Diagnosing Malignant Bone Tumors In The Lower Extremity
Many lesions of bone that arise with relative frequency in the feet are seen less commonly in alternate locations. Similarly, there are a host of trends with regard to the biology of bone tumors that are unique to the distal extremities, particularly the feet. With that said, let’s review the most common malignant tumors of the bones of the feet and key clinical features that can aid in arriving at the most appropriate diagnosis and subsequent treatment. While it is far from the most common malignant tumor of the skeletal system at large, Ewing’s sarcoma/primitive neuroectodermal tumor (PNET) has been documented as the most common non-hematopoietic primary malignancy of the bones of the feet in series’ assembled at two major cancer centers and elsewhere.1,2,3 In the Memorial Sloan Kettering series, which summarized all tumors of the bones of the feet over a 15-year time span, this highly aggressive neoplasm accounted for 11 percent of all bone tumors and 25 percent of all those that were malignant.1 At the Mayo clinic, Dahlin and Unni noted Ewing’s sarcoma accounted for 28 percent of all malignant bone tumors involving the bones of the feet.2 Although Ewing’s sarcoma and primitive neuroectodermal tumor are considered variations of the same disease, Ewing’s sarcoma is commonly taken to connote tumors that lack neuroectodermal differentiation by light microscopy, electron microscopy and immunohistochemistry. The term “primitive neuroectodermal tumor” is applied when one or more of these techniques demonstrates such differentiation. Poorly differentiated tumors typically require a combination of light microscopic and genetic analysis to be diagnosed as Ewing’s sarcoma. Ewing’s sarcoma and PNET have a chromosomal translocation t(11; 22) (q24; q12) in common in 85 to 90 percent of cases.4,5 The remaining 10 to 15 percent of these malignant neoplasms are believed to have alternate mutations involving the Ewing’s sarcoma gene on chromosome 22.6 Ewing’s sarcoma may affect any bone of the foot including the phalanx although the calcaneus appears to be the most commonly involved.1,2,7-11 This is of profound clinical significance as calcaneal lesions impart a worse prognosis than those arising elsewhere in the foot.1,7 Researchers have shown that males are affected more commonly than females, both when this tumor is primary to the feet and when it is seen elsewhere in the skeletal system.1,2,8 Ewing’s sarcoma predominantly affects people in their second decade of life.1,7,8 People over the age of 30 are only rarely affected. For reasons that are unclear, African-American individuals are less commonly affected by Ewing’s sarcoma than Caucasians. As is the case with many bone tumors, the radiologic features of Ewing’s sarcoma in the feet contrast somewhat with the radiologic features of the sarcoma when it affects the long bones.12 When Ewing’s sarcoma is present in the long bones of the appendicular skeleton, one would note a diaphyseal-based tumor with admixed lytic and sclerotic features, and characteristic “onion skinning.” However, when Ewing’s sarcoma is present in the feet, onion skinning is an uncommon finding. While plain film radiographs may demonstrate a host of non-specific features that are suggestive of malignancy, they may not be particularly indicative of Ewing’s sarcoma. Reinus, et. al., noted transcortical permeation in 75 percent of cases, diffuse sclerosis in 42 percent of cases, pure lysis in 25 percent of cases, bone expansion in 33 percent of cases and cystic degeneration in 25 percent of cases of Ewing’s sarcoma involving the foot. What You Need To Know About Osteogenic Sarcoma Osteogenic sarcoma, also known as osteosarcoma (OS), is the most common of all non-hematopoietic primary malignant neoplasms of bone found in the skeletal system. However, in the foot, researchers at Memorial Sloan-Kettering noted its incidence to be lower than Ewing’s sarcoma.1 Osteogenic sarcoma was diagnosed less than both Ewing’s sarcoma and chondrosarcoma at the Mayo Clinic.2-3 Keep in mind that osteogenic sarcoma or osteosarcoma encompass a number of distinct tumor subtypes with a spectrum of clinical aggressiveness. The single unifying feature is the production of osteoid by a population of malignant cells. Osteogenic sarcoma is classified into various subtypes based on the site of origin, pattern of growth, cytologic features, the type of stroma produced and the tumor grade. One may see tumors arise on the external surface of the involved bone, within the cortex or within the medullary canal. Alternatively, neoplastic cells may form large telangiectatic spaces