- Email: [email protected]
Metastases Involving Bone
24
Metastases Involving Bone Yasuaki Nakashima
Metastatic tumor of bone is the secondary skeletal deposit of a neoplasm from another primary site and is the most common form of all malignant tumors invol ving bone. The metastatic lesions are multiple or, less frequently, solitary. Most of the primary malignant tumors are carcinomas. Rarely, neoplasms showing benign histology can metastasize to bone. If the histol ogy of a primary site is known, fine-needle aspiration biopsy (cytology) or core needle biopsies of meta static lesions may determine the diagnosis. Primary malignancies can invade bone by direct extension or through lymphatic and vascular channels including vertebral Batson plexus of veins. Bony change seen in metastatic tumors is osteolytic or, less frequently, osteoblastic or mixed. They may be modulated by the postulated effects of humoral factors or cytokines, including transforming growth factor-β (TGF-β), fibroblast growth factor, bone morphogenetic pro teins, prostaglandins, interleukin-1, parathormonerelated protein, among others, secreted by neoplastic cells. Activity of osteoclasts transformed from macro phages may also induce the structural change of bones affected by metastasis.
Clinical Features Because the incidence of primary sarcomas of bone is substantially less than that of carcinomas in other organs, metastatic carcinomas are the most common malignant tumor involving the bone, and after the lungs and liver, the skeleton is the third most frequent site of metastatic disease. According to several reports, approx imately 30% to 90% of the patients with common carci nomas are estimated to have skeletal metastases in their course of the disease. As is often the case with the sec ondary malignancy, bone metastases tend to affect older patients, and more than 60% of patients are in their sixth to seventh decade of life. Osseous metastatic dis ease in children is rare and most commonly originates from neuroblastoma, clear cell sarcoma of kidney, osteo sarcoma, Ewing sarcoma/primitive neuroectodermal tumor (PNET) group, and rhabdomyosarcoma. It is dif ficult to determine significant sex predilection. 446
Metastases can affect any bone containing red arrow. Nearly 70% occur in axial skeleton, including m the cranium, vertebrae, rib, sternum, sacrum, and pelvis. Approximately 30% of bone metastases involve the appendicular skeleton, but rarely distal to the knee and elbow. Metastatic tumor involving the small bones of the hands and feet is rare, and usually originates from the lung or kidney. In more than 80% of patients, a pertinent clinical search, including physical examination, laboratory stud ies, and radiological investigations, usually identifies the primary site. Lung, breast, prostate, kidney, and thyroid gland account for more than 80% of all skeletal metas tases. Carcinomas of the kidney and thyroid gland fre quently involve the skull, sternum, pelvis, bones of the shoulder girdle, and pelvic flat bones. These locations comprise more than 70% of all sites for metastatic deposits. Skeletal metastasis of sarcoma is relatively rare and more frequently seen in children. Examples of skip metastasis or even bone-to-bone metastasis of osteosarcoma are reported. Symptoms of patients with metastatic carcinoma are generally nonspecific. Pain, with or without swelling, pathologic fracture, and neurological symptoms when the lesion affects spine are common findings. Systemic symptoms, including hypercalcemia secondary to oste olysis and Collet–Sicard syndrome in skull base metas tases, may occur. Hypercalcemia and increased serum alkaline phosphatase may be seen due to extensive osteolytic activity of metastatic tumor. Prominent osteo blastic metastases of prostate carcinoma may cause osteomalacia secondary to the high calcium demand for new bone formation.
Radiologic Features Radiographically, most metastases produce osteolytic and destructive changes predominantly located in the marrow cavity (Figures 24-1 and 24-2). Osteoblastic or mixed lytic and blastic change can also occur (Fig ure 24-3). In the long bones, metastatic deposits tend to involve the metaphysis, and a solitary lesion can mimic a primary bone sarcoma. Metastatic renal cell
447
Chapter 24 Metastases Involving Bone
A
B
D
C
E
Figure 24-1 Metastatic carcinoma involving the proximal femur. A, Anteroposterior view shows osteolytic lesions in the proximal femur. B, T1-weighted and C, T2-weighted coronal magnetic resonance images and D, an axial computed tomographic image demonstrate osteolytic and destructive lesions with ill-defined margins. E, Radioisotope scintigram using technetium-99m is positive in the proximal femur.
448
BONE AND SOFT TISSUE PATHOLOGY
A
C
B
D
Figure 24-2 Metastatic renal cell carcinoma involving the spine and rib. A, Anteroposterior view of radiograph, B, anteroposterior tomographic view, and C, an axial computed tomographic (CT) image visualize medullary osteolysis and destruction of vertebral body. D, An axial CT image shows osteolytic and destructive change of the rib.
c arcinoma frequently produces purely lytic destruc tion with aneurysmal bone cyst-like change. Similar radiographic features are occasionally seen in metas tases from carcinoma of the gastrointestinal tract, thy roid carcinoma, or malignant melanoma. Metastases from lung or breast can show mixed lytic and blastic change. Prostatic adenocarcinoma is one of the wellknown examples frequently presenting with purely osteoblastic metastasis. When such a sclerotic meta static lesion is solitary and associated with periosteal reaction, differentiation from a primary bone sarcoma
may be difficult. Florid ossification due to pathologic fracture of a metastatic tumor may even simulate the roentgenologic features of osteosarcoma. Computed tomography (CT) scan and magnetic resonance imag ing (MRI) have the advantage of detecting metastatic lesions in the vertebrae where only about a quarter of metastases are identified by conventional plain radio graphs. Radioisotope scintigram bone scan of meta static carcinoma is almost invariably positive and thus useful for detecting multiple skeletal metastases (see Figure 24-3C).
