InternalMed_Harrison

InternalMed_Harrison. grade iii (anaPlastic) astrocytoma These account for approximately 15–20% of high-grade astrocytomas. They generally present in the fourth and fifth decades of life as variably enhancing tumors. Treatment is the same as for glioblastoma, consisting of maximal safe surgical resection followed by RT with concurrent and adjuvant temozolomide or by RT and adjuvant temozolomide alone.


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InternalMed_Harrison. grade iv astrocytoma (glioBlastoma) Glioblastoma accounts for the majority of high-grade astrocytomas. They are the most common malignant primary brain tumor, with over 10,000 cases diagnosed each year in the United States. Patients usually present in the sixth and seventh decades of life with headache, seizures, or focal neurologic deficits. The tumors appear as ring-enhancing masses with central necrosis and surrounding edema (Fig. 118-2). These are highly infiltrative tumors, and the areas of increased T2/FLAIR signal surrounding the main tumor mass contain invading tumor cells. Treatment involves maximal surgical resection followed by partial-field external-beam RT (6000 cGy in thirty 200-cGy fractions) with concomitant temozolomide, followed by 6–12 months of adjuvant temozolomide. With this regimen, median survival is increased to 14.6 months compared to only 12 months with RT alone, and 2-year survival is increased to 27%, compared to 10% with RT alone. Patients whose tumor


InternalMed_Harrison

InternalMed_Harrison. With this regimen, median survival is increased to 14.6 months compared to only 12 months with RT alone, and 2-year survival is increased to 27%, compared to 10% with RT alone. Patients whose tumor contains the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are relatively resistant to temozolomide and have a worse prognosis compared to those whose tumors contain low levels of MGMT as a result of silencing of the MGMT gene by promoter hypermethylation. Implantation of biodegradable polymers containing the chemotherapeutic agent carmustine into the tumor bed after resection of the tumor also produces a modest improvement in survival.


InternalMed_Harrison

InternalMed_Harrison. Despite optimal therapy, glioblastomas invariably recur. Treatment options for recurrent disease may include reoperation, carmustine wafers, and alternate chemotherapeutic regimens. Reirradiation is rarely helpful. Bevacizumab, a humanized vascular endothelial growth factor (VEGF) monoclonal antibody, has activity in recurrent glioblastoma, increasing progression-free survival and reducing peritumoral edema and glucocorticoid use (Fig. 118-3). Treatment decisions for patients with recurrent glioblastoma must be made on an individual basis, taking into consideration such factors as previous therapy, time to relapse, performance status, and quality of life. Whenever feasible, patients with recurrent disease should be enrolled in clinical trials. Novel therapies undergoing evaluation in patients with glioblastoma include targeted molecular agents directed at receptor tyrosine kinases and signal transduction pathways; antiangiogenic agents, especially those directed at the VEGF receptors;


InternalMed_Harrison

InternalMed_Harrison. with glioblastoma include targeted molecular agents directed at receptor tyrosine kinases and signal transduction pathways; antiangiogenic agents, especially those directed at the VEGF receptors; chemotherapeutic agents that cross the blood-brain barrier more effectively than currently available drugs; gene therapy; immunotherapy; and infusion of radiolabeled drugs and targeted toxins into the tumor and surrounding brain by means of convection-enhanced delivery.


InternalMed_Harrison

InternalMed_Harrison. The most important adverse prognostic factors in patients with high-grade astrocytomas are older age, histologic features of glioblastoma, poor Karnofsky performance status, and unresectable tumor. Patients whose tumor contains an unmethylated MGMT promoter resulting in the presence of the repair enzyme in tumor cells and resistance to temozolomide also have a worse prognosis. Gliomatosis Cerebri Rarely, patients may present with a highly infiltrating, nonenhancing tumor of variable histologic grade involving more than two lobes of the brain. These tumors may be indolent initially, but will eventually behave aggressively and have a poor outcome. Treatment involves RT and temozolomide chemotherapy. Oligodendrogliomas account for approximately 15–20% of gliomas. They are classified by the WHO into well-differentiated oligodendrogliomas (grade II) or anaplastic oligodendrogliomas (AOs) (grade III). Tumors with oligodendroglial components have distinctive pathologic


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InternalMed_Harrison. FIGURE 118-3 Postgadolinium T1 MRI of a recurrent glioblastoma before (A) and after (B) administration of bevacizumab. Note the decreased enhancement and mass effect. features such as perinuclear clearing—giving rise to a “fried-egg” appearance—and a reticular pattern of blood vessel growth. Some tumors have both an oligodendroglial as well as an astrocytic component. These mixed tumors, or oligoastrocytomas (OAs), are also classified into well-differentiated OA (grade II) or anaplastic oligoastrocytomas (AOAs) (grade III). Grade II oligodendrogliomas and OAs are generally more responsive to therapy and have a better prognosis than pure astrocytic tumors. These tumors present similarly to grade II astrocytomas in young adults. The tumors are nonenhancing and often partially calcified. They should be treated with surgery and, if necessary, RT and chemotherapy. Patients with oligodendrogliomas have a median survival in excess of 10 years.


InternalMed_Harrison

InternalMed_Harrison. AOs and AOAs present in the fourth and fifth decades as variably enhancing tumors. They are more responsive to therapy than grade III astrocytomas. Co-deletion of chromosomes 1p and 19q, mediated by an unbalanced translocation of 19p to 1q, occurs in 61–89% of patients with AO and 14–20% of patients with AOA. Tumors with the 1p and 19q co-deletion are particularly sensitive to chemotherapy with procarbazine, lomustine (cyclohexylchloroethylnitrosourea [CCNU]), and vincristine (PCV) or temozolomide, as well as to RT. Median survival of patients with AO or AOA is approximately 3–6 years, but 601 those with co-deleted tumors can have a median survival of 10–14 years if treated with RT and chemotherapy.


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InternalMed_Harrison. Ependymomas are tumors derived from ependymal cells that line the ventricular surface. They account for approximately 5% of childhood tumors and frequently arise from the wall of the fourth ventricle in the posterior fossa. Although adults can have intracranial ependymomas, they occur more commonly in the spine, especially in the filum terminale of the spinal cord where they have a myxopapillary histology. Ependymomas that can be completely resected are potentially curable. Partially resected ependymomas will recur and require irradiation. The less common anaplastic ependymoma is more aggressive and is treated with resection and RT; chemotherapy has limited efficacy. Subependymomas are slow-growing benign lesions arising in the wall of ventricles that often do not require treatment.


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InternalMed_Harrison. Gangliogliomas and pleomorphic xanthoastrocytomas occur in young adults. They behave as more indolent forms of grade II gliomas and are treated in the same way. Brainstem gliomas usually occur in children or young adults. Despite treatment with RT and chemotherapy, the prognosis is poor, with a median survival of only 1 year. Gliosarcomas contain both an astrocytic as well as a sarcomatous component and are treated in the same way as glioblastomas. Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin lymphoma accounting for less than 3% of primary brain tumors. For unclear reasons, its incidence is increasing, particularly in immunocompetent individuals.


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InternalMed_Harrison. PCNSL in immunocompetent patients usually consists of a diffuse large B cell lymphoma. PCNSL may also occur in immunocompromised patients, usually those infected with the human immunodeficiency virus (HIV) or organ transplant recipients on immunosuppressive therapy. PCNSL in immunocompromised patients is typically large cell with immunoblastic and more aggressive features. These patients are usually severely immunocompromised, with CD4 counts of less than 50/mL. The Epstein-Barr virus (EBV) frequently plays an important role in the pathogenesis of HIV-related PCNSL. Immunocompetent patients with PCNSL are older (median 60 years) compared to patients with HIV-related PCNSL (median 31 years). PCNSL usually presents as a mass lesion, with neuropsychiatric symptoms, symptoms of increased intracranial pressure, lateralizing signs, or seizures.


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InternalMed_Harrison. On contrast-enhanced MRI, PCNSL usually appears as a densely enhancing tumor (Fig. 118-4). Immunocompetent patients have solitary lesions more often than immunosuppressed patients. Frequently there is involvement of the basal ganglia, corpus callosum, or periventricular region. Although the imaging features are often characteristic, PCNSL can sometimes be difficult to differentiate from high-grade gliomas, infections, or demyelination. Stereotactic biopsy is necessary to obtain a histologic diagnosis. Whenever possible, glucocorticoids should be withheld until after the biopsy has been obtained because they have a cytolytic effect on lymphoma cells and may lead to nondiagnostic tissue. In addition, patients should be tested for HIV and the extent of disease should be assessed by performing PET or CT of the body, MRI of the spine, CSF analysis, and slit-lamp examination of the eye. Bone marrow biopsy and testicular ultrasound are occasionally performed.


InternalMed_Harrison

InternalMed_Harrison. PCNSL is more sensitive to glucocorticoids, chemotherapy, and RT than other primary brain tumors. Durable complete responses and long-term survival are possible with these treatments. High-dose methotrexate, a folate antagonist that interrupts DNA synthesis, produces response rates ranging from 35–80% and median Primary and Metastatic Tumors of the Nervous System FIGURE 118-4 Postgadolinium T1 MRI demonstrating a large bifrontal primary central nervous system lymphoma (PCNSL). The periventricular location and diffuse enhancement pattern are characteristic of lymphoma.


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InternalMed_Harrison. survival of up to 50 months. The combination of methotrexate with other chemotherapeutic agents such as cytarabine increases the response rate to 70–100%. The addition of whole-brain RT to methotrexate-based chemotherapy prolongs progression-free survival but not overall survival. Furthermore, RT is associated with delayed neurotoxicity, especially in patients over the age of 60 years. As a result, full-dose RT is frequently omitted, but there may be a role for reduced-dose RT. The anti-CD20 monoclonal antibody rituximab has activity in PCNSL and is often incorporated into the chemotherapy regimen. For some patients, high-dose chemotherapy with autologous stem cell rescue may offer the best chance of preventing relapse. At least 50% of patients will eventually develop recurrent disease. Treatment options include RT for patients who have not had prior irradiation, re-treatment with methotrexate, as well as other agents such as temozolomide, rituximab, procarbazine, topotecan, and


InternalMed_Harrison

InternalMed_Harrison. Treatment options include RT for patients who have not had prior irradiation, re-treatment with methotrexate, as well as other agents such as temozolomide, rituximab, procarbazine, topotecan, and pemetrexed. High-dose chemotherapy with autologous stem cell rescue may have a role in selected patients with relapsed disease.