filled with blood (telangiectatic OS) or, from a cytologic perspective, might be comprised of small hyperchromatic cells reminiscent of Ewing’s sarcoma (small cell OS). The tumor grade is related to the degree of cytologic atypia, mitotic activity and necrosis. (See “Differentiating Between High-Grade And Low-Grade Osteogenic Sarcoma” below.) Differentiating Between High-Grade And Low-Grade Osteogenic Sarcoma High-grade lesions disclose marked cytologic atypia and evidence of rapid proliferation. These lesions include conventional intramedullary OS, telangiectatic OS, small cell OS and high-grade surface OS. Low-grade lesions typically lack cytologic atypia and exhibit features indicative of slow indolent growth. These low-grade neoplasms include parosteal OS, well-differentiated intramedullary (central low-grade) OS and intracortical OS. It is particularly important to keep in mind the high frequency with which one sees low-grade OS. Just as is the case with regard to most other forms of sarcoma, the prognosis is vastly different for people affected by low-grade OS as compared to those who suffer from high-grade OS. High-grade OS is viewed as a systemic disease at diagnosis due to the extremely high rate of pulmonary metastasis. For this reason, affected individuals require preoperative chemotherapy followed by complete excision and an additional regimen of postoperative chemotherapy.13 In contrast, low-grade lesions almost uniformly remain localized at the time of diagnosis and are adequately treated with wide local excision in most cases. The overall incidence of low-grade OS in the skeletal system is essentially negligible, ranging from 3 to 6 percent in published series. However, among the bones of the foot, they account for between 15.4 and 42 percent of all cases.1,2,14-17 This trend imparts a much better than expected prognosis and less complicated course of therapy for a significant fraction of those people suffering from OS of the pedal bones. Key Insights In Diagnosing High-Grade OS The high-grade portion of the OS spectrum consists of conventional intramedullary OS, high-grade surface OS, telangiectatic OS and small cell OS. Conventional intramedullary is by far the most common variety of osteogenic sarcoma, accounting for more than 90 percent of all cases.2 One may subclassify these exceedingly aggressive neoplasms even further, according to their histologic appearance, as either osteoblastic, chondroblastic, fibroblastic or giant cell rich. Additionally, many authorities choose to include both telangiectatic and small cell OS as histologic subsets of conventional intramedullary OS. Like all types of osteogenic sarcoma, there is a male predominance that becomes less pronounced with progressive age.2 Osteogenic sarcoma has a somewhat bimodal age distribution in the general population. While over 60 percent of OS cases occur in people under the age of 25, there is a second peak beyond 60 years of age. This second peak is largely related to secondary factors such as Paget’s disease and radiation exposure.18,19 Investigators who have reviewed cases limited to the bones of the feet have reported slightly older mean ages at diagnosis, ranging from 26.9 to 34.8 years of age.1,16,17 The most common presenting complaint is pain but concurrent swelling is a routine finding.17 Researchers have shown that 51 percent of conventional intramedullary OS cases arise within the area of the knee.14 Over 90 percent of cases arise within the metaphysis of long bones, with the diaphysis primarily affected in roughly 8 percent of cases.2 In the foot, the calcaneus is the most commonly affected bone, followed by the talus and the metatarsals.17 Radiologically, most pedal cases disclose transcortical penetration with soft tissue extension at diagnosis. There is an admixture of lysis, sclerosis and rarefaction in most cases, although a single pattern often predominates.16,17 One may see “starburst” phenomenon and Codman’s triangle in the bones of the feet but these are not typical findings. Researchers have reported two profoundly sclerotic cases of conventional osteosarcoma, designated as "sclerosing OS," that arose within a hallux phalangeal bone.20,21 Clinicians must keep in mind that in one study, OS of the foot was misdiagnosed in 50 percent of cases. Some of the original diagnoses in these cases were osteoblastoma, chondroblastoma, osteomyelitis, chondrosarcoma, osteoid osteoma or desmoid fibroma.16 Also be aware that high-grade OS may resemble giant cell tumor or aneurysmal bone cyst in plain film radiographs. What To Look For With Intermediate Grade OS The sole osteogenic sarcoma subtype that falls into the category of