449
Chapter 24 Metastases Involving Bone
A
B
C
Figure 24-3 Multiple skeletal meta������������������������������������������ stases of adenocarcinoma from the stomach. A, Anteroposterior view of the femur and B, lateral view of the spine show diffuse sclerotic change. C, Radioi��������������������������������������� sotope scintigram using technetium-99m is positive in multiple bones of the axial skeleton.
Pathologic Features Gross Findings
The gross appearance of metastatic carcinoma involv ing bone is nonspecific and oftentimes not too disimilar from that of primary bone sarcomas (Figure ���������������� 24-4)������� Osteo blastic metastases can be particularly dense and hard, simulating osteosarcoma. Extraosseous extension of metastatic deposits can also produce a soft tissue mass.
arcomatoid carcinomas, especially from the kidney, S lung, or thyroid gland, sometimes lack apparent epi thelial differentiation and therefore simulate primary spindle cell sarcomas of bone (Figure 24-6). Osteoblastic metastases such as prostate, neuroendocrine, and breast carcinomas are occasionally associated with reactive bone formation and therefore simulate osteosarcoma with epithelioid features (Figure 24-7). When the pro liferation of osteoclastic multinucleated giant cells is prominent, metastatic tumors can even be confused with giant cell tumor of bone.
Microscopic Findings
Osseous metastatic carcinoma tends to resemble the histology of the primary tumor, and in most cases, its metastatic nature is histologically evident. Metastatic adenocarcinomas or squamous cell carcinomas from the most common primary sites, including the lung, breast, kidney, prostate, and thyroid gland, usually retain their inherent morphologic features and cause practically no diagnostic problems (Figure 24-5). Reactive stromal changes, including fibroblastic spindle cell proliferation, vascular proliferation, and infiltration of osteoclastic multinucleated giant cells are relatively common. In the case of poorly differentiated or undifferentiated carci nomas, it may be difficult to determine the primary site.
Immunohistochemistry Immunostains for epithelial membrane antigen (EMA) and keratins (CAM 5.2, AE1/3, CK7, CK20, among others) are frequently positive in epithelial tumors and negative in most mesenchymal lesions. Therefore, they may be useful for differentiating between meta static carcinomas and primary bone sarcomas. Since rare keratin positive cells can be seen in some sarcomas, caution should be taken when interpreting results. In some cases, immunohistochemical markers may be help ful in identifying the primary site and histologic type
450 A
BONE AND SOFT TISSUE PATHOLOGY
B
Figure 24-4 A, Gross photograph of a mid femur with metastatic gastric adenocarcinoma, showing a well-circumscribed pale mass with focal myxoid change. B, Gross appearance of an amputated proximal phalanx of the finger with metastatic renal cell carcinoma. C, Microscopically, the tumor is composed of clear cells expanding the bone. Kidney and lung are the most common primary sites of acral metastasis.
C
A
B
Figure 24-5 A, Histology of metastatic renal cell carcinoma with clear cell features. B, Metastatic squamous cell carcinoma from the cervix shows epithelial nests associated with dense fibrosis.
of the metastatic tumor. Some examples include thyroid transcription factor-1 (TTF-1) for lung or thyroid can cer, prostatic-specific antigen (PSA) for carcinoma of the prostate, estrogen and progesterone receptors for breast cancer, S-100 protein, HMB-45, or Melan-A for malig nant melanoma, and chromogranin A for neuroendo crine tumors. Immunohistochemical studies tend to be positive more often in well-to moderately-differentiated tumors. They are of more limited value in poorly differ entiated tumors.
Differential Diagnosis For any bone malignant tumor in patients older than 60 years, whether histologically showing epithelioid spindle cell or round cell features, one should always be concerned about the possibility of metastatic carcinoma. Meticulous clinical and imaging evaluations are manda tory for patients with a bone lesion suggestive of metas tasis. Nevertheless, even with immunohistochemical
451
Chapter 24 Metastases Involving Bone
A
B
Figure 24-6 A, Metastatic sarcomatoid carcinoma from papillary thyroid carcinoma, closely simulating primary spindle cell sarcoma of bone. B, Metastatic sarcomatoid renal cell carcinoma from the kidney.
A
B
C Figure 24-7 A, Low-power view of a metastatic adenocarcinoma from the prostate with osteosclerotic change. B, Osteoblastic metastasis of carcinoma from the breast. C, Metastatic adenocarcinoma from the stomach. Only a few malignant cells are scattered in the intertrabecular fibrous stroma.