InternalMed_Harrison

InternalMed_Harrison. PCNSL in immunocompromised patients often produces multiple ring-enhancing lesions that can be difficult to differentiate from metastases and infections such as toxoplasmosis. The diagnosis is usually established by examination of the CSF for cytology and EBV DNA, toxoplasmosis serologic testing, brain PET imaging for hypermetabolism of the lesions consistent with tumor instead of infection, and, if necessary, brain biopsy. Since the advent of highly active antiretroviral drugs, the incidence of HIV-related PCNSL has declined. These patients may be treated with whole-brain RT, high-dose methotrexate, and initiation of highly active antiretroviral therapy. In organ transplant recipients, reduction of immunosuppression may improve outcome.


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InternalMed_Harrison. Medulloblastomas are the most common malignant brain tumor of childhood, accounting for approximately 20% of all primary CNS tumors among children. They arise from granule cell progenitors or from multipotent progenitors from the ventricular zone. Approximately 5% of children have inherited disorders with germline mutations of genes that predispose to the development of medulloblastoma. Gorlin syndrome, the most common of these inherited disorders, is due to mutations in the patched-1 (PTCH-1) gene, a key component in the sonic hedgehog pathway. Turcot syndrome, caused by mutations in the adenomatous polyposis coli (APC) gene and familial adenomatous polyposis, has also been associated with an increased incidence of medulloblastoma. Histologically, medulloblastomas are highly cellular tumors with abundant dark staining, round nuclei, and rosette formation (Homer-Wright rosettes). They present with headache, ataxia, and signs of brainstem involvement. On MRI they appear as densely


InternalMed_Harrison

InternalMed_Harrison. tumors with abundant dark staining, round nuclei, and rosette formation (Homer-Wright rosettes). They present with headache, ataxia, and signs of brainstem involvement. On MRI they appear as densely enhancing tumors in the posterior fossa, sometimes associated with hydrocephalus. Seeding of the CSF is common. Treatment involves maximal surgical resection, craniospinal irradiation, and chemotherapy with agents such as cisplatin, lomustine, cyclophosphamide, and vincristine. Approximately 70% of patients have long-term survival but usually at the cost of significant neurocognitive impairment. A major goal of current research is to improve survival while minimizing long-term complications.


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InternalMed_Harrison. A large number of tumors can arise in the region of the pineal gland. These typically present with headache, visual symptoms, and hydrocephalus. Patients may have Parinaud syndrome characterized by impaired upgaze and accommodation. Some pineal tumors such as pineocytomas and benign teratomas can be treated simply by surgical resection. Germinomas respond to irradiation, whereas pineoblastomas and malignant germ cell tumors require craniospinal radiation and chemotherapy. Meningiomas are diagnosed with increasing frequency as more people undergo neuroimaging for various indications. They are now the most common primary brain tumor, accounting for approximately 35% of the total. Their incidence increases with age. They tend to be more common in women and in patients with neurofibromatosis type 2. They also occur more commonly in patients with a past history of cranial irradiation.


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InternalMed_Harrison. Meningiomas arise from the dura mater and are composed of neoplastic meningothelial (arachnoidal cap) cells. They are most commonly located over the cerebral convexities, especially adjacent to the sagittal sinus, but can also occur in the skull base and along the dorsum of the spinal cord. Meningiomas are classified by the WHO into three histologic grades of increasing aggressiveness: grade I (benign), grade II (atypical), and grade III (malignant). Many meningiomas are found incidentally following neuroimaging for unrelated reasons. They can also present with headaches, seizures, or focal neurologic deficits. On imaging studies they have a characteristic appearance usually consisting of a partially calcified, densely enhancing extraaxial tumor arising from the dura (Fig. 118-5). Occasionally they may have a dural tail, consisting of thickened, enhanced dura extending like a tail from the mass. The main differential diagnosis of meningioma is a dural metastasis.


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InternalMed_Harrison. If the meningioma is small and asymptomatic, no intervention is necessary and the lesion can be observed with serial MRI studies. Larger, symptomatic lesions should be resected. If complete resection is achieved, the patient is cured. Incompletely resected tumors tend to recur, although the rate of recurrence can be very slow with grade I tumors. Tumors that cannot be resected, or can only be partially removed, may benefit from treatment with external-beam RT or stereotactic radiosurgery (SRS). These treatments may also be helpful in patients whose tumor has recurred after surgery. Hormonal therapy and chemotherapy are currently unproven. Rarer tumors that resemble meningiomas include hemangiopericytomas and solitary fibrous tumors. These are treated with surgery and RT but have a higher propensity to recur locally or metastasize systemically.


InternalMed_Harrison

InternalMed_Harrison. These are generally benign tumors arising from the Schwann cells of cranial and spinal nerve roots. The most common schwannomas, termed vestibular schwannomas or acoustic neuromas, arise from the vestibular portion of the eighth cranial nerve and account for approximately 9% of primary brain tumors. Patients with neurofibromatosis type 2 have a high incidence of vestibular schwannomas that are frequently bilateral. Schwannomas arising from other cranial nerves, such as the trigeminal nerve (cranial nerve V), occur with much lower frequency. Neurofibromatosis type 1 is associated with an increased incidence of schwannomas of the spinal nerve roots. FIGURE 118-5 Postgadolinium T1 MRI demonstrating multiple meningiomas along the falx and left parietal cortex.


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InternalMed_Harrison. FIGURE 118-5 Postgadolinium T1 MRI demonstrating multiple meningiomas along the falx and left parietal cortex. Vestibular schwannomas may be found incidentally on neuroimaging or present with progressive unilateral hearing loss, dizziness, tinnitus, or less commonly, symptoms resulting from compression of the brainstem and cerebellum. On MRI they appear as densely enhancing lesions, enlarging the internal auditory canal and often extending into the cerebellopontine angle (Fig. 118-6). The differential diagnosis includes meningioma. Very small, asymptomatic lesions can be observed with serial MRIs. Larger lesions should be treated with surgery or SRS. The optimal treatment will depend on the size of the tumor, symptoms, and the patient’s preference. In patients with small vestibular schwannomas and relatively intact hearing, early surgical 603 intervention increases the chance of preserving hearing.


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InternalMed_Harrison. FIGURE 118-6 Postgadolinium MRI of a right vestibular schwan-noma. The tumor can be seen to involve the internal auditory canal. PITUITARY TUMORS (CHAP. 401e)


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InternalMed_Harrison. PITUITARY TUMORS (CHAP. 401e) These account for approximately 9% of primary brain tumors. They can be divided into functioning and nonfunctioning tumors. Functioning tumors are usually microadenomas (<1 cm in diameter) that secrete hormones and produce specific endocrine syndromes (e.g., acromegaly for growth hormone–secreting tumors, Cushing syndrome for adrenocorticotropic hormone [ACTH]-secreting tumors, and galactorrhea, amenorrhea, and infertility for prolactin-secreting tumors). Nonfunctioning pituitary tumors tend to be macroadenomas (>1 cm) that produce symptoms by mass effect, giving rise to headaches, visual impairment (such as bitemporal hemianopia), and hypopituitarism. Prolactin-secreting tumors respond well to dopamine agonists such as bromocriptine and cabergoline. Other pituitary tumors usually require treatment with surgery and sometimes RT or radiosurgery and hormonal therapy.


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InternalMed_Harrison. Craniopharyngiomas are rare, usually suprasellar, partially calcified, solid, or mixed solid-cystic benign tumors that arise from remnants of Rathke’s pouch. They have a bimodal distribution, occurring predominantly in children but also between the ages of 55 and 65 years. They present with headaches, visual impairment, and impaired growth in children and hypopituitarism in adults. Treatment involves surgery, RT, or a combination of the two. Dysembryoplastic Neuroepithelial Tumors (DNTs) These are benign, supratentorial tumors, usually in the temporal lobe. They typically occur in children and young adults with a long-standing history of seizures. Surgical resection is curative.


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InternalMed_Harrison. Epidermoid Cysts These consist of squamous epithelium surrounding a keratin-filled cyst. They are usually found in the cerebellopontine angle and the intrasellar and suprasellar regions. They may present with headaches, cranial nerve abnormalities, seizures, or hydrocephalus. Imaging studies demonstrate extraaxial lesions with characteristics that are similar to CSF but have restricted diffusion. Treatment involves surgical resection.


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InternalMed_Harrison. Dermoid Cysts Like epidermoid cysts, dermoid cysts arise from epithelial cells that are retained during closure of the neural tube. They contain both epidermal and dermal structures such as hair follicles, sweat glands, and sebaceous glands. Unlike epidermoid cysts, these tumors usually have a midline location. They occur most frequently in the posterior fossa, especially the vermis, fourth ventricle, and suprasellar cistern. Radiographically, dermoid cysts resemble lipomas, demonstrating T1 hyperintensity and variable signal on T2. Symptomatic dermoid cysts can be treated with surgery. Colloid Cysts These usually arise in the anterior third ventricle and may present with headaches, hydrocephalus, and, very rarely, sudden death. Surgical resection is curative, or a third ventriculostomy may relieve the obstructive hydrocephalus and be sufficient therapy.