intermediate grade is periosteal (juxtacortical chondroblastic) OS. This form of OS accounts for roughly 2 percent of all cases and is roughly one-third as common as low-grade parosteal OS.22 The age distribution and localization of periosteal OS is similar as that for conventional OS. However, unlike conventional OS, periosteal OS commonly affects the diaphysis of long bones.23 Also in contrast to conventional OS, the most common presenting complaint is localized swelling followed closely by pain.23 Periosteal OS is associated with a significantly better prognosis than conventional OS although metastases will manifest in up 15 percent of patients and recurrences are an expected finding in the absence of wide surgical excision.22,23 Radiologically, because periosteal OS arises on the external surface of long bones, the tumor is not typically confused with conventional intramedullary OS. However, one must distinguish periosteal OS from other surface tumors. In contrast to the uniformly dense appearance of low-grade parosteal OS, periosteal OS has a stippled appearance with radiating spicules of calcification extending out perpendicular to the surface of the bone.24 The underlying cortex may be focally eroded. However, tumors that show transcortical penetration into the medullary cavity are conventionally categorized as primary conventional intramedullary (high-grade) OS with secondary soft tissue extension.23,24 How To Recognize Low-Grade OS The low-grade portion of the OS spectrum is comprised of parosteal OS, intracortical OS and well-differentiated (low-grade) intramedullary OS. Parosteal OS accounts for roughly 80 percent of all cases of low-grade OS.2 This form of OS arises on the external surface of long bones with a predilection for the distal posterior femur (70 percent of cases), tibia and humerus. However, the bones of the feet may similarly be affected.1,2,15,25-27 While males overwhelmingly predominate with conventional OS, males and females have a similar rate of occurrence with parosteal OS.2,15 This altered gender ration persists among other low-grade OS variants such as low-grade intraosseous OS in which there is a slight female predominance.28 Also in contrast to conventional intramedullary OS, the chief complaint with regard to parosteal OS is pain-free swelling. These patients may also occasionally present with limitation of movement.15 All low-grade variants of OS have a tendency toward local recurrence although metastases at presentation are extremely uncommon. A particular concern is the tendency for parosteal OS recurrences to exhibit high-grade histology.27,28 Such high-grade recurrences behave in an extremely aggressive fashion and impart a poor prognosis.14,27,28 In part due to the poor prognosis associated with recurrences, wide local excision is mandated for all low-grade variants of OS. Radiologically, parosteal OS appears in plain film radiographs as a dense, heavily mineralized mass attached to the external surface of tubular bones by a broad base. Tumor density typically becomes greater closer to the site of attachment.29 Clinicians may see a vaguely delineated line of hypodensity between the tumor and the underlying cortical surface. One must distinguish these neoplasms from high-grade surface OS, extraosseous extension of intramedullary well-differentiated OS and periosteal OS. Pertinent Facts On Chrondrosarcomas The malignant neoplasm chondrosarcoma (CHS) exhibits differentiation toward hyaline cartilage. Although researchers have found CHS to be less common than osteogenic sarcoma in series’ that reviewed tumors of the entire skeletal system, CHS has shown a higher frequency of occurrence than osteogenic sarcoma in at least one series when tumors of the foot were reviewed in isolation.2,14,30 In the foot, Ostrowski and Spjut found CHS to be the most common malignant pedal bone tumor in their study.2,30 This report appeared to show a significant bias as its cases were largely derived from the authors’ consultation files and included lesions from the hand.30 In contrast, it was the third most common primary non-hematopoietic malignancy of the bones of the foot at the Memorial Sloan-Kettering Cancer Center.1 Despite its relative frequency in the foot as compared to most other malignant neoplasms of bone, roughly 98 percent of all CHS is seen within bones external to the foot.31,32 Similar to OS, primary bone CHS may arise within the medullary canal or upon the periosteal surface. Additionally, there are several histopathologic subtypes and a spectrum of tumor grades, each exhibiting different clinical behavior. Conventional CHS accounts for over 90 percent of all lesions with