452
BONE AND SOFT TISSUE PATHOLOGY
METASTASES INVOLVING BONE—FACT SHEET Definition ▸▸ Secondary bone involvement of tumor originating from another primary site Incidence and Location ▸▸ Most common malignant tumor involving bone ▸▸ Predominantly occurs in cranium, vertebrae, rib, sternum, sacrum, pelvis, pelvic girdles including proximal femur ▸▸ Frequently multiple ▸▸ In the long bones, tends to involve the metaphysis ▸▸ Rare in small bones of the hands and feet Morbidity and Mortality ▸▸ Up to 90% of the patients with common carcinomas may have skeletal metastasis ▸▸ Metastatic carcinoma from lung, breast, prostate, kidney, and thyroid glands accounts for more than 80% ▸▸ Skeletal metastasis of sarcoma is rare and most frequently seen in children ▸▸ Mortality depends on histologic type and site of the primary tumor Sex, Race, and Age Distribution ▸▸ No significant sex predilection ▸▸ Peak incidence at 40 to 60 years Clinical Features ▸▸ Symptoms are nonspecific and simulate those of a primary bone sarcoma ▸▸ Pain, with or without swelling, and pathologic fracture are main symptoms ▸▸ Neurologic symptoms may be noted with the lesion of the spine ▸▸ Hypercalcemia and increased serum alkaline phosphatase secondary to osteolysis may be demonstrated. ▸▸ Collet–Sicard syndrome in skull base metastasis may occur ▸▸ Prominent osteoblastic metastases may cause osteomalacia secondary to the high calcium demand Radiologic Features ▸▸ Usually suggests a malignant tumor ▸▸ Osteolytic and destructive change mainly located in marrow cavity ▸▸ Osteoblastic or mixed lytic and blastic change may occur ▸▸ Prostatic adenocarcinoma frequently shows purely osteoblastic metastasis ▸▸ Periosteal reaction and florid ossification with pathologic fracture may simulate osteosarcoma ▸▸ CT scan and MRI particularly useful for detecting metastatic lesions in the vertebrae ▸▸ Radioisotope scintigram bone scan is positive for metastatic carcinoma Prognosis and Treatment ▸▸ Prognosis depends on the primary site of the tumor, histologic type of neoplasm, and extent of disease ▸▸ Relief of pain and prevention of fracture are goals of treatment ▸▸ A localized single deposit may be surgically resected ▸▸ Radiation and chemotherapy may be effective in controlling the symptoms ▸▸ Specific therapies, including hormonal treatment for breast and prostate carcinoma, may be indicated
studies confusion between metastatic sarcomatoid car cinoma and primary skeletal spindle cell sarcoma may be inevitable. Multiple myeloma commonly presents as multiple osteolytic lesions in older patients and thus may simulate metastatic carcinoma. Radioisotope bone scan is generally negative, and demonstration of monoclonal ��������������� protein ������� in the serum and urine is practically diagnostic. Angiosarcoma of bone can also involve multiple skeletal sites similar to metastatic carcinoma. The histologic features of angiosar coma, particularly epithelioid angiosarcoma, can mimic metastatic carcinoma. Immunostains for CD31 and CD34 are, however, generally positive in angiosarcomas and negative in carcinoma. However, both malignancies can be positive with keratin. Since osteosarcomas occasionally show epithelial features and, on the other hand, reactive bone production may be prominent in some osteoblastic metastases, differentiation between osteosarcoma and metastatic carcinoma may sometimes be difficult. The age of the patient, location of the lesion, and immunohisto chemical studies may help solve the problem. Adamanti noma of long bones usually have an epithelial component and therefore mimic metastatic carcinoma. Characteris tic involvement of the tibia or, less frequently, the fibula may be a clue in making the correct diagnosis. Primary leiomyosarcoma of bone is extremely rare, and therefore the possibility of metastasis from uterine leiomyosarcoma should be completely excluded before establishing this unusual diagnosis. Melanocytic malignancy involving bone is almost always metastatic tumor from another pri mary site. Squamous cell carcinoma, usually well differ entiated, can occur in association with draining sinus in longstanding osteomyelitis. Clinical history of the patient and roentgenologic study are of great help in the differ ential diagnosis of secondary squamous cell carcinoma in chronic osteomyelitis from metastatic carcinoma.
Prognosis and Treatment Metastatic tumors of bone always represent advanced disease, generally associated with a poor outcome. The prognosis of patients may depend on the primary site of the tumor, histologic type of neoplasm, and extent of disease. Palliative therapies for relief of pain and for prevention of fracture are the most common treatments of choice. A localized single deposit may be surgically resected. Radiation and chemotherapy may be effective in diminishing the symptoms and in detaining progres sion of the disease. Radioactive iodine is used for con trolling some thyroid cancers. Carcinomas from breast and prostate may be treated by hormonal medication. Immunostains for HER2/neu protein and estrogen and progesterone receptors help guide treatment of meta static breast carcinoma.