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InternalMed_Harrison. A number of genetic disorders are characterized by cutaneous lesions and an increased risk of brain tumors. Most of these disorders have an autosomal dominant inheritance with variable penetrance. NF1 is an autosomal dominant disorder with an incidence of approximately 1 in 2600–3000. Approximately one-half the cases are familial; the remainder are caused by new mutations arising in patients with unaffected parents. The NF1 gene on chromosome 17q11.2 encodes a protein, neurofibromin, a guanosine triphosphatase (GTPase)-activating protein (GAP) that modulates signaling through the ras pathway. Mutations of NF1 result in a large number of nervous system tumors


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InternalMed_Harrison. Primary and Metastatic Tumors of the Nervous System 604 including neurofibromas, plexiform neurofibromas, optic nerve gliomas, astrocytomas, and meningiomas. In addition to neurofibromas, which appear as multiple, soft, rubbery cutaneous tumors, other cutaneous manifestations of NF1 include café-au-lait spots and axillary freckling. NF1 is also associated with hamartomas of the iris termed Lisch nodules, pheochromocytomas, pseudoarthrosis of the tibia, scoliosis, epilepsy, and mental retardation.


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InternalMed_Harrison. NF2 is less common than NF1, with an incidence of 1 in 25,000– 40,000. It is an autosomal dominant disorder with full penetrance. As with NF1, approximately one-half the cases arise from new mutations. The NF2 gene on 22q encodes a cytoskeletal protein, merlin (moesin, ezrin, radixin-like protein) that functions as a tumor suppressor. NF2 is characterized by bilateral vestibular schwannomas in over 90% of patients, multiple meningiomas, and spinal ependymomas and astrocytomas. Treatment of bilateral vestibular schwannomas can be challenging because the goal is to preserve hearing for as long as possible. These patients may also have diffuse schwannomatosis that may affect the cranial, spinal, or peripheral nerves; posterior subcapsular lens opacities; and retinal hamartomas.


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InternalMed_Harrison. This is an autosomal dominant disorder with an incidence of approximately 1 in 5000–10,000 live births. It is caused by mutations in either the TSC1 gene, which maps to chromosome 9q34 and encodes a protein termed hamartin, or the TSC2 gene, which maps to chromosome 16p13.3 and encodes the protein tuberin. Hamartin forms a complex with tuberin, which inhibits cellular signaling through the mTOR, and acts as a negative regulator of the cell cycle. Patients with tuberous sclerosis may have seizures, mental retardation, adenoma sebaceum (facial angiofibromas), shagreen patch, hypomelanotic macules, periungual fibromas, renal angiomyolipomas, and cardiac rhabdomyomas. These patients have an increased incidence of subependymal nodules, cortical tubers, and subependymal giant-cell astrocytomas (SEGA). Patients frequently require anticonvulsants for seizures. SEGAs do not always require therapeutic intervention, but the most effective therapy is with the mTOR inhibitors sirolimus or


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InternalMed_Harrison. (SEGA). Patients frequently require anticonvulsants for seizures. SEGAs do not always require therapeutic intervention, but the most effective therapy is with the mTOR inhibitors sirolimus or everolimus, which often decrease seizures as well as SEGA size.


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InternalMed_Harrison. Brain metastases arise from hematogenous spread and frequently either arise from a lung primary or are associated with pulmonary metastases. Most metastases develop at the gray matter–white matter junction in the watershed distribution of the brain where intravascular tumor cells lodge in terminal arterioles. The distribution of metastases in the brain approximates the proportion of blood flow such that about 85% of all metastases are supratentorial and 15% occur in the posterior fossa. The most common sources of brain metastases are lung and breast carcinomas; melanoma has the greatest propensity to metastasize to the brain, being found in 80% of patients at autopsy Table 118-3). Other tumor Abbreviations: ESCC, epidural spinal cord compression; GIT, gastrointestinal tract; LM, leptomeningeal metastases.


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InternalMed_Harrison. Abbreviations: ESCC, epidural spinal cord compression; GIT, gastrointestinal tract; LM, leptomeningeal metastases. types such as ovarian and esophageal carcinoma rarely metastasize to the brain. Prostate and breast cancer also have a propensity to metastasize to the dura and can mimic meningioma. Leptomeningeal metastases are common from hematologic malignancies and also breast and lung cancers. Spinal cord compression primarily arises in patients with prostate and breast cancer, tumors with a strong propensity to metastasize to the axial skeleton.


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InternalMed_Harrison. Brain metastases are best visualized on MRI, where they usually appear as well-circumscribed lesions (Fig. 118-7). The amount of perilesional edema can be highly variable, with large lesions causing minimal edema and sometimes very small lesions causing extensive edema. Enhancement may be in a ring pattern or diffuse. Occasionally, intracranial metastases will hemorrhage; although melanoma, thyroid, and kidney cancer have the greatest propensity to hemorrhage, the most common cause of a hemorrhagic metastasis is lung cancer because it accounts for the majority of brain metastases. The radiographic appearance of brain metastasis is nonspecific, and similar-appearing lesions can occur with infection including brain abscesses and also with demyelinating lesions, sarcoidosis, radiation necrosis in a previously treated patient, or a primary brain tumor that may be a second malignancy in a patient with systemic cancer. However, biopsy is rarely necessary for diagnosis in most patients


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InternalMed_Harrison. in a previously treated patient, or a primary brain tumor that may be a second malignancy in a patient with systemic cancer. However, biopsy is rarely necessary for diagnosis in most patients because imaging alone in the appropriate clinical situation usually suffices. This is straightforward for the majority of patients with brain metastases because they have a known systemic cancer. However, in approximately 10% of patients, a systemic cancer may present with a brain metastasis, and if there is not an easily accessible systemic site to biopsy, then a brain lesion must be removed for diagnostic purposes.


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InternalMed_Harrison. The number and location of brain metastases often determine the therapeutic options. The patient’s overall condition and the current or potential control of the systemic disease are also major determinants. Brain metastases are single in approximately one-half of patients and multiple in the other half.


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InternalMed_Harrison. The standard treatment for brain metastases has been whole-brain radiotherapy (WBRT) usually administered to a total dose of 3000 cGy in 10 fractions. This affords rapid palliation, and approximately 80% of patients improve with glucocorticoids and RT. However, it is not curative. Median survival is only 4–6 months. More recently, SRS delivered through a variety of techniques including the gamma knife, linear accelerator, proton beam, and CyberKnife all can deliver highly focused doses of RT, usually in a single fraction. SRS can effectively sterilize the visible lesions and afford local disease control in 80–90% of patients. In addition, there are some patients who have clearly been cured of their brain metastases using SRS, whereas this is distinctly rare with WBRT. However, SRS can be used only for lesions 3 cm or less in diameter and should be confined to patients with only one to three metastases. The addition of WBRT to SRS improves disease control in the nervous system but does


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InternalMed_Harrison. only for lesions 3 cm or less in diameter and should be confined to patients with only one to three metastases. The addition of WBRT to SRS improves disease control in the nervous system but does not prolong survival.


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InternalMed_Harrison. Randomized controlled trials have demonstrated that surgical extirpation of a single brain metastasis followed by WBRT is superior to WBRT alone. Removal of two lesions or a single symptomatic mass, particularly if compressing the ventricular system, can also be useful. This is particularly useful in patients who have highly radioresistant lesions such as renal carcinoma. Surgical resection can afford rapid symptomatic improvement and prolonged survival. WBRT administered after complete resection of a brain metastasis improves disease control but does not prolong survival.


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InternalMed_Harrison. Chemotherapy is rarely useful for brain metastases. Metastases from certain tumor types that are highly chemosensitive, such as germ cell tumors or small-cell lung cancer, may respond to chemotherapeutic regimens chosen according to the underlying malignancy. Increasingly, there are data demonstrating responsiveness of brain metastases to chemotherapy including small molecule–targeted therapy when the lesion possesses the target. This has been best illustrated in patients with lung cancer harboring EGFR mutations that sensitize them to EGFR inhibitors. Antiangiogenic agents such as bevacizumab may also prove efficacious in the treatment of CNS metastases.


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InternalMed_Harrison. Leptomeningeal metastases are also identified as carcinomatous meningitis, meningeal carcinomatosis, or in the case of specific tumors, leukemic or lymphomatous meningitis. Among the hematologic malignancies, acute leukemia is the most common to metastasize to the subarachnoid space, and in lymphomas the aggressive diffuse lymphomas can metastasize to the subarachnoid space frequently as well. Among solid tumors, breast and lung carcinomas and melanoma most frequently spread in this fashion. Tumor cells reach the subarachnoid space via the arterial circulation or occasionally through retrograde flow in venous systems that drain metastases along the bony spine or cranium. In addition, leptomeningeal metastases may develop as a direct consequence of prior brain metastases and can develop in almost 40% of patients who have a metastasis resected from the cerebellum.


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InternalMed_Harrison. Leptomeningeal metastases are characterized clinically by multilevel symptoms and signs along the neuraxis. Combinations of lumbar and cervical radiculopathies, cranial neuropathies, seizures, confusion, and encephalopathy from hydrocephalus or raised intracranial pressure can be present. Focal deficits such as hemiparesis or aphasia are rarely due to leptomeningeal metastases unless there is direct brain infiltration, and they are more often associated with coexisting brain lesions. New-onset limb pain in patients with breast cancer, lung cancer, or melanoma should prompt consideration of leptomeningeal spread.


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InternalMed_Harrison. Leptomeningeal metastases are particularly challenging to diagnose because identification of tumor cells in the subarachnoid compartment may be elusive. MRI can be definitive in patients when there are clear tumor nodules adherent to the cauda equina or spinal cord, enhancing cranial nerves, or subarachnoid enhancement on brain imaging (Fig. 118-8). Imaging is diagnostic in approximately 75% of patients and is more often positive in patients with solid tumors. Demonstration of tumor cells in the CSF is definitive and often considered the gold standard. However, CSF cytologic examination is positive in only 50% of patients on the first lumbar puncture and still misses 10% after three CSF samples. CSF cytologic examination is most useful in hematologic malignancies. Accompanying CSF abnormalities include an elevated protein concentration and an elevated white count. Hypoglycorrhachia is noted in less than 25% of patients but is useful when present. Identification of tumor markers or


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InternalMed_Harrison. include an elevated protein concentration and an elevated white count. Hypoglycorrhachia is noted in less than 25% of patients but is useful when present. Identification of tumor markers or molecular confirmation of clonal proliferation with techniques such as flow cytometry within the CSF can also be definitive when present. Tumor markers are usually specific to solid tumors, and chromosomal or molecular markers are most useful in patients with hematologic malignancies. New technologies, such as rare cell capture, may enhance identification of tumor cells in the CSF.