the remaining 10 percent being comprised of an admixture of clear cell CHS, myxoid CHS, dedifferentiated CHS and mesenchymal CHS. Grade 1 lesions have a low probability of demonstrating metastasis while higher grade lesions (particularly tumors with grade 3 histology) metastasize more readily. Grade 1 lesions predominate in the bones of the feet. Of 163 cases of CHS of the hands and feet that were reviewed at the Mayo Clinic, 116 disclosed grade 1 histology, 44 were grade 2 and only three were grade 3.33 Although similar findings were reflected in the Memorial Sloan-Kettering Cancer Center series, alternate investigators have recorded a slightly higher proportion of high grade lesions in the foot.1,30,31,34 Keep in mind there is a profoundly higher propensity for metastasis when CHS arises in the tarsal bones of the posterior foot, relative to those that are primary to the phalanges.31,35 Some investigators have questioned whether CHS of the digits have true malignant potential although reports of metastases and deaths secondary to primary digital CHS have been reported.31,33 Chondrosarcoma is largely a disease of middle-aged adults and the elderly but there have been reports of cases occurring in children as young as 5.2,32 In the largest published series of CHS of the hands and feet, the mean age was 53 and there was a slight male predominance.34 This correlates well with the average age and gender distribution among patients with CHS elsewhere in the skeletal system.2 CHS appears to arise in a significantly older age group when it occurs in the phalanges, with a mean age of 67 in one series.33 The most common location for CHS in the foot is the calcaneus but it may affect any bone, including the sesamoids.31,34 When it occurs in the digits, the proximal phalanx is most commonly involved.33 Most affected individuals present with pain, swelling or both. In the foot, the presence of pain and an older patient age may be important clues in diagnosing CHS as opposed to enchondromas, which are uniformly painless and more common in young adults.31 The radiological appearance of CHS is exceedingly important for the correct diagnosis of low and intermediate grade lesions. In many instances, the histopathologic diagnosis of low-grade CHS cannot be done without radiographic analysis. Chondrosarcoma is characteristically a lytic process but one may see punctuate mineralization, which is typical of these lesions. In the bones of the feet, the most common single feature is endosteal erosion (94 percent) with or without frank cortical destruction (92 percent).34 Bony expansion, soft tissue extension and a permeative pattern of growth are additional findings that suggest the diagnosis of CHS over enchondroma.31,34 How To Diagnose Angiosarcomas And Epithelioid Hemangioendotheliomas Angiosarcomas (AS) and epithelioid hemangioendotheliomas (EHE) exhibit endothelial (vascular) differentiation. In some cases, such differentiation is not apparent by light microscopy and must be demonstrated with immunohistochemical studies or electron microscopy.36 Traditional angiosarcoma may exhibit a spectrum of differentiation, ranging from extremely well-differentiated tumors that resemble benign hemangiomas to poorly differentiated neoplasms with few if any vascular features by light microscopy. As is the case with many neoplasms, the prognosis is worse for higher-grade tumors that are less differentiated. In a series by Wold, the disease free survival rate was 95 percent for people with grade 1 lesions and plummeted to only 20 percent for individuals suffering with grade 3 tumors.37 Weiss and Enzinger initially described EHE as a vascular neoplasm characterized by cells with low-grade cytologic features and an epithelioid appearance.36 People affected by this low-grade variant have a relatively good prognosis but be aware that some EHE may pursue an aggressive clinical course.38-40 Most investigators now believe that EHE and AS are part of the same spectrum of disease. The trend is to use the term “hemangioendothelioma” to denote those lesions that are low-grade (well differentiated) and “angiosarcoma” to refer to those tumors that are of a higher tumor grade (poorly differentiated). Others use these terms interchangeably and then simply qualify the diagnosis with a particular grade (i.e. angiosarcoma, grade 3).2 Together, EHE and AS ranked fourth in frequency amongst non-hematopoietic primary malignancies of the pedal bones in the Memorial Sloan-Kettering Cancer Center series, which listed 10 such cases among the 68 malignant neoplasms diagnosed at that institution.1 Vascular sarcoma was the fifth most common type of primary bone malignancy in the series assembled by Ostrowski and Spjut.30 Overall, they account for roughly 1 percent of all malignant bone tumors. However, their frequency is likely higher in the foot as a disproportionately high number of EHEs arise at that site.2,38 When arising in bone, these tumors are multicentric in 20 to 50 percent of cases.38,41 There may be widespread bone involvement.42 Such synchronous growth may be an important clue as to the diagnosis of angiosarcoma/EHE prior to biopsy. Traditional AS does not favor any particular age group as it occurs equally among those between the ages of 10 and 70.2 In contrast, those tumors classified as EHE tend to affect people in their second, third and fourth decade of life.38 Each gender is affected equally by EHE whereas traditional AS may show a slight male predominance.2,38 The long bones of the lower extremity are most commonly affected by EHE, though the small bone of the hands are involved in a relatively high percentage of cases.2,38 Kleer noted seven of 68 (10 percent) cases of EHE at the Mayo clinic involved the bones of the feet while Unni documented that seven of 80 (9 percent) of the malignant vascular tumors in their series arose in that location.2,38 Pain is the most common presenting complaint. Radiologically, malignant vascular tumors produce non-specific lytic lesions that may be multicentric. Clustering of distinct lesions in a single region is highly suggestive of EHE or traditional AS.2,38 In some instances, there may be a vague sclerotic rim which is more prominent in low-grade lesions, particularly EHE. Most lesions are poorly demarcated. Pathologic fracture and soft tissue extension are more likely to occur in association with high-grade or poorly differentiated neoplasms but they may also be precipitated by EHE. What You Should Know About Metastases Metastases to the small bones of the feet are uncommon events, accounting for only a single case of the 240 “lesions” of the bones of the hands and feet in one series.30 Huvos noted 10 metastases among the 68 malignant pedal bone tumors (14.7 percent) identified at Memorial Sloan-Kettering Cancer Center, making it the fourth most common non-hematopoietic malignancy of bone in that series.1 The most common primary sites to metastasize to the bones of the foot are the lower intestinal tract, followed closely by the genitourinary system and lower respiratory tract.43,44 This contrasts with metastases to the bones of the hand in which pulmonary primaries overwhelmingly predominate.45 Metastases to bone are indicative of end-stage disease. Not surprisingly, patient survival following such events averages less than 12 months.43 The incidence of bone metatases rises with advancing age. As such, it is most common among the elderly, an age group most commonly affected by the primary carcinoma. This parallels the age at which most individuals are affected by the primary carcinomas. In the rare instances when children are affected, the most common offending neoplasms are neuroblastoma, rhabdomyosarcoma and clear cell sarcoma of the kidney. In the vast majority of cases, especially in the non-pediatric age group, treatment options are palliative, consisting of radiotherapy, chemotherapy and occasionally surgery with the goal of minimizing pain and preserving function. Radiologically, metastases may produce lytic lesions, sclerotic (osteoblastic) lesions or a combination of the two. Sclerotic (osteoblastic) metastases induce the production of new bone, thereby appearing radioopaque in plain film radiographs. The vast majority of bony metastases are either entirely lytic or mixed in nature. In general, gastrointestinal carcinoma, thyroid carcinoma and renal cell carcinoma are lytic. Lung and breast metastases are typically lytic but one may occasionally see focally sclerotic lesions.46,47 Prostatic adenocarcinoma is characteristically sclerotic.48 Pathologic fracture is a common complication of metastases of all types. In exceptional cases, metastases may produce an irregular periosteal reaction similar to what one might see with an osteogenic sarcoma.49Dr. Bakotic is the Director of the Divisions of Podiatric and Dermatopathology at ProPath Services in Dallas, Texas. He is also a Diplomate of the American Board of Pathology. Editor’s Note: Portions of this article have been adapted with permission from the Data Trace Publishing Company from the following article citation: Bakotic BW, Bone Tumors of the Lower Extremity, in Principles and Practice of Podiatric Medicine, Leonard Levy, Vincent Herrington, eds., 2nd edition, Copyright 2005, Data Trace Publishing Company.
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