Chapter 24 Metastases Involving Bone
MESTASTASES INVOLVING BONE—PATHOLOGIC FEATURES Gross Findings ▸▸ Usually nonspecific and simulate primary bone sarcomas ▸▸ Frequently osteolytic, soft, and hemorrhagic ▸▸ Grayish white, firm, and fibrotic by desmoplastic reaction of the stroma ▸▸ Dense and hard osteoblastic metastases, particularly in metastatic prostatic carcinoma ▸▸ Periosteal new bone formation is infrequent ▸▸ Extraosseous extension with a soft tissue mass may occur Microscopic Findings ▸▸ Tend to retain the morphologic features of the primary tumor ▸▸ Adenocarcinomas or squamous cell carcinomas from the lung, breast, kidney, prostate, and thyroid gland are common ▸▸ Fibroblastic proliferation, vascular proliferation, and osteoclastic multinucleated giant cells in the stroma are frequent ▸▸ Sarcomatoid carcinomas may simulate primary or secondary spindle cell sarcomas ▸▸ Metastases from the prostate, breast, or neuroendocrine tumor, among others, are occasionally associated with reactive bone formation or production of osteoid Immunohistochemical Findings ▸▸ EMA or keratins (CAM 5.2, AE1/3, CK7, CK20, among others) are frequently positive in metastatic carcinomas ▸▸ Sarcomatoid carcinomas tend to be positive for vimentin and negative or focally positive for keratins ▸▸ Immunohistochemical markers frequently used are TTF-1 for lung or thyroid cancer, PSA for carcinoma of the prostate, estrogen and progesterone receptors for breast cancer, S-100 protein, HMB-45, or Melan-A for malignant melanoma, and chromogranin A or CD56 for neuroendocrine tumors Differential Diagnosis
▸▸ Plasmacytoma ▸▸ Angiosarcoma ▸▸ Osteosarcomas with epithelioid features ▸▸ Adamantinoma of long bones ▸▸ Fibrosarcoma or malignant fibrous histiocytoma of bone ▸▸ Squamous cell carcinoma arising in longstanding osteomyelitis
SUGGESTED READINGS 1. Aebi M: Spinal metastasis in the elderly. Eur Spine J 2003;12(suppl 2): S202–S213. 2. Ali SM, Harvey HA, Lipton A: Metastatic breast cancer: overview of treatment. Clin Orthop 2003;(415 suppl):S132–S137. 3. Bendre M, Gaddy D, Nicholas RW, et al: Breast cancer metastasis to bone: it is not all about PTHrP. Clin Orthop 2003;(415 suppl): S39–S45.
453 4. Brage ME, Simon MA: Evaluation, prognosis, and medical treatment considerations of metastatic bone tumors. Orthopedics 1992;15(5):589–596. 5. Campanacci M: Bone and Soft Tissue Tumors. Berlin, Germany: Springer-Verlag, 1999, pp 756–787. 6. Carlin BI, Andriole GL: The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 2000;88(12 suppl):2989–2994. 7. Cheville JC, Tindall D, Boelter C, et al: Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancerspecific survival. Cancer 2002;95(5):1028–1036. 8. Choong PF: The molecular basis of skeletal metastases. Clin Orthop 2003;(415 suppl):S19–S31. 9. Dorfman HD: Czerniak B: Bone Tumors. St. Louis, MO: Mosby, 1998, 1009–1040. 10. Falkmer U, Jarhult J, Wersall P, et al: A systematic overview of radiation therapy effects in skeletal metastases. Acta Oncol 2003;42: 620–633. 11. Goltzman D, Karaplis AC, Kremer R, et al: Molecular basis of the spectrum of skeletal complications of neoplasia. Cancer 2000;88(12 suppl):2903–2908. 12. Guise TA: Molecular mechanisms of osteolytic bone metastases. Cancer 2000;88(12 suppl):2892–2898. 13. Healey JH, Turnbull AD, Miedema B, et al: Acrometastases. A study of twenty-nine patients with osseous involvement of the hands and feet. J Bone Joint Surg Am 1986;68:743–746. 14. James JJ, Evans AJ, Pinder SE, et al: Bone metastases from breast carcinoma: histopathological-radiological correlations and prognostic features. Br J Cancer 2003;89:660–665. 15. Kager L, Zoubek A, Potschger U, et al: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003;21:2011–2018. 16. Kakonen SM, Mundy GR: Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 2003;97(3 suppl):834–839. 17. Mundy GR: Mechanisms of bone metastasis. Cancer 1997;80 (8 suppl):1546–1556. 18. Peterson JJ, Kransdorf MJ, O’Connor MI: Diagnosis of occult bone metastases: Positron emission tomography. Clin Orthop 2003;(415 suppl):S120–S128. 19. Resnick D: Bone and Joint Imaging. Philadelphia, Saunders, 1996, pp 1076–1091. 20. Rodan GA: The development and function of the skeleton and bone metastases. Cancer 2003;97(3 suppl):726–732. 21. Rougraff BT: Evaluation of the patient with carcinoma of unknown origin metastatic to bone. Clin Orthop 2003;(415 suppl):S105–S109. 22. San-Julian M, Diaz-de-Rada P, Noain E, et al: Bone metastases from osteosarcoma. Int Orthop 2003;27:117–120. 23. Simon MA, Bartucci EJ: The search for the primary tumor in patients with skeletal metastases of unknown origin. Cancer 1986;58: 1088–1095. 24. Troncoso A, Ro JY, Grignon DJ, et al: Renal cell carcinoma with acrometastasis: report of two cases and review of the literature. Mod Pathol 1991;4:66–69. 25. Unni KK: Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. Philadelphia: Lippincott-Raven, 1996, pp 355–360. 26. Weber MH, Goltzman D, Kostenuik P, et al: Mechanisms of tumor metastasis to bone. Crit Rev Eukaryot Gene Expr 2000;10:281–302. 27. Wilner D: Radiology of Bone Tumors and Allied Disorders, vol. 4. Philadelphia, Saunders, 1982, pp 3641–3908.
Metastases Involving Bone Yasuaki Nakashima
Metastatic tumor of bone is the secondary skeletal deposit of a neoplasm from another primary site and is the most common form of all malignant tumors invol ving bone. The metastatic lesions are multiple or, less frequently, solitary. Most of the primary malignant tumors are carcinomas. Rarely, neoplasms showing benign histology can metastasize to bone. If the histol ogy of a primary site is known, fine-needle aspiration biopsy (cytology) or core needle biopsies of meta static lesions may determine the diagnosis. Primary malignancies can invade bone by direct extension or through lymphatic and vascular channels including vertebral Batson plexus of veins. Bony change seen in metastatic tumors is osteolytic or, less frequently, osteoblastic or mixed. They may be modulated by the postulated effects of humoral factors or cytokines, including transforming growth factor-β (TGF-β), fibroblast growth factor, bone morphogenetic pro teins, prostaglandins, interleukin-1, parathormonerelated protein, among others, secreted by neoplastic cells. Activity of osteoclasts transformed from macro phages may also induce the structural change of bones affected by metastasis.
Clinical Features Because the incidence of primary sarcomas of bone is substantially less than that of carcinomas in other organs, metastatic carcinomas are the most common malignant tumor involving the bone, and after the lungs and liver, the skeleton is the third most frequent site of metastatic disease. According to several reports, approx imately 30% to 90% of the patients with common carci nomas are estimated to have skeletal metastases in their course of the disease. As is often the case with the sec ondary malignancy, bone metastases tend to affect older patients, and more than 60% of patients are in their sixth to seventh decade of life. Osseous metastatic dis ease in children is rare and most commonly originates from neuroblastoma, clear cell sarcoma of kidney, osteo sarcoma, Ewing sarcoma/primitive neuroectodermal tumor (PNET) group, and rhabdomyosarcoma. It is dif ficult to determine significant sex predilection. 446
Metastases can affect any bone containing red arrow. Nearly 70% occur in axial skeleton, including m the cranium, vertebrae, rib, sternum, sacrum, and pelvis. Approximately 30% of bone metastases involve the appendicular skeleton, but rarely distal to the knee and elbow. Metastatic tumor involving the small bones of the hands and feet is rare, and usually originates from the lung or kidney. In more than 80% of patients, a pertinent clinical search, including physical examination, laboratory stud ies, and radiological investigations, usually identifies the primary site. Lung, breast, prostate, kidney, and thyroid gland account for more than 80% of all skeletal metas tases. Carcinomas of the kidney and thyroid gland fre quently involve the skull, sternum, pelvis, bones of the shoulder girdle, and pelvic flat bones. These locations comprise more than 70% of all sites for metastatic deposits. Skeletal metastasis of sarcoma is relatively rare and more frequently seen in children. Examples of skip metastasis or even bone-to-bone metastasis of osteosarcoma are reported. Symptoms of patients with metastatic carcinoma are generally nonspecific. Pain, with or without swelling, pathologic fracture, and neurological symptoms when the lesion affects spine are common findings. Systemic symptoms, including hypercalcemia secondary to oste olysis and Collet–Sicard syndrome in skull base metas tases, may occur. Hypercalcemia and increased serum alkaline phosphatase may be seen due to extensive osteolytic activity of metastatic tumor. Prominent osteo blastic metastases of prostate carcinoma may cause osteomalacia secondary to the high calcium demand for new bone formation.
Radiologic Features Radiographically, most metastases produce osteolytic and destructive changes predominantly located in the marrow cavity (Figures 24-1 and 24-2). Osteoblastic or mixed lytic and blastic change can also occur (Fig ure 24-3). In the long bones, metastatic deposits tend to involve the metaphysis, and a solitary lesion can mimic a primary bone sarcoma. Metastatic renal cell
447
Chapter 24 Metastases Involving Bone
A
B
D
C
E
Figure 24-1 Metastatic carcinoma involving the proximal femur. A, Anteroposterior view shows osteolytic lesions in the proximal femur. B, T1-weighted and C, T2-weighted coronal magnetic resonance images and D, an axial computed tomographic image demonstrate osteolytic and destructive lesions with ill-defined margins. E, Radioisotope scintigram using technetium-99m is positive in the proximal femur.
448
BONE AND SOFT TISSUE PATHOLOGY
A
C
B
D
Figure 24-2 Metastatic renal cell carcinoma involving the spine and rib. A, Anteroposterior view of radiograph, B, anteroposterior tomographic view, and C, an axial computed tomographic (CT) image visualize medullary osteolysis and destruction of vertebral body. D, An axial CT image shows osteolytic and destructive change of the rib.
c arcinoma frequently produces purely lytic destruc tion with aneurysmal bone cyst-like change. Similar radiographic features are occasionally seen in metas tases from carcinoma of the gastrointestinal tract, thy roid carcinoma, or malignant melanoma. Metastases from lung or breast can show mixed lytic and blastic change. Prostatic adenocarcinoma is one of the wellknown examples frequently presenting with purely osteoblastic metastasis. When such a sclerotic meta static lesion is solitary and associated with periosteal reaction, differentiation from a primary bone sarcoma
may be difficult. Florid ossification due to pathologic fracture of a metastatic tumor may even simulate the roentgenologic features of osteosarcoma. Computed tomography (CT) scan and magnetic resonance imag ing (MRI) have the advantage of detecting metastatic lesions in the vertebrae where only about a quarter of metastases are identified by conventional plain radio graphs. Radioisotope scintigram bone scan of meta static carcinoma is almost invariably positive and thus useful for detecting multiple skeletal metastases (see Figure 24-3C).
449
Chapter 24 Metastases Involving Bone
A
B
C
Figure 24-3 Multiple skeletal meta������������������������������������������ stases of adenocarcinoma from the stomach. A, Anteroposterior view of the femur and B, lateral view of the spine show diffuse sclerotic change. C, Radioi��������������������������������������� sotope scintigram using technetium-99m is positive in multiple bones of the axial skeleton.
Pathologic Features Gross Findings
The gross appearance of metastatic carcinoma involv ing bone is nonspecific and oftentimes not too disimilar from that of primary bone sarcomas (Figure ���������������� 24-4)������� Osteo blastic metastases can be particularly dense and hard, simulating osteosarcoma. Extraosseous extension of metastatic deposits can also produce a soft tissue mass.
arcomatoid carcinomas, especially from the kidney, S lung, or thyroid gland, sometimes lack apparent epi thelial differentiation and therefore simulate primary spindle cell sarcomas of bone (Figure 24-6). Osteoblastic metastases such as prostate, neuroendocrine, and breast carcinomas are occasionally associated with reactive bone formation and therefore simulate osteosarcoma with epithelioid features (Figure 24-7). When the pro liferation of osteoclastic multinucleated giant cells is prominent, metastatic tumors can even be confused with giant cell tumor of bone.
Microscopic Findings
Osseous metastatic carcinoma tends to resemble the histology of the primary tumor, and in most cases, its metastatic nature is histologically evident. Metastatic adenocarcinomas or squamous cell carcinomas from the most common primary sites, including the lung, breast, kidney, prostate, and thyroid gland, usually retain their inherent morphologic features and cause practically no diagnostic problems (Figure 24-5). Reactive stromal changes, including fibroblastic spindle cell proliferation, vascular proliferation, and infiltration of osteoclastic multinucleated giant cells are relatively common. In the case of poorly differentiated or undifferentiated carci nomas, it may be difficult to determine the primary site.
Immunohistochemistry Immunostains for epithelial membrane antigen (EMA) and keratins (CAM 5.2, AE1/3, CK7, CK20, among others) are frequently positive in epithelial tumors and negative in most mesenchymal lesions. Therefore, they may be useful for differentiating between meta static carcinomas and primary bone sarcomas. Since rare keratin positive cells can be seen in some sarcomas, caution should be taken when interpreting results. In some cases, immunohistochemical markers may be help ful in identifying the primary site and histologic type
450 A
BONE AND SOFT TISSUE PATHOLOGY
B
Figure 24-4 A, Gross photograph of a mid femur with metastatic gastric adenocarcinoma, showing a well-circumscribed pale mass with focal myxoid change. B, Gross appearance of an amputated proximal phalanx of the finger with metastatic renal cell carcinoma. C, Microscopically, the tumor is composed of clear cells expanding the bone. Kidney and lung are the most common primary sites of acral metastasis.
C
A
B
Figure 24-5 A, Histology of metastatic renal cell carcinoma with clear cell features. B, Metastatic squamous cell carcinoma from the cervix shows epithelial nests associated with dense fibrosis.
of the metastatic tumor. Some examples include thyroid transcription factor-1 (TTF-1) for lung or thyroid can cer, prostatic-specific antigen (PSA) for carcinoma of the prostate, estrogen and progesterone receptors for breast cancer, S-100 protein, HMB-45, or Melan-A for malig nant melanoma, and chromogranin A for neuroendo crine tumors. Immunohistochemical studies tend to be positive more often in well-to moderately-differentiated tumors. They are of more limited value in poorly differ entiated tumors.
Differential Diagnosis For any bone malignant tumor in patients older than 60 years, whether histologically showing epithelioid spindle cell or round cell features, one should always be concerned about the possibility of metastatic carcinoma. Meticulous clinical and imaging evaluations are manda tory for patients with a bone lesion suggestive of metas tasis. Nevertheless, even with immunohistochemical
451
Chapter 24 Metastases Involving Bone
A
B
Figure 24-6 A, Metastatic sarcomatoid carcinoma from papillary thyroid carcinoma, closely simulating primary spindle cell sarcoma of bone. B, Metastatic sarcomatoid renal cell carcinoma from the kidney.
A
B
C Figure 24-7 A, Low-power view of a metastatic adenocarcinoma from the prostate with osteosclerotic change. B, Osteoblastic metastasis of carcinoma from the breast. C, Metastatic adenocarcinoma from the stomach. Only a few malignant cells are scattered in the intertrabecular fibrous stroma.
452
BONE AND SOFT TISSUE PATHOLOGY
METASTASES INVOLVING BONE—FACT SHEET Definition ▸▸ Secondary bone involvement of tumor originating from another primary site Incidence and Location ▸▸ Most common malignant tumor involving bone ▸▸ Predominantly occurs in cranium, vertebrae, rib, sternum, sacrum, pelvis, pelvic girdles including proximal femur ▸▸ Frequently multiple ▸▸ In the long bones, tends to involve the metaphysis ▸▸ Rare in small bones of the hands and feet Morbidity and Mortality ▸▸ Up to 90% of the patients with common carcinomas may have skeletal metastasis ▸▸ Metastatic carcinoma from lung, breast, prostate, kidney, and thyroid glands accounts for more than 80% ▸▸ Skeletal metastasis of sarcoma is rare and most frequently seen in children ▸▸ Mortality depends on histologic type and site of the primary tumor Sex, Race, and Age Distribution ▸▸ No significant sex predilection ▸▸ Peak incidence at 40 to 60 years Clinical Features ▸▸ Symptoms are nonspecific and simulate those of a primary bone sarcoma ▸▸ Pain, with or without swelling, and pathologic fracture are main symptoms ▸▸ Neurologic symptoms may be noted with the lesion of the spine ▸▸ Hypercalcemia and increased serum alkaline phosphatase secondary to osteolysis may be demonstrated. ▸▸ Collet–Sicard syndrome in skull base metastasis may occur ▸▸ Prominent osteoblastic metastases may cause osteomalacia secondary to the high calcium demand Radiologic Features ▸▸ Usually suggests a malignant tumor ▸▸ Osteolytic and destructive change mainly located in marrow cavity ▸▸ Osteoblastic or mixed lytic and blastic change may occur ▸▸ Prostatic adenocarcinoma frequently shows purely osteoblastic metastasis ▸▸ Periosteal reaction and florid ossification with pathologic fracture may simulate osteosarcoma ▸▸ CT scan and MRI particularly useful for detecting metastatic lesions in the vertebrae ▸▸ Radioisotope scintigram bone scan is positive for metastatic carcinoma Prognosis and Treatment ▸▸ Prognosis depends on the primary site of the tumor, histologic type of neoplasm, and extent of disease ▸▸ Relief of pain and prevention of fracture are goals of treatment ▸▸ A localized single deposit may be surgically resected ▸▸ Radiation and chemotherapy may be effective in controlling the symptoms ▸▸ Specific therapies, including hormonal treatment for breast and prostate carcinoma, may be indicated
studies confusion between metastatic sarcomatoid car cinoma and primary skeletal spindle cell sarcoma may be inevitable. Multiple myeloma commonly presents as multiple osteolytic lesions in older patients and thus may simulate metastatic carcinoma. Radioisotope bone scan is generally negative, and demonstration of monoclonal ��������������� protein ������� in the serum and urine is practically diagnostic. Angiosarcoma of bone can also involve multiple skeletal sites similar to metastatic carcinoma. The histologic features of angiosar coma, particularly epithelioid angiosarcoma, can mimic metastatic carcinoma. Immunostains for CD31 and CD34 are, however, generally positive in angiosarcomas and negative in carcinoma. However, both malignancies can be positive with keratin. Since osteosarcomas occasionally show epithelial features and, on the other hand, reactive bone production may be prominent in some osteoblastic metastases, differentiation between osteosarcoma and metastatic carcinoma may sometimes be difficult. The age of the patient, location of the lesion, and immunohisto chemical studies may help solve the problem. Adamanti noma of long bones usually have an epithelial component and therefore mimic metastatic carcinoma. Characteris tic involvement of the tibia or, less frequently, the fibula may be a clue in making the correct diagnosis. Primary leiomyosarcoma of bone is extremely rare, and therefore the possibility of metastasis from uterine leiomyosarcoma should be completely excluded before establishing this unusual diagnosis. Melanocytic malignancy involving bone is almost always metastatic tumor from another pri mary site. Squamous cell carcinoma, usually well differ entiated, can occur in association with draining sinus in longstanding osteomyelitis. Clinical history of the patient and roentgenologic study are of great help in the differ ential diagnosis of secondary squamous cell carcinoma in chronic osteomyelitis from metastatic carcinoma.
Prognosis and Treatment Metastatic tumors of bone always represent advanced disease, generally associated with a poor outcome. The prognosis of patients may depend on the primary site of the tumor, histologic type of neoplasm, and extent of disease. Palliative therapies for relief of pain and for prevention of fracture are the most common treatments of choice. A localized single deposit may be surgically resected. Radiation and chemotherapy may be effective in diminishing the symptoms and in detaining progres sion of the disease. Radioactive iodine is used for con trolling some thyroid cancers. Carcinomas from breast and prostate may be treated by hormonal medication. Immunostains for HER2/neu protein and estrogen and progesterone receptors help guide treatment of meta static breast carcinoma.
Chapter 24 Metastases Involving Bone
MESTASTASES INVOLVING BONE—PATHOLOGIC FEATURES Gross Findings ▸▸ Usually nonspecific and simulate primary bone sarcomas ▸▸ Frequently osteolytic, soft, and hemorrhagic ▸▸ Grayish white, firm, and fibrotic by desmoplastic reaction of the stroma ▸▸ Dense and hard osteoblastic metastases, particularly in metastatic prostatic carcinoma ▸▸ Periosteal new bone formation is infrequent ▸▸ Extraosseous extension with a soft tissue mass may occur Microscopic Findings ▸▸ Tend to retain the morphologic features of the primary tumor ▸▸ Adenocarcinomas or squamous cell carcinomas from the lung, breast, kidney, prostate, and thyroid gland are common ▸▸ Fibroblastic proliferation, vascular proliferation, and osteoclastic multinucleated giant cells in the stroma are frequent ▸▸ Sarcomatoid carcinomas may simulate primary or secondary spindle cell sarcomas ▸▸ Metastases from the prostate, breast, or neuroendocrine tumor, among others, are occasionally associated with reactive bone formation or production of osteoid Immunohistochemical Findings ▸▸ EMA or keratins (CAM 5.2, AE1/3, CK7, CK20, among others) are frequently positive in metastatic carcinomas ▸▸ Sarcomatoid carcinomas tend to be positive for vimentin and negative or focally positive for keratins ▸▸ Immunohistochemical markers frequently used are TTF-1 for lung or thyroid cancer, PSA for carcinoma of the prostate, estrogen and progesterone receptors for breast cancer, S-100 protein, HMB-45, or Melan-A for malignant melanoma, and chromogranin A or CD56 for neuroendocrine tumors Differential Diagnosis
▸▸ Plasmacytoma ▸▸ Angiosarcoma ▸▸ Osteosarcomas with epithelioid features ▸▸ Adamantinoma of long bones ▸▸ Fibrosarcoma or malignant fibrous histiocytoma of bone ▸▸ Squamous cell carcinoma arising in longstanding osteomyelitis
SUGGESTED READINGS 1. Aebi M: Spinal metastasis in the elderly. Eur Spine J 2003;12(suppl 2): S202–S213. 2. Ali SM, Harvey HA, Lipton A: Metastatic breast cancer: overview of treatment. Clin Orthop 2003;(415 suppl):S132–S137. 3. Bendre M, Gaddy D, Nicholas RW, et al: Breast cancer metastasis to bone: it is not all about PTHrP. Clin Orthop 2003;(415 suppl): S39–S45.
453 4. Brage ME, Simon MA: Evaluation, prognosis, and medical treatment considerations of metastatic bone tumors. Orthopedics 1992;15(5):589–596. 5. Campanacci M: Bone and Soft Tissue Tumors. Berlin, Germany: Springer-Verlag, 1999, pp 756–787. 6. Carlin BI, Andriole GL: The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 2000;88(12 suppl):2989–2994. 7. Cheville JC, Tindall D, Boelter C, et al: Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancerspecific survival. Cancer 2002;95(5):1028–1036. 8. Choong PF: The molecular basis of skeletal metastases. Clin Orthop 2003;(415 suppl):S19–S31. 9. Dorfman HD: Czerniak B: Bone Tumors. St. Louis, MO: Mosby, 1998, 1009–1040. 10. Falkmer U, Jarhult J, Wersall P, et al: A systematic overview of radiation therapy effects in skeletal metastases. Acta Oncol 2003;42: 620–633. 11. Goltzman D, Karaplis AC, Kremer R, et al: Molecular basis of the spectrum of skeletal complications of neoplasia. Cancer 2000;88(12 suppl):2903–2908. 12. Guise TA: Molecular mechanisms of osteolytic bone metastases. Cancer 2000;88(12 suppl):2892–2898. 13. Healey JH, Turnbull AD, Miedema B, et al: Acrometastases. A study of twenty-nine patients with osseous involvement of the hands and feet. J Bone Joint Surg Am 1986;68:743–746. 14. James JJ, Evans AJ, Pinder SE, et al: Bone metastases from breast carcinoma: histopathological-radiological correlations and prognostic features. Br J Cancer 2003;89:660–665. 15. Kager L, Zoubek A, Potschger U, et al: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003;21:2011–2018. 16. Kakonen SM, Mundy GR: Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 2003;97(3 suppl):834–839. 17. Mundy GR: Mechanisms of bone metastasis. Cancer 1997;80 (8 suppl):1546–1556. 18. Peterson JJ, Kransdorf MJ, O’Connor MI: Diagnosis of occult bone metastases: Positron emission tomography. Clin Orthop 2003;(415 suppl):S120–S128. 19. Resnick D: Bone and Joint Imaging. Philadelphia, Saunders, 1996, pp 1076–1091. 20. Rodan GA: The development and function of the skeleton and bone metastases. Cancer 2003;97(3 suppl):726–732. 21. Rougraff BT: Evaluation of the patient with carcinoma of unknown origin metastatic to bone. Clin Orthop 2003;(415 suppl):S105–S109. 22. San-Julian M, Diaz-de-Rada P, Noain E, et al: Bone metastases from osteosarcoma. Int Orthop 2003;27:117–120. 23. Simon MA, Bartucci EJ: The search for the primary tumor in patients with skeletal metastases of unknown origin. Cancer 1986;58: 1088–1095. 24. Troncoso A, Ro JY, Grignon DJ, et al: Renal cell carcinoma with acrometastasis: report of two cases and review of the literature. Mod Pathol 1991;4:66–69. 25. Unni KK: Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. Philadelphia: Lippincott-Raven, 1996, pp 355–360. 26. Weber MH, Goltzman D, Kostenuik P, et al: Mechanisms of tumor metastasis to bone. Crit Rev Eukaryot Gene Expr 2000;10:281–302. 27. Wilner D: Radiology of Bone Tumors and Allied Disorders, vol. 4. Philadelphia, Saunders, 1982, pp 3641–3908.