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InternalMed_Harrison. The treatment of leptomeningeal metastasis is palliative because there is no curative therapy. RT to the symptomatically involved areas, such as skull base for cranial neuropathy, can relieve pain and sometimes improve function. Whole-neuraxis RT has extensive toxicity with myelosuppression and gastrointestinal irritation as well as limited effectiveness. Systemic chemotherapy with agents that can penetrate the blood-CSF barrier may be helpful. Alternatively, intrathecal chemotherapy can be effective, particularly in hematologic malignancies. This is optimally delivered through an intraventricular cannula (Ommaya reservoir) rather than by lumbar puncture. Few drugs can be delivered safely into the subarachnoid space, and they have a limited spectrum of antitumor activity, perhaps accounting for the relatively poor response to this approach. In addition, impaired CSF flow dynamics can compromise intrathecal drug delivery. Surgery has a limited role in the treatment of leptomeningeal


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InternalMed_Harrison. for the relatively poor response to this approach. In addition, impaired CSF flow dynamics can compromise intrathecal drug delivery. Surgery has a limited role in the treatment of leptomeningeal metastasis, but placement of a ventriculoperitoneal shunt can relieve raised intracranial pressure. However, it compromises delivery of chemotherapy into the CSF.


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InternalMed_Harrison. Primary and Metastatic Tumors of the Nervous System FIGURE 118-8 Postgadolinium MRI images of extensive leptomeningeal metastases from breast cancer. Nodules along the dorsal surface of the spinal cord (A) and cauda equina (B) are seen. Epidural metastasis occurs in 3–5% of patients with a systemic malignancy and causes neurologic compromise by compressing the spinal cord or cauda equina. The most common cancers that metastasize to the epidural space are those malignancies that spread to bone, such as breast and prostate. Lymphoma can cause bone involvement and compression, but it can also invade the intervertebral foramens and cause spinal cord compression without bone destruction. The thoracic spine is affected most commonly, followed by the lumbar and then cervical spine.


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InternalMed_Harrison. Back pain is the presenting symptom of epidural metastasis in virtually all patients; the pain may precede neurologic findings by weeks or months. The pain is usually exacerbated by lying down; by contrast, arthritic pain is often relieved by recumbency. Leg weakness is seen in about 50% of patients, as is sensory dysfunction. Sphincter problems are present in about 25% of patients at diagnosis. FIGURE 118-9 Postgadolinium T1 MRI showing circumferential epidural tumor around the thoracic spinal cord from esophageal cancer.


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InternalMed_Harrison. FIGURE 118-9 Postgadolinium T1 MRI showing circumferential epidural tumor around the thoracic spinal cord from esophageal cancer. Diagnosis is established by imaging, with MRI of the complete spine being the best test (Fig. 118-9). Contrast is not needed to identify spinal or epidural lesions. Any patient with cancer who has severe back pain should undergo an MRI. Plain films, bone scans, or even CT scans may show bone metastases, but only MRI can reliably delineate epidural tumor. For patients unable to have an MRI, CT myelography should be performed to outline the epidural space. The differential diagnosis of epidural tumor includes epidural abscess, acute or chronic hematomas, and rarely, extramedullary hematopoiesis.


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InternalMed_Harrison. Epidural metastasis requires immediate treatment. A randomized controlled trial demonstrated the superiority of surgical resection followed by RT compared to RT alone. However, patients must be able to tolerate surgery, and the surgical procedure of choice is a complete removal of the mass, which is typically anterior to the spinal canal, necessitating an extensive approach and resection. Otherwise, RT is the mainstay of treatment and can be used for patients with radiosensitive tumors, such as lymphoma, or for those unable to undergo surgery. Chemotherapy is rarely used for epidural metastasis unless the patient has minimal to no neurologic deficit and a highly chemosensitive tumor such as lymphoma or germinoma. Patients generally fare well if treated before there is severe neurologic deficit. Recovery after paraparesis is better after surgery than with RT alone, but survival is often short due to widespread metastatic tumor.


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InternalMed_Harrison. RT can cause a variety of toxicities in the CNS. These are usually described based on their relationship in time to the administration of RT: acute (occurring within days of RT), early delayed (months), or late delayed (years). In general, the acute and early delayed syndromes resolve and do not result in persistent deficits, whereas the late delayed toxicities are usually permanent and sometimes progressive. Acute Toxicity Acute cerebral toxicity usually occurs during RT to the brain. RT can cause a transient disruption of the blood-brain barrier, resulting in increased edema and elevated intracranial pressure. This is usually manifest as headache, lethargy, nausea, and vomiting and can be both prevented and treated with the administration of glucocorticoids. There is no acute RT toxicity that affects the spinal cord.


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InternalMed_Harrison. Early Delayed Toxicity Early delayed toxicity is usually apparent weeks to months after completion of cranial irradiation and is likely due to focal demyelination. Clinically it may be asymptomatic or take the form of worsening or reappearance of a preexisting neurologic deficit. At times a contrast-enhancing lesion can be seen on MRI/ CT that can mimic the tumor for which the patient received the RT. For patients with a malignant glioma, this has been described as “pseudoprogression” because it mimics tumor recurrence on MRI but actually represents inflammation and necrotic debris engendered by effective therapy. This is seen with increased frequency when chemotherapy, particularly temozolomide, is given concurrently with RT. Pseudoprogression can resolve on its own or, if very symptomatic, may require resection. A rare form of early delayed toxicity is the somnolence syndrome that occurs primarily in children and is characterized by marked sleepiness.


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InternalMed_Harrison. In the spinal cord, early delayed RT toxicity is manifest as a Lhermitte symptom with paresthesias of the limbs or along the spine when the patient flexes the neck. Although frightening, it is benign, resolves on its own, and does not portend more serious problems.


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InternalMed_Harrison. Late Delayed Toxicity Late delayed toxicities are the most serious because they are often irreversible and cause severe neurologic deficits. In the brain, late toxicities can take several forms, the most common of which include radiation necrosis and leukoencephalopathy. Radiation necrosis is a focal mass of necrotic tissue that is contrast enhancing on CT/MRI and may be associated with significant edema. This may appear identical to pseudoprogression but is seen months to years after RT and is always symptomatic. Clinical symptoms and signs include seizure and lateralizing findings referable to the location of the necrotic mass. The necrosis is caused by the effect of RT on cerebral vasculature with resultant fibrinoid necrosis and occlusion of the blood vessels. It can mimic tumor radiographically, but unlike tumor, it is typically hypometabolic on a PET scan and has reduced perfusion on perfusion MR sequences. It may require resection for diagnosis and treatment unless it can be


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InternalMed_Harrison. but unlike tumor, it is typically hypometabolic on a PET scan and has reduced perfusion on perfusion MR sequences. It may require resection for diagnosis and treatment unless it can be managed with glucocorticoids. There are rare reports of improvement with hyperbaric oxygen or anticoagulation, but the usefulness of these approaches is questionable.


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InternalMed_Harrison. Leukoencephalopathy is seen most commonly after WBRT as opposed to focal RT. On T2 or FLAIR MR sequences, there is diffuse increased signal seen throughout the hemispheric white matter, often bilaterally and symmetrically. There tends to be a periventricular predominance that may be associated with atrophy and ventricular enlargement. Clinically, patients develop cognitive impairment, gait disorder, and later urinary incontinence, all of which can progress over time. These symptoms mimic those of normal pressure hydrocephalus, and placement of a ventriculoperitoneal shunt can improve function in some patients but does not reverse the deficits completely. Increased age is a risk factor for leukoencephalopathy but not for radiation necrosis. Necrosis appears to depend on an as yet unidentified predisposition.


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InternalMed_Harrison. Other late neurologic toxicities include endocrine dysfunction if the pituitary or hypothalamus was included in the RT port. An RT-induced neoplasm can occur many years after therapeutic RT for either a prior CNS tumor or a head and neck cancer; accurate diagnosis requires surgical resection or biopsy. In addition, RT causes accelerated atherosclerosis, which can cause stroke either from intracranial vascular disease or carotid plaque from neck irradiation. The peripheral nervous system is relatively resistant to RT toxicities. Peripheral nerves are rarely affected by RT, but the plexus is more Acute encephalopathy (delirium) Seizures Methotrexate (high-dose IV, IT) Methotrexate Cisplatin Etoposide (high-dose) Vincristine Cisplatin Asparaginase Vincristine Procarbazine Asparaginase 5-Fluorouracil (± levamisole) Nitrogen mustard Cytarabine (high-dose) Carmustine Nitrosoureas (high-dose or Dacarbazine (intraarterial or


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InternalMed_Harrison. Abbreviations: IT, intrathecal; IV, intravenous; PRES, posterior reversible encephalopathy syndrome. vulnerable. Plexopathy develops more commonly in the brachial distribution than in the lumbosacral distribution. It must be differentiated from tumor progression in the plexus, which is usually accomplished with CT/MR imaging of the area or PET scan demonstrating tumor infiltrating the region. Clinically, tumor progression is usually painful, whereas RT-induced plexopathy is painless. Radiation plexopathy is also more commonly associated with lymphedema of the affected limb. Sensory loss and weakness are seen in both.


