcts and osteonecrosis, osteomyelitis, bone elongation (pseudo Marfan syndrome), and structural abnormality of the teeth, serve as distinguishing features for sickle cell anemia. While these appear to be substantial in number, the types of skeletal changes associated with sickle cell anemia overlap with other conditions/diseases (e.g., necrosis and osteomyelitis) and/or appear in areas of the

body vulnerable to taphonomic destruction (e.g., vertebral bodies and epiphyseal ends of tubular bones).

IRON-DEFICIENCY ANEMIA Two examples from the National Museum of Natural History, Washington, DC, provide useful insight into the expression of PH caused by marrow hyperplasia in archeological populations. Both cases are from the American Southwest (NMNH 327074 and 327107) and are skeletons of young children from the Pueblo Bonito Ruin, Chaco Canyon, New Mexico. This site is associated with the precontact Pueblo III cultural period and is dated between AD 919 and 1130 (Seltzer, 1944: 25). During this period, skulls show marked cultural modification characterized by occipital flattening. The dental age of the first specimen (NMNH 327074) is about 11/2 years (Fig. 14.24C F). The lesions in this specimen are primarily porous, but some labyrinth-like lesions are present as well. The affected area involves the frontal bone including the orbital roofs, but predominantly involves the outer table of the parietal bones; the inner table is not affected. The skeleton is characterized by severe occipital flattening and the lesion encroaches only slightly on the deformed part of the skull. The facial bones and mandible are not markedly affected, although the region surrounding the zygomaticofacial foramen on the zygomatic bone suggests an inflammatory reaction. The lateral X-ray film shows the perpendicular striations found in many examples of PH. A postmortem break through the lesion in the right parietal reveals an intact inner table, greatly enlarged diploe¨, and the virtual elimination of the outer table. Radiographic evaluation of the extant long bones including major portions of both femora, right tibia, both humeri, and ulnae, reveals relatively enlarged marrow cavities and greatly diminished thickness of the cortices in all long bones. The second case (NMNH 327107) has a dental age of about 2 years. The state of preservation is not as good. Like the previous example, the most severely affected region is the external table of the parietals (Fig. 14.25A and B). The lesion does not cross the sagittal suture. The left frontal bone is also affected and the disease process is continuous across the coronal suture. Only portions of the right orbit are present. They reveal no evidence of PH. The left temporal bone is abnormal: it has an irregular surface that is thickened and slightly porous. Like the first skeleton, the long bones are affected by the disease process. An X-ray film of the complete right femur and the partially complete tibiae, left femur, and humerus reveals a generalized enlargement of the medullary cavity and much thinner cortex than normal. Comparison of the abnormal femur with normal femora (Fig. 14.25C) of similar size from the same population reveals a cortical

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FIGURE 14.25 Bone marrow reactions in a skeleton with porotic hyperostosis. (A) Porous labyrinth-like lesions of the skull vault. (B) Broken sections of the parietal that demonstrate hyperplasia of the diploe¨. (C) Radiograph of the femur of a skeleton with anemia (center) compared with the femora of two children from the same site who did not have skeletal evidence of anemia. Note the enlarged marrow space and thinned cortex. (2-year-old child from the pre-Columbian site of Pueblo Bonito, New Mexico; NMNH 327107.)

thickness of less than 1 mm for the abnormal specimen, whereas the normal femora are between 2 and 3 mm. Two features distinguish this case from the preceding one. First, the lesion does occur in the region of deformation. This may be related to the fact that the occipital deformation is not as severe. Second, unlike the preceding example, there appears to be slight deposition of reactive bone on the inner table. The abnormal bone is concentrated in the region of the anterior fontanel and reactive tissue is apparent at its sutural borders. There is a solitary lesion on the left parietal boss. A lateral radiograph of the skull reveals vertical striations in the area where PH is most pronounced. Also apparent in the film is the absence of the outer cortex in the porous area. The lesion itself is slightly different from the first specimen in that it is more variable in appearance. Beginning on either side of the sagittal suture, the parietal lesion has a narrow zone of finely porous bone. This quickly merges with bone that is labyrinthian in gross appearance. Continuing in a lateral direction the lesion is characterized by a circular porosity that becomes finer and less pronounced in the area below the temporal muscle. Here the bone takes on the lumpy quality seen in the left temporal bone. Certainly, a diagnosis of some type of anemia is a strong probability in the two cases described. However, determining the specific type of anemia is more problematic. Moseley (1963: 6, 1966: 128) reported that the long bones are not affected in IDA. This conclusion is not supported by Lanzkowsky (1968: 24), who found widened medullary spaces and thinned cortices in the postcranial bones, particularly the metacarpals and phalanges. This

difference of opinion highlights the need for additional research on the manifestations of the anemias that can affect the skeleton. The research reported by Hershkovitz et al. (1997) on skeletal pathology associated with thalassemia, sickle cell anemia, and acquired anemia is a helpful step in clarifying these differences, but much remains to be known about the overlap between these anemias, particularly in cases where the skeletal manifestations are less severe. It will also be important to pursue additional research on various biochemical and epidemiological variables that have the potential to aid in differential diagnosis. If some types of PH are caused by acquired anemia, in which a deficiency of iron is a factor, the formation of tissues dependent in some way on iron might be altered as well. Von Endt and Ortner (1982) hypothesized that bone collagen might reflect iron deficiency because it is an important cofactor in the hydroxylation of two amino acids, lysine and proline, in the synthesis of hydroxylysine and hydroxyproline, which are important constituents of bone collagen. More specifically, bone tissue from skeletons with PH due to IDA should show relatively reduced amounts of hydroxylysine and hydroxyproline compared to normal controls. Von Endt and Ortner evaluated this possibility using one of the specimens described previously (NMNH 327107). They compared the amino acid residues of bone protein from the skeleton of this child with presumed anemia with a similar skeleton from the same site that did not have PH. A bone protein sample from a modern child who died from accidental causes was used as an additional control. The hydroxylysine and

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hydroxyproline residues of the archeological and modern skeletal samples that did not have PH were virtually identical. In the bone of the child who had PH there was 5% less hydroxyproline and 25% less hydroxylysine. The authors argued that these reduced concentrations support a diagnosis of IDA in the skeleton with PH. There is the further problem of differentiation between PH from anemia and similar lesions seen in cancer, infectious diseases, and metabolic diseases. Briefly, porous lesions of the skull in infectious diseases are usually periosteal. They do not involve expansion of marrow space. The lesion typically is superficial to normal bone. In early stages of the periosteal lesion the outer cortex remains intact. However, in later stages the outer table may undergo remodeling and a section through that part of the skull may resemble the PH of anemia. The bony reactions that occur in scurvy (Ortner and Ericksen, 1997; Ortner et al., 1999, 2001) could be confused easily with those of anemia or infectious disease. Hypertrophic lesions are less common in scurvy, but they do occur. However, this hypertrophy does not involve marrow hyperplasia. The porous bone associated with rickets occurs in the skull and postcranial skeleton (Ortner and Mays, 1998). The porosity of the skull is much finer and could not be confused with PH associated with anemia. However, keep in mind that anemia resulting from dietary deficiency can also be associated with other deficiencies including those that result in scurvy and rickets.

Leukemia In general, detecting and diagnosing the presence of neoplastic disease in human skeletal remains is especially difficult. In part, this is due to the overlapping and relatively narrow skeletal responses created by different types of cancer (Marquez et al., 2017; Ragsdale et al., 2017). It is exacerbated by taphonomic factors, which might compromise or destroy remnants of the body’s lytic responses over time. Regardless, leukemias are cancers of the myeloid and lymphoid hematopoietic cells of the bone marrow, which might be detected in the archeological record. Both myeloid and lymphoid cancers occur in acute and chronic forms in children and adults, with tumor cells extensively replacing normal bone marrow throughout the skeleton. Although adult and chronic forms of leukemia can affect the skeleton, the changes are nonspecific and often difficult to immediately diagnose (Riccio et al., 2013). Skeletal manifestations include generalized loss of bone mass and diffuse, small osteolytic lesions, joint compression, vertebral collapse, pathological fractures, and periosteal reaction (Sinigaglia et al., 2008). Since the major changes that affect the skeleton occur in acute leukemia of childhood, that will be the focus of the following discussion.

Bone changes in acute leukemia of childhood occur in 50% 70% of cases (Resnick and Haghighi, 1995: 2248). In growing bones of children, the replacement of the normal marrow cells by tumor cells and their subsequent proliferation results in recognizable alterations to the bone structure. The most frequent lesion is a narrow radiolucent line on the metaphyseal side of the growth plate. This change is not specific and resembles, to some extent, the lucent metaphyseal zone in scurvy. Another alteration seen in acute childhood leukemias involves the cortical surface of the metaphyses. Normally, in these areas, osteoclastic resorption of the modeling process creates a rough and somewhat grooved or porous cortical surface. In acute leukemia, these areas of the periosteum may be colonized by tumor cells that emanate through the vascular foramina. This leads to widening of the vascular foramina and exaggerated grooving and porosity of the metaphyseal cortical surface. This may be the most characteristic bone lesion of acute leukemia. Occasionally, widespread nonspecific subperiosteal bone deposits are observed over thinned cortices of long bones and ribs (Fig. 14.26). In spite of the rarity of leukemia, careful differential diagnosis has been used to detect its presence in the past. Most recently, Klaus (2016) attributes relatively diffuse abnormal porous loci and periosteal reaction on the clavicle and ribs of a child associated with the Lambayeque Valley Complex of the north coast of Peru, dated AD 1533-1620, to acute leukemia.

Myeloma Myeloma is a highly malignant disorder of plasma cells that usually arises in hematopoietic bone marrow. The disease is the most common primary malignancy of bone: it has an incidence of between 2 and 4 cases per 100,000 (Mulligan, 2000: 127). It may begin as a single site, at which stage it is known as solitary plasmacytoma. However, virtually all cases move on quickly to multiple myeloma (Mulligan, 2000). Skeletal involvement is common (noted in 80% 90% of modern cases) and often affects many, if not most, areas of the skeleton (Kuehl and Bergsagel, 2002). The lesions are sharply defined holes typically 5 mm to 2 cm in diameter and often penetrate both tables in the skull. They often have scalloped margins. Endosteal scalloping of the cortex is an important radiographic feature in the long bones (Mulligan, 2000: 127). The malignant plasma cells inhibit local osteoblastic activity at the site of the lytic focus, so sclerotic margins do not occur in most cases. This feature, along with the extensive involvement of the skeleton, is helpful in differential diagnosis with metastatic carcinoma. Even the mandible may be involved and this is very uncommon in metastatic carcinoma (Mulligan, 2000: 128).

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FIGURE 14.27 Multiple myeloma. Endocranial view of the cranial vault that shows multiple lytic lesions destroying the internal table. (65-year-old male; MGH autopsy 33606.)

FIGURE 14.26 Acute leukemia in a child. Note the considerable amount of periosteal new bone growth along the diaphysis of the femur and the faint radiolucent line along the metaphysis. Courtesy of Drs. T. Demos and L. Lomasney, Department of Radiology, Loyola University Chicago Medical Center.

The initial lesion usually arises in the axial skeleton because that part of the skeleton contains hematopoietic marrow. In the long bones, lesions can occur in the proximal metaphyses, especially of the femur and the humerus. Single tumor cells disseminate through the blood and colonize mostly in the areas of hematopoietic marrow. In the cranial vault and portions of the long bones of the extremities, reactivated hematopoietic marrow appears, secondary to massive marrow involvement in the trunk. The small bones of the extremities are usually spared. A typical location for the primary lesion is the proximal metaphysis of the femur and humerus. The initial lesion may remain localized and solitary for months or years (solitary plasmacytoma), but dissemination to other parts of the skeleton almost always occurs. The solitary lesion is slow

FIGURE 14.28 Multiple myeloma. Bisected spine and ribs with severe osteoporosis, compression fractures, and kyphosis. Notice the disseminated small lytic lesions in the ribs and spinous processes. (77-year-old female; IPAZ autopsy 1703, 1954.)

growing, creating an osteolytic defect and ultimately eroding the cortex. The lesion can include formation of an expanded bony shell with ridge-like internal reinforcements. These appear as a “soap bubble” pattern in

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radiographs. Pathological fractures through the lesion are a complicating factor and callus formation is normal. The lesion usually does not extend into the head of the humerus or femur. This distinguishes it from giant cell tumor and chondroblastoma. In dry bone, the solitary lesion cannot be differentiated with certainty from unicameral bone cysts, chondromyxoid fibroma, or nonossifying fibroma, except for the fact that these would usually occur in a younger age group. Differentiation of the lesion from solitary lytic metastasis of renal or thyroid carcinoma may be impossible. The most frequently observed and most characteristic manifestation of myeloma is the disseminated form (multiple myeloma). The lesions start within bone marrow and in long bones tend to destroy the endosteal surface of the cortex, producing the scalloped appearance in radiographs. In most affected bones (vertebrae, ribs, sternum, clavicles, scapulae, pelvis, calvarium, and long bones) the individual lesions create punched out, purely lytic defects without reactive bony margins (Fig. 14.27). Most lesions are round and small, but individual large lesions, particularly the primary lesion, do occur and small lesions can become confluent, often showing scalloped margins. In vertebral bodies this confluence of individual lesions is particularly common. The spinous processes are often involved. Destruction of the vertebral spongiosa often

leads to collapse of multiple vertebrae, frequently with deep cupping of the endplates due to pressure from the intervertebral disks (Fig. 14.28). Wedge-shaped vertebrae, kyphosis, and scoliosis are common. The ribs also frequently show multiple transverse fractures and a coarsely reticulated irregular pattern of the few remaining trabeculae. Differential diagnosis between multiple myeloma and osteolytic metastatic cancer, particularly of the breast, is difficult (Marques et al., 2013). The male prevalence in myeloma and the female predominance in breast cancer are helpful considerations, along with the more extensive involvement of the skeleton in multiple myeloma. Furthermore, in metastatic carcinoma, even if it is predominately lytic, some of the lesions usually show an osteoblastic response in association with at least some of the lesions. Multiple myeloma frequently involves the glenoid fossa of the scapula and the lateral portion of the clavicle, and disseminates into the radius and the ulna, a condition that is uncommon in metastatic carcinoma (Schinz et al., 1951 1952: 951). The presence of a larger, older lesion also helps in the differentiation from metastatic carcinoma. Rarely, multiple myeloma may leave the bone structure unchanged or produce only a pattern of diffuse osteoporosis without distinct lytic lesions. These changes are nonspecific, making differential diagnosis even more troublesome. FIGURE 14.29 Multiple lytic lesions of the skull and postcranial skeleton. (A) Left lateral view of the skull and mandible. (B) Lateral radiograph of the skull that shows multiple lytic lesions of relatively uniform size. (C) Posterior view of the left scapula that shows lytic lesions and porous bone hypertrophy (arrow) adjacent to the lytic focus. (Adult female from Indian Knoll, Kentucky; NMNH 2990064.)

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Paleopathology It is not surprising that the identification of myeloma in paleopathological specimens is particularly complicated given the similarity between bone lesions of myeloma and some types of metastatic carcinoma, and taphonomic effects over time. In spite of these obstacles, a number of researchers have cautiously suggested the presence of multiple myeloma in the archeological record (see, for example, Ritchie and Warren, 1932; Williams et al., 1941; Brooks and Melbye, 1967; Morse et al., 1974; Wells, 1964; Strouhal, 1991; and most recently Abegg and Desideri, 2017), with a number of the earlier cases being called into question by Ortner (2003). Three paleopathological specimens from the National Museum of Natural History, Washington, DC, provide further insight into the problems of differentiating

523

between multiple myeloma and osteolytic metastatic carcinoma. The first of these is a female skeleton (NMNH 290064) from the Indian Knoll site in Kentucky. Most of the artifacts from this site are dated in the Late Archaic period (c.3000 1000 BC); however, some components date to the Late Woodland period (c. AD 800 1700). Thus, the archeological age of this specimen remains obscure. The age of the individual cannot be determined, but certainly is adult. The disease process consists of multifocal, mostly lytic lesions distributed in the skull, mandible, axial skeleton, and the proximal left femur (the right femur is missing). The bones of the hands and feet are unaffected except for a slight, superficial osteoporosis of the superior surface of the calcanei. The gross lesions vary in size from barely detectable to about 15 mm in diameter. Most of the cranial lesions (Fig. 14.29A) FIGURE 14.30 Multiple scalloped lesions of the skull in a probable case of multiple myeloma. (A) Left lateral view of the skull that shows lytic lesions of varying size. (B) Lateral radiograph of the skull that shows multiple lytic lesions of relatively uniform size. (C) Mid-sagittal coronal computed tomography (CT) scan that demonstrates lack of sclerosis in the margins of the lesions. (D) Mid-frontal coronal CT scan that shows lack of marginal sclerosis in lytic lesions. (E) Scanning electron microscope photomicrograph of the surface in a lytic lesion of the skull. Virtually the entire surface consists of Howship’s lacunae, indicating active bone destruction at the time of death. There is no evidence of osteoblastic repair in any field. (Adult female from Caudivilla, Peru; NMNH 242559.)

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penetrate both tables and have no clear pattern with regard to which table is most extensively affected. The lytic process is more extensive in the diploe¨, suggesting that the marrow was the focal point for the disease process. The roentgen films of the skull and long bones reveal additional lytic foci that are not visible from the outside (Fig. 14.29B). The scapulae are present and both show multiple lytic foci (Fig. 14.29C). The glenoid fossa is normal, although there are lytic foci in adjacent tissue. However, unlike lesions elsewhere in the skeleton, there is a slight osteoblastic response adjacent to several of the lytic foci. With this exception, there is no osteoblastic reaction to any of the other lytic lesions in the skeleton. This suggests a rather acute disease process. Steinbock (1976: 381 384) reported on this case and concluded that “the size, location, and appearance of the destructive lesions in this Archaic Indian are highly indicative of multiple myeloma rather than metastatic carcinoma.” While conceding that multiple myeloma is a strong possibility based on some aspects of the gross and roentgen film morphology of the lesions, there is other evidence supportive of a diagnosis of metastatic carcinoma. The peripheral bone reaction on the scapulae is more characteristic of metastatic carcinoma, as is the age and sex of the skeleton. However, the presence of a lytic lesion on the mandible is more typical of multiple myeloma. Another possible case of multiple myeloma is a female skull from Peru (NMNH 242559). This specimen is fully adult. The archeological age is unknown. The external gross aspect of the entire skull, except the face, reveals several scalloped, lytic lesions (Fig. 14.30A) that vary in size from pinholes to 15 mm in diameter. There is no evidence of bony circumscription either by inspection or on roentgen films (Fig. 14.30B). This is confirmed in coronal computed tomography slices (Fig. 14.30C and D). Scanning electron microscopy of one of the lesions shows virtually all surfaces covered with Howship’s lacunae and no evidence of osteoblastic repair on any surface (Fig. 14.30E). The size and morphology of the lytic lesions as well as the absence of any evidence of repair make a strong case for multiple myeloma, although metastatic carcinoma remains a possibility. The third case from the National Museum of Natural History, Washington, DC, is also a female skull from Peru (NMNH 242578). Age at death is unknown, but like the two previous cases, clearly adult. The archeological age is unknown. Unlike the lesions in the preceding two cases, the external appearance of these lesions is much less obvious. The lytic lesions that do penetrate the surface are small holes, typically 1 2 mm in diameter. On the internal table, the lesions are somewhat more pronounced. All bones of the skull are affected, but the facial bones and occipital bone show much less involvement. The greater wings of the sphenoid and the body of the

FIGURE 14.31 Lateral radiograph that shows multiple lytic lesions of the skull. Note the lack of sharply defined boundaries of the lytic foci. (Adult female from Peru, NMNH 242578.)

sphenoid are markedly affected; much of the latter is totally destroyed. In the radiograph (Fig. 14.31), it is apparent that the major focus of the lytic process is the diploe¨. There is no evidence of any osteoblastic reaction in any of the lesions. In the radiograph, a typical lesion consists of a lytic focus that ranges in diameter up to 2 cm. Many of the lesions coalesce. The overall picture presented by this case is not typical of either multiple myeloma or metastatic carcinoma. However, Schinz et al. (1951 1952: 947, 949) briefly described a case of atypical multiple myeloma in which “rather numerous individual foci are distinctly delimited, and a moth-eaten, finely mottled kind of osteolysis develops. . ..” This description and their published roentgen film views closely match the appearance of the Peruvian skull. However, Schinz et al. cautioned that the case they described is not easily distinguishable from metastatic carcinoma. Provisionally, however, it is might be useful to consider this skull as an example of atypical multiple myeloma.

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