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InternalMed_Harrison. Neurotoxicity is second to myelosuppression as the dose-limiting toxicity of chemotherapeutic agents (Table 118-4). Chemotherapy causes peripheral neuropathy from a number of commonly used agents, and the type of neuropathy can differ, depending on the drug. Vincristine causes paresthesias but little sensory loss and is associated with motor dysfunction, autonomic impairment (frequently ileus), and rarely cranial nerve compromise. Cisplatin causes large fiber sensory loss resulting in sensory ataxia but little cutaneous sensory loss and no weakness. The taxanes also cause a predominately sensory neuropathy. Agents such as bortezomib and thalidomide also cause neuropathy.


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InternalMed_Harrison. Encephalopathy and seizures are common toxicities from chemotherapeutic drugs. Ifosfamide can cause a severe encephalopathy, which is reversible with discontinuation of the drug and the use of methylene blue for severely affected patients. Fludarabine also causes a severe global encephalopathy that may be permanent. Bevacizumab and other anti-VEGF agents can cause posterior reversible encephalopathy syndrome. Cisplatin can cause hearing loss and less frequently vestibular dysfunction. Immunotherapy with anti-CTLA-4 monoclonal antibodies, such as ipilimumab, can cause an autoimmune hypophysitis. Primary and Metastatic Tumors of the Nervous System


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InternalMed_Harrison. Primary and Metastatic Tumors of the Nervous System Soft tissue and Bone Sarcomas and Bone Metastases Shreyaskumar R. Patel, Robert S. Benjamin Sarcomas are rare (<1% of all malignancies) mesenchymal neoplasms that arise in bone and soft tissues. These tumors are usually of meso-119e dermal origin, although a few are derived from neuroectoderm, and they are biologically distinct from the more common epithelial malignancies. Sarcomas affect all age groups; 15% are found in children <15 years of age, and 40% occur after age 55 years. Sarcomas are one of the most common solid tumors of childhood and are the fifth most common cause of cancer deaths in children. Sarcomas may be divided into two groups, those derived from bone and those derived from soft tissues.


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InternalMed_Harrison. Soft tissues include muscles, tendons, fat, fibrous tissue, synovial tissue, vessels, and nerves. Approximately 60% of soft tissue sarcomas arise in the extremities, with the lower extremities involved three times as often as the upper extremities. Thirty percent arise in the trunk, the retroperitoneum accounting for 40% of all trunk lesions. The remaining 10% arise in the head and neck. Approximately 11,410 new cases of soft tissue sarcomas occurred in the United States in 2013. The annual age-adjusted incidence is 3 per 100,000 population, but the incidence varies with age. Soft tissue sarcomas constitute 0.7% of all cancers in the general population and 6.5% of all cancers in children.


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InternalMed_Harrison. Malignant transformation of a benign soft tissue tumor is extremely rare, with the exception that malignant peripheral nerve sheath tumors (neurofibrosarcoma, malignant schwannoma) can arise from neurofibromas in patients with neurofibromatosis. Several etiologic factors have been implicated in soft tissue sarcomas. Environmental Factors Trauma or previous injury is rarely involved, but sarcomas can arise in scar tissue resulting from a prior operation, burn, fracture, or foreign body implantation. Chemical carcinogens such as polycyclic hydrocarbons, asbestos, and dioxin may be involved in the pathogenesis. Iatrogenic Factors Sarcomas in bone or soft tissues occur in patients who are treated with radiation therapy. The tumor nearly always arises in the irradiated field. The risk increases with time.


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InternalMed_Harrison. Iatrogenic Factors Sarcomas in bone or soft tissues occur in patients who are treated with radiation therapy. The tumor nearly always arises in the irradiated field. The risk increases with time. Viruses Kaposi’s sarcoma (KS) in patients with HIV type 1, classic KS, and KS in HIV-negative homosexual men is caused by human herpesvirus (HHV) 8 (Chap. 219). No other sarcomas are associated with viruses. Immunologic Factors Congenital or acquired immunodeficiency, including therapeutic immunosuppression, increases the risk of sarcoma.


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InternalMed_Harrison. Li-Fraumeni syndrome is a familial cancer syndrome in which affected individuals have germline abnormalities of the tumor- suppressor gene p53 and an increased incidence of soft tissue sarcomas and other malignancies, including breast cancer, osteosarcoma, brain tumor, leukemia, and adrenal carcinoma (Chap. 101e). Neurofibromatosis 1 (NF-1, peripheral form, von Recklinghausen’s disease) is characterized by multiple neurofibromas and café-au-lait spots. Neurofibromas occasionally undergo malignant degeneration to become malignant peripheral nerve sheath tumors. The gene for NF-1 is located in the pericentromeric region of chromosome 17 and encodes neurofibromin, a tumor-suppressor protein with guanosine 5′-triphosphate (GTP)ase-activating activity that inhibits Ras function 119e-1 (Chap. 118). Germline mutation of the Rb-1 locus (chromosome 13q14) in patients with inherited retinoblastoma is associated with the development of osteosarcoma in those who survive the retinoblastoma and of


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InternalMed_Harrison. Germline mutation of the Rb-1 locus (chromosome 13q14) in patients with inherited retinoblastoma is associated with the development of osteosarcoma in those who survive the retinoblastoma and of soft tissue sarcomas unrelated to radiation therapy. Other soft tissue tumors, including desmoid tumors, lipomas, leiomyomas, neuroblastomas, and paragangliomas, occasionally show a familial predisposition.


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InternalMed_Harrison. Ninety percent of synovial sarcomas contain a characteristic chromosomal translocation t(X;18)(p11;q11) involving a nuclear transcription factor on chromosome 18 called SYT and two breakpoints on X. Patients with translocations to the second X breakpoint (SSX2) may have longer survival than those with translocations involving SSX1. Insulin-like growth factor (IGF) type II is produced by some sarcomas and may act as an autocrine growth factor and as a motility factor that promotes metastatic spread. IGF-II stimulates growth through IGF-I receptors, but its effects on motility are through different receptors. If secreted in large amounts, IGF-II may produce hypoglycemia (Chaps. 121 and 420).


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InternalMed_Harrison. Approximately 20 different groups of sarcomas are recognized on the basis of the pattern of differentiation toward normal tissue. For example, rhabdomyosarcoma shows evidence of skeletal muscle fibers with cross-striations; leiomyosarcomas contain interlacing fascicles of spindle cells resembling smooth muscle; and liposarcomas contain adipocytes. When precise characterization of the group is not possible, the tumors are called unclassified sarcomas. All of the primary bone sarcomas can also arise from soft tissues (e.g., extraskeletal osteosarcoma). The entity malignant fibrous histiocytoma (MFH) includes many tumors previously classified as fibrosarcomas or as pleomorphic variants of other sarcomas and is characterized by a mixture of spindle (fibrous) cells and round (histiocytic) cells arranged in a storiform pattern with frequent giant cells and areas of pleomorphism. As immunohistochemical suggestion of differentiation, particularly myogenic differentiation, may be found in a


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InternalMed_Harrison. arranged in a storiform pattern with frequent giant cells and areas of pleomorphism. As immunohistochemical suggestion of differentiation, particularly myogenic differentiation, may be found in a significant fraction of these patients, many are now characterized as poorly differentiated leiomyosarcomas, and the terms undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma are replacing MFH and myxoid MFH.


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InternalMed_Harrison. For purposes of treatment, most soft tissue sarcomas can be considered together. However, some specific tumors have distinct features. For example, liposarcoma can have a spectrum of behaviors. Pleomorphic liposarcomas and dedifferentiated liposarcomas behave like other high-grade sarcomas; in contrast, well-differentiated liposarcomas (better termed atypical lipomatous tumors) lack metastatic potential, and myxoid liposarcomas metastasize infrequently, but, when they do, they have a predilection for unusual metastatic sites containing fat, such as the retroperitoneum, mediastinum, and subcutaneous tissue. Rhabdomyosarcomas, Ewing’s sarcoma, and other small-cell sarcomas tend to be more aggressive and are more responsive to chemotherapy than other soft tissue sarcomas.


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InternalMed_Harrison. Gastrointestinal stromal cell tumors (GISTs), previously classified as gastrointestinal leiomyosarcomas, are now recognized as a distinct entity within soft tissue sarcomas. Its cell of origin resembles the interstitial cell of Cajal, which controls peristalsis. The majority of malignant GISTs have activating mutations of the c-kit gene that result in ligand-independent phosphorylation and activation of the KIT receptor tyrosine kinase, leading to tumorigenesis. Approximately 5–10% of tumors will have a mutation in the platelet-derived growth factor receptor α (PDGFRA). GISTs that are wild type for both KIT and PDGFRA mutations may show mutations in SDH B, C, or D and may be driven by the IGF-I pathway.


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InternalMed_Harrison. The most common presentation is an asymptomatic mass. Mechanical symptoms referable to pressure, traction, or entrapment of nerves or muscles may be present. All new and persistent or growing masses should be biopsied, either by a cutting needle (core-needle biopsy) or by a small incision, placed so that it can be encompassed in the to that achieved by radical excisions and Moderately differentiated (G2) >5 cm (T2) Involved (N1) Present (M1) amputations. Limb-sparing approaches Poorly differentiated (G3) Superficial fascial involvement (Ta) are indicated except when negative margins are not obtainable, when the risks of radiation are prohibitive, or when neuro-


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InternalMed_Harrison. Poorly differentiated (G3) Superficial fascial involvement (Ta) are indicated except when negative margins are not obtainable, when the risks of radiation are prohibitive, or when neuro- Disease Stage 5-Year Survival, % subsequent excision without compromising a definitive resection. Lymph node metastases occur in 5%, except in synovial and epithelioid sarcomas, clear-cell sarcoma (melanoma of the soft parts), angiosarcoma, and rhabdomyosarcoma, where nodal spread may be seen in 17%. The pulmonary parenchyma is the most common site of metastases. Exceptions are GISTs, which metastasize to the liver; myxoid liposarcomas, which seek fatty tissue; and clear-cell sarcomas, which may metastasize to bones. Central nervous system metastases are rare, except in alveolar soft part sarcoma.


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InternalMed_Harrison. Radiographic Evaluation Imaging of the primary tumor is best with plain radiographs and magnetic resonance imaging (MRI) for tumors of the extremities or head and neck and by computed tomography (CT) for tumors of the chest, abdomen, or retroperitoneal cavity. A radiograph and CT scan of the chest are important for the detection of lung metastases. Other imaging studies may be indicated, depending on the symptoms, signs, or histology. The histologic grade, relationship to fascial planes, and size of the primary tumor are the most important prognostic factors. The current American Joint Committee on Cancer (AJCC) staging system is shown in Table 119e-1. Prognosis is related to the stage. Cure is common in the absence of metastatic disease, but a small number of patients with metastases can also be cured. Most patients with stage IV disease die within 12 months, but some patients may live with slowly progressive disease for many years.


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InternalMed_Harrison. AJCC stage I patients are adequately treated with surgery alone. Stage II patients are considered for adjuvant radiation therapy. Stage III patients may benefit from adjuvant chemotherapy. Stage IV patients are managed primarily with chemotherapy, with or without other modalities. Soft tissue sarcomas tend to grow along fascial planes, with the surrounding soft tissues compressed to form a pseudocapsule that gives the sarcoma the appearance of a well-encapsulated lesion. This is invariably deceptive because “shelling out,” or marginal excision, of such lesions results in a 50–90% probability of local recurrence. Wide excision with a negative margin, incorporating the biopsy site, is the standard surgical procedure for local disease. The adjuvant use of radiation therapy and/or chemotherapy vascular structures are involved so that resection will result in serious functional consequences to the limb.


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InternalMed_Harrison. External-beam radiation therapy is an adjuvant to limb-sparing surgery for improved local control. Preoperative radi ation therapy allows the use of smaller a higher rate of wound complications. given to larger fields, because the entire surgical bed must be encompassed, and in higher doses to compensate for hypoxia in the operated field. This results in a higher rate of late complications. Brachytherapy or interstitial therapy, in which the radiation source is inserted into the tumor bed, is comparable in efficacy (except in low-grade lesions), less time-consuming, and less expensive.


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InternalMed_Harrison. Chemotherapy is the mainstay of treatment for Ewing’s primitive neuroectodermal tumors (PNET) and rhabdomyosarcomas. Meta-analysis of 14 randomized trials revealed a significant improvement in local control and disease-free survival in favor of doxorubicinbased chemotherapy. Overall survival improvement was 4% for all sites and 7% for the extremity site. An updated meta-analysis including four additional trials with doxorubicin and ifosfamide combination has reported a statistically significant 6% survival advantage in favor of chemotherapy. A chemotherapy regimen including an anthracycline and ifosfamide with growth factor support improved overall survival by 19% for high-risk (high-grade, ≥5 cm primary, or locally recurrent) extremity soft tissue sarcomas.


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InternalMed_Harrison. Metastatic soft tissue sarcomas are largely incurable, but up to 20% of patients who achieve a complete response become long-term survivors. The therapeutic intent, therefore, is to produce a complete remission with chemotherapy (<10%) and/or surgery (30–40%). Surgical resection of metastases, whenever possible, is an integral part of the management. Some patients benefit from repeated surgical excision of metastases. The two most active chemotherapeutic agents are doxorubicin and ifosfamide. These drugs show a steep dose-response relationship in sarcomas. Gemcitabine with or without docetaxel has become an established second-line regimen and is particularly active in patients with undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcomas. Dacarbazine also has some modest activity. Taxanes have selective activity in angiosarcomas, and vincristine, etoposide, and irinotecan are effective in rhabdomyosarcomas and Ewing’s sarcomas. Pazopanib, an inhibitor of the vascular endothelial


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InternalMed_Harrison. have selective activity in angiosarcomas, and vincristine, etoposide, and irinotecan are effective in rhabdomyosarcomas and Ewing’s sarcomas. Pazopanib, an inhibitor of the vascular endothelial growth factor, platelet-derived growth factor (PDGF), and c-kit is now approved for patients with advanced soft tissue sarcomas excluding liposarcomas after failure of chemotherapy. Imatinib targets the KIT and PDGF tyrosine kinase activity and is standard therapy for advanced/metastatic GISTs and dermatofibrosarcoma protuberans. Imatinib is now also indicated as adjuvant therapy for completely resected primary GISTs. Three years of adjuvant imatinib appears to be superior to 1 year of therapy for high-risk GISTs, although the optimal treatment duration remains unknown.


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InternalMed_Harrison. Bone sarcomas are rarer than soft tissue sarcomas; they accounted for only 0.2% of all new malignancies and 2890 new cases in the United States in 2013. Several benign bone lesions have the potential for malignant transformation. Enchondromas and osteochondromas can transform into chondrosarcoma; fibrous dysplasia, bone infarcts, and Paget’s disease of bone can transform into either UPS or osteosarcoma. CLASSIFICATION Benign Tumors The common benign bone tumors include enchondroma, osteochondroma, chondroblastoma, and chondromyxoid fibroma, of cartilage origin; osteoid osteoma and osteoblastoma, of bone origin; fibroma and desmoplastic fibroma, of fibrous tissue origin; hemangioma, of vascular origin; and giant-cell tumor, of unknown origin.


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InternalMed_Harrison. Malignant Tumors The most common malignant tumors of bone are plasma cell tumors (Chap. 136). The four most common malignant nonhematopoietic bone tumors are osteosarcoma, chondrosarcoma, Ewing’s sarcoma, and UPS. Rare malignant tumors include chordoma (of notochordal origin), malignant giant-cell tumor and adamantinoma (of unknown origin), and hemangioendothelioma (of vascular origin).


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InternalMed_Harrison. Musculoskeletal Tumor Society Staging System Sarcomas of bone are staged according to the Musculoskeletal Tumor Society staging system based on grade and compartmental localization. A Roman numeral reflects the tumor grade: stage I is low grade, stage II is high grade, and stage III includes tumors of any grade that have lymph node or distant metastases. In addition, the tumor is given a letter reflecting its compartmental localization. Tumors designated A are intracompartmental (i.e., confined to the same soft tissue compartment as the initial tumor), and tumors designated B are extracompartmental (i.e., extending into the adjacent soft tissue compartment or into bone). The tumor-nodemetastasis (TNM) staging system is shown in Table 119e-2.


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InternalMed_Harrison. Osteosarcoma, accounting for almost 45% of all bone sarcomas, is a spindle cell neoplasm that produces osteoid (unmineralized bone) or bone. Approximately 60% of all osteosarcomas occur in children and adolescents in the second decade of life, and approximately 10% occur in the third decade of life. Osteosarcomas in the fifth and sixth decades of life are frequently secondary to either radiation therapy or transformation in a preexisting benign condition, such as Paget’s disease. Males are affected 1.5–2 times as often as females. Osteosarcoma has a predilection for metaphyses of long bones; the most common sites of involvement are the distal femur, proximal tibia, and proximal humerus. The classification of osteosarcoma is complex, but 75% of osteosarcomas fall into the “classic” category, which include osteoblastic, chondroblastic, and fibroblastic osteosarcomas. The remaining 25% are classified as “variants” on the basis of (1) clinical characteristics, as in the case of


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InternalMed_Harrison. category, which include osteoblastic, chondroblastic, and fibroblastic osteosarcomas. The remaining 25% are classified as “variants” on the basis of (1) clinical characteristics, as in the case of osteosarcoma of the jaw, postradiation osteosarcoma, or Paget’s osteosarcoma; (2) morphologic characteristics, as in the case of telangiectatic osteosarcoma, small-cell osteosarcoma, or epithelioid osteosarcoma; or (3) location, as in parosteal or periosteal osteosarcoma. Diagnosis usually requires a synthesis of clinical, radiologic, and pathologic features. Patients typically present with pain and swelling of the affected area. A plain radiograph reveals a destructive lesion with a moth-eaten appearance, a spiculated periosteal reaction (sunburst appearance), and a cuff of periosteal new bone formation at the margin of the soft tissue mass (Codman’s triangle). A CT scan of the primary tumor is best for defining bone destruction and the pattern of calcification, whereas MRI is better for


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InternalMed_Harrison. formation at the margin of the soft tissue mass (Codman’s triangle). A CT scan of the primary tumor is best for defining bone destruction and the pattern of calcification, whereas MRI is better for defining intramedullary and soft tissue extension. A chest radiograph and CT scan are used to detect lung metastases. Metastases to the bony skeleton should be imaged by a bone scan or by fluorodeoxyglucose positron emission tomography (FDG-PET). Almost all osteosarcomas are hypervascular. Angiography is not helpful for diagnosis, but it is the most sensitive test for assessing the response to preoperative


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InternalMed_Harrison. Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor ≤8 cm in greatest dimension T2 Tumor >8 cm in greatest dimension T3 Discontinuous tumors in the primary Histologic grade (G) GX Grade cannot be assessed G1 Well differentiated—low grade G2 Moderately differentiated—low grade G3 Poorly differentiated—high grade G4 Undifferentiated—high grade (Ewing’s is Stage IA T1 N0 M0 G1,2 low grade Stage IB T2 N0 M0 G1,2 low grade Stage IIA T1 N0 M0 G3,4 high grade


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InternalMed_Harrison. Stage IIB T2 N0 M0 G3,4 high grade chemotherapy. Pathologic diagnosis is established either with a core-needle biopsy, where feasible, or with an open biopsy with an appropriately placed incision that does not compromise future limb-sparing resection. Most osteosarcomas are high-grade. The most important prognostic factor for long-term survival is response to chemotherapy. Preoperative chemotherapy followed by limb-sparing surgery (which can be accomplished in >80% of patients) followed by postoperative chemotherapy is standard management. The effective drugs are doxorubicin, ifosfamide, cisplatin, and high-dose methotrexate with leucovorin rescue. The various combinations of these agents that have been used have all been about equally successful. Long-term survival rates in extremity osteosarcoma range from 60 to 80%. Osteosarcoma is radioresistant; radiation therapy has no role in the routine management. UPS is considered a part of the spectrum of osteosarcoma and is managed


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InternalMed_Harrison. osteosarcoma range from 60 to 80%. Osteosarcoma is radioresistant; radiation therapy has no role in the routine management. UPS is considered a part of the spectrum of osteosarcoma and is managed similarly.


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InternalMed_Harrison. Chondrosarcoma, which constitutes ~20–25% of all bone sarcomas, is a tumor of adulthood and old age with a peak incidence in the fourth to sixth decades of life. It has a predilection for the flat bones, especially the shoulder and pelvic girdles, but can also affect the diaphyseal portions of long bones. Chondrosarcomas can arise de novo or as a malignant transformation of an enchondroma or, rarely, of the cartilaginous cap of an osteochondroma. Chondrosarcomas have an indolent natural history and typically present as pain and swelling. Radiographically, the lesion may have a lobular appearance with mottled or punctate or annular calcification of the cartilaginous matrix. It is difficult to distinguish low-grade chondrosarcoma from benign lesions by x-ray or histologic examination. The diagnosis is therefore influenced by clinical history and physical examination. A new onset of pain, signs of inflammation, and progressive increase in the size of the mass suggest malignancy. The


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InternalMed_Harrison. diagnosis is therefore influenced by clinical history and physical examination. A new onset of pain, signs of inflammation, and progressive increase in the size of the mass suggest malignancy. The histologic classification is complex, but most tumors fall within the classic category. Like other bone sarcomas, high-grade chondrosarcomas spread to the lungs. Most chondrosarcomas are resistant to chemotherapy, and surgical resection of primary or recurrent tumors, including pulmonary metastases, is the mainstay of therapy. This rule does not hold for two histologic variants. Dedifferentiated chondrosarcoma has a high-grade osteosarcoma or a malignant fibrous histiocytoma component that responds to chemotherapy. Mesenchymal chondrosarcoma, a rare variant composed of a small-cell element, also is responsive to systemic chemotherapy and is treated like Ewing’s sarcoma.


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InternalMed_Harrison. Ewing’s sarcoma, which constitutes ~10–15% of all bone sarcomas, is common in adolescence and has a peak incidence in the second decade of life. It typically involves the diaphyseal region of long bones and also has an affinity for flat bones. The plain radiograph may show a characteristic “onion peel” periosteal reaction with a generous soft tissue mass, which is better demonstrated by CT or MRI. This mass is composed of sheets of monotonous, small, round, blue cells and can be confused with lymphoma, embryonal rhabdomyosarcoma, and small-cell carcinoma. The presence of p30/32, the product of the mic-2 gene (which maps to the pseudoautosomal region of the X and Y chromosomes), is a cell-surface marker for Ewing’s sarcoma (and other members of the Ewing’s family of tumors, sometimes called PNETs). Most PNETs arise in soft tissues; they include peripheral neuroepithelioma, Askin’s tumor (chest wall), and esthesioneuroblastoma. Glycogen-filled cytoplasm detected by staining with


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InternalMed_Harrison. called PNETs). Most PNETs arise in soft tissues; they include peripheral neuroepithelioma, Askin’s tumor (chest wall), and esthesioneuroblastoma. Glycogen-filled cytoplasm detected by staining with periodic acid–Schiff is also characteristic of Ewing’s sarcoma cells. The classic cytogenetic abnormality associated with this disease (and other PNETs) is a reciprocal translocation of the long arms of chromosomes 11 and 22, t(11;22), which creates a chimeric gene product of unknown function with components from the fli-1 gene on chromosome 11 and ews on 22. This disease is very aggressive, and it is therefore considered a systemic disease. Common sites of metastases are lung, bones, and bone marrow. Systemic chemotherapy is the mainstay of therapy, often being used before surgery. Doxorubicin, cyclophosphamide or ifosfamide, etoposide, vincristine, and dactinomycin are active drugs. Topotecan or irinotecan in combination with an alkylating agent is often used in relapsed patients.


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InternalMed_Harrison. cyclophosphamide or ifosfamide, etoposide, vincristine, and dactinomycin are active drugs. Topotecan or irinotecan in combination with an alkylating agent is often used in relapsed patients. Targeted therapy with an anti-IGF-I receptor antibody in combination with an inhibitor of mammalian target of rapamycin (mTOR) appears to have promising activity in refractory cases. Local treatment for the primary tumor includes surgical resection, usually with limb salvage or radiation therapy. Patients with lesions below the elbow and below the mid-calf have a 5-year survival rate of 80% with effective treatment. Ewing’s sarcoma at first presentation is a curable tumor, even in the presence of obvious metastatic disease, especially in children <11 years old.


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InternalMed_Harrison. Bone is a common site of metastasis for carcinomas of the prostate, breast, lung, kidney, bladder, and thyroid and for lymphomas and sarcomas. Prostate, breast, and lung primaries account for 80% of all bone metastases. Metastatic tumors of bone are more common than primary bone tumors. Tumors usually spread to bone hematogenously, but local invasion from soft tissue masses also occurs. In descending order of frequency, the sites most often involved are the vertebrae, proximal femur, pelvis, ribs, sternum, proximal humerus, and skull. Bone metastases may be asymptomatic or may produce pain, swelling, nerve root or spinal cord compression, pathologic fracture, or myelophthisis (replacement of the marrow). Symptoms of hypercalcemia may be noted in cases of bony destruction.


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InternalMed_Harrison. Pain is the most frequent symptom. It usually develops gradually over weeks, is usually localized, and often is more severe at night. When patients with back pain develop neurologic signs or symptoms, emergency evaluation for spinal cord compression is indicated (Chap. 331). Bone metastases exert a major adverse effect on quality of life in cancer patients.


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InternalMed_Harrison. Cancer in the bone may produce osteolysis, osteogenesis, or both. Osteolytic lesions result when the tumor produces substances that can directly elicit bone resorption (vitamin D–like steroids, prostaglandins, or parathyroid hormone–related peptide) or cytokines that can induce the formation of osteoclasts (interleukin 1 and tumor necrosis factor). Osteoblastic lesions result when the tumor produces cytokines that activate osteoblasts. In general, purely osteolytic lesions are best detected by plain radiography, but they may not be apparent until they are >1 cm. These lesions are more commonly associated with hypercalcemia and with the excretion of hydroxyproline-containing peptides indicative of matrix destruction. When osteoblastic activity is prominent, the lesions may be readily detected using radionuclide bone scanning (which is sensitive to new bone formation), and the radiographic appearance may show increased bone density or sclerosis. Osteoblastic lesions are associated with


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InternalMed_Harrison. using radionuclide bone scanning (which is sensitive to new bone formation), and the radiographic appearance may show increased bone density or sclerosis. Osteoblastic lesions are associated with higher serum levels of alkaline phosphatase and, if extensive, may produce hypocalcemia. Although some tumors may produce mainly osteolytic lesions (e.g., kidney cancer) and others mainly osteoblastic lesions (e.g., prostate cancer), most metastatic lesions produce both types of lesion and may go through stages where one or the other predominates.


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InternalMed_Harrison. In older patients, particularly women, it may be necessary to distinguish metastatic disease of the spine from osteoporosis. In osteoporosis, the cortical bone may be preserved, whereas cortical bone destruction is usually noted with metastatic cancer.


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InternalMed_Harrison. Treatment of metastatic bone disease depends on the underlying malignancy and the symptoms. Some metastatic bone tumors are curable (lymphoma, Hodgkin’s disease), and others are treated with palliative intent. Pain may be relieved by local radiation therapy. Hormonally responsive tumors are responsive to hormone inhibition (antiandrogens for prostate cancer, antiestrogens for breast cancer). Strontium-89, samarium-153, and radium-223 are bone-seeking radionuclides that can exert antitumor effects and relieve symptoms. Denosumab, a monoclonal antibody that binds to RANK ligand, inhibits osteoclastic activity and increases bone mineral density. Bisphosphonates such as pamidronate may relieve pain and inhibit bone resorption, thereby maintaining bone mineral density and reducing risk of fractures in patients with osteolytic metastases from breast cancer and multiple myeloma. Careful monitoring of serum electrolytes and creatinine is recommended. Monthly administration prevents


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InternalMed_Harrison. of fractures in patients with osteolytic metastases from breast cancer and multiple myeloma. Careful monitoring of serum electrolytes and creatinine is recommended. Monthly administration prevents bone-related clinical events and may reduce the incidence of bone metastases in women with breast cancer. When the integrity of a weight-bearing bone is threatened by an expanding metastatic lesion that is refractory to radiation therapy, prophylactic internal fixation is indicated. Overall survival is related to the prognosis of the underlying tumor. Bone pain at the end of life is particularly common; an adequate pain relief regimen including sufficient amounts of narcotic analgesics is required. The management of hypercalcemia is discussed in Chap. 424.


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InternalMed_Harrison. Carcinoma of Unknown primary Gauri R. Varadhachary, James L. Abbruzzese Carcinoma of unknown primary (CUP) is a biopsy-proven malig-nancy for which the anatomic site of origin remains unidentified after 120e an intensive search. CUP is one of the 10 most frequently diagnosed cancers worldwide, accounting for 3–5% of all cancers. Most investigators limit CUP to epithelial cancers and do not include lymphomas, metastatic melanomas, and metastatic sarcomas because these cancers have specific histologyand stage-based treatments that guide management.


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InternalMed_Harrison. The emergence of sophisticated imaging, robust immunohistochemistry (IHC), and genomic and proteomic tools has challenged the “unknown” designation. Additionally, effective targeted therapies in several cancers have moved the paradigm from empiricism to considering a personalized approach to CUP management. The reasons cancers present as CUP remain unclear. One hypothesis is that the primary tumor either regresses after seeding the metastasis or remains so small that it is not detected. It is possible that CUP falls on the continuum of cancer presentation where the primary has been contained or eliminated by the natural body defenses. Alternatively, CUP may represent a specific malignant event that results in an increase in metastatic spread or survival relative to the primary. Whether the CUP metastases truly define a clone that is genetically and phenotypically unique to this diagnosis remains to be determined.


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InternalMed_Harrison. Studies looking for unique signature abnormalities in CUP tumors have not been positive. Abnormalities in chromosomes 1 and 12 and other complex cytogenetic abnormalities have been reported. Aneuploidy has been described in 70% of CUP patients with metastatic adenocarcinoma or undifferentiated carcinoma. The overexpression of various genes, including Ras, bcl-2 (40%), her-2 (11%), and p53 (26–53%), has been studied in CUP samples, but they have no effect on response to therapy or survival. The extent of angiogenesis in CUP relative to that in metastases from known primaries has also been evaluated, but no consistent findings have emerged. Using the Sequenom (SQM) Massarray platform, a study in consecutive CUP patients showed that the overall mutational rate was surprisingly low (18%). No “new” low-frequency mutations were found using a panel of mutations involving the P13K/AKT pathway, MEK pathway, receptors, and downstream effectors. Nevertheless, it is possible that newer “deep


InternalMed_Harrison

InternalMed_Harrison. No “new” low-frequency mutations were found using a panel of mutations involving the P13K/AKT pathway, MEK pathway, receptors, and downstream effectors. Nevertheless, it is possible that newer “deep sequencing” techniques in select patients may yield consistent abnormalities.


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InternalMed_Harrison. Initial CUP evaluation has two goals: search for the primary tumor based on pathologic evaluation of the metastases and determine the extent of disease. Obtaining a thorough medical history from CUP patients is essential, including paying particular attention to previous surgeries, removed lesions, and family medical history to assess potential hereditary cancers. Adequate physical examination, including a digital rectal examination in men and breast and pelvic examinations in women, should be performed based on clinical presentation.


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InternalMed_Harrison. Role of Serum Tumor Markers and Cytogenetics Most tumor markers, including CEA, CA-125, CA 19-9, and CA 15-3, when elevated, are nonspecific and not helpful in determining the primary tumor site. Men who present with adenocarcinoma and osteoblastic metastasis should undergo a prostate-specific antigen (PSA) test. In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated β-human chorionic gonadotropin (β-hCG) and α fetoprotein (AFP) levels suggest the possibility of an extragonadal germ cell (testicular) tumor. With the availability of IHC, cytogenetic studies are rarely needed.


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InternalMed_Harrison. Role of Imaging Studies In the absence of contraindications, a baseline 120e-1 IV contrast computed tomography (CT) scan of the chest, abdomen, and pelvis is the standard of care. This helps to search for the primary tumor, evaluate the extent of disease, and select the most accessible biopsy site. Older studies suggested that the primary tumor site is detected in 20–35% of patients who undergo a CT scan of the abdomen and pelvis, although by current definition, these patients do not have CUP. These studies also suggest a latent primary tumor prevalence of 20%; with more sophisticated imaging, this has decreased to ≤5% today.


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InternalMed_Harrison. Mammography should be performed in all women who present with metastatic adenocarcinoma, especially in those with adenocarcinoma and isolated axillary lymphadenopathy. Magnetic resonance imaging (MRI) of the breast is a follow-up modality in patients with axillary adenopathy and suspected occult primary breast carcinoma following a negative mammography and ultrasound. The results of these imaging modalities can influence surgical management; a negative breast MRI result predicts a low tumor yield at mastectomy.


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InternalMed_Harrison. A conventional workup for a squamous cell carcinoma and cervical CUP (neck lymphadenopathy with no known primary tumor) includes a CT scan or MRI and invasive studies, including indirect and direct laryngoscopy, bronchoscopy, and upper endoscopy. Ipsilateral (or bilateral) staging tonsillectomy has been recommended for these patients. 18-Fluorodeoxyglucose positron emission tomography (18-FDG-PET) scans are useful in this patient population and may help guide the biopsy; determine the extent of disease; facilitate the appropriate treatment, including planning radiation fields; and help with disease surveillance. A smaller radiation field encompassing the primary (when found) and metastatic adenopathy decreases the risk of chronic xerostomia. Several studies have evaluated the utility of PET in patients with squamous cervical CUP, and head and neck primary tumors were identified in ~21–30%.


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InternalMed_Harrison. The diagnostic contribution of PET to the evaluation of other CUP (outside of the neck adenopathy indication) remains controversial and is not routinely recommended. PET-CT can be helpful for patients who are candidates for surgical intervention for solitary metastatic disease because the presence of disease outside the primary site may affect surgical planning. Invasive studies, including upper endoscopy, colonoscopy, and bronchoscopy, should be limited to symptomatic patients or those with laboratory, imaging, or pathologic abnormalities that suggest that these techniques will result in a high yield in finding a primary cancer. Role of Pathologic Studies A detailed pathologic examination of the most accessible biopsied tissue specimen is mandatory in CUP patients. Pathologic evaluation typically consists of hematoxylin and eosin stains and immunohistochemical tests.


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InternalMed_Harrison. LIGHT MICROSCOPY EVALUATION Adequate tissue obtained preferably by excisional biopsy or core-needle biopsy (instead of only a fine-needle aspiration) is stained with hematoxylin and eosin and subjected to light microscopic examination. On light microscopy, 60–65% of CUP is adenocarcinoma, and 5% is squamous cell carcinoma. The remaining 30–35% is poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasm. A small percentage of lesions are diagnosed as neuroendocrine cancers (2%), mixed tumors (adenosquamous or sarcomatoid carcinomas), or undifferentiated neoplasms (Table 120e-1). Histology Proportion, % Chapter 120e Carcinoma of Unknown Primary Well to moderately differentiated adenocarcinoma 60 Squamous cell cancer 5 Poorly differentiated adenocarcinoma, poorly FIGURE 120e-1 Approach to cytokeratin (CK7 and CK20) markers used in adenocarcinoma of unknown primary.


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InternalMed_Harrison. ROLE OF IMMUNOHISTOCHEMICAL ANALYSIS Immunohistochemical stains are peroxidase-labeled antibodies against specific tumor antigens that are used to define tumor lineage. The number of available immunohistochemical stains is ever-increasing. However, in CUP cases, more is not necessarily better, and immunohistochemical stains should be used in conjunction with the patient’s clinical presentation and imaging studies to select the best therapy. Communication between the clinician and pathologist is essential. No stain is 100% specific, and overinterpretation should be avoided. PSA and thyroglobulin tissue markers, which are positive in prostate and thyroid cancer, respectively, are the most specific of the current marker panel. However, these cancers rarely present as CUP, so the yield of these tests may be low. Fig. 120e-1 delineates a simple algorithm for immunohistochemical staining in CUP cases. Table 120e-2 lists additional tests that may be useful to further define the tumor


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InternalMed_Harrison. of these tests may be low. Fig. 120e-1 delineates a simple algorithm for immunohistochemical staining in CUP cases. Table 120e-2 lists additional tests that may be useful to further define the tumor lineage. A more comprehensive algorithm may improve the diagnostic accuracy but can make the process complex. With the use of immunohistochemical markers, electron microscopic analysis, which is time-consuming and expensive, is rarely needed.


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InternalMed_Harrison. There are >20 subtypes of cytokeratin (CK) intermediate filaments with different molecular weights and differential expression in various cell types and cancers. Monoclonal antibodies to specific CK subtypes have been used to help classify tumors according to their site of origin; commonly used CK stains in adenocarcinoma CUP are CK7 and CK20. CK7 is found in tumors of the lung, ovary, endometrium, breast, and upper gastrointestinal tract including pancreaticobiliary cancers, whereas CK20 is normally expressed in the gastrointestinal epithelium, urothelium, and Merkel cells. The nuclear CDX-2 transcription factor, which is the product of a homeobox gene necessary for intestinal organogenesis, is often used to aid in the diagnosis of gastrointestinal adenocarcinomas.


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InternalMed_Harrison. Thyroid transcription factor 1 (TTF-1) nuclear staining is typically positive in lung and thyroid cancers. Approximately 68% of adenocarcinomas and 25% of squamous cell lung cancers stain positive for TTF-1, which helps differentiate a lung primary tumor from metastatic adenocarcinoma in a pleural effusion, the mediastinum, or the lung parenchyma. Gross cystic disease fibrous protein-15, a 15-kDa monomer protein, is a marker of apocrine differentiation that is detected in 62–72% of breast carcinomas. UROIII, high-molecular-weight cytokeratin, thrombomodulin, and CK20 are the markers used to diagnose lesions of urothelial origin.


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InternalMed_Harrison. IHC performs the best when used in groups that give rise to patterns that are strongly indicative of certain profiles. For example, the TTF-1/CK7+ and CK20+/CDX-2+/CK7– phenotypes have been reported as very suggestive of lung and lower gastrointestinal cancer profiles, respectively, although these patterns have not been validated prospectively in the absence of a primary cancer. IHC is not without its limitations; several factors affect tissue antigenicity (antigen retrieval, specimen processing, and fixation), interpretation of stains in tumor (nuclear, cytoplasmic, membrane) versus normal tissue, inter-and intraobserver variability, and tissue heterogeneity and inadequacy (given small biopsy sizes). Communication with the pathologist is critical to determine if additional tissue will be beneficial in the pathologic evaluation.


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InternalMed_Harrison. ROLE OF TISSUE OF ORIGIN MOLECULAR PROFILING In the absence of a known primary, developing therapeutic strategies for CUP is challenging. The current diagnostic yield with imaging and immunochemistry is ~20– 30% for CUP patients. The use of gene expression studies holds the Commonly Considered IHC to Assist in Likely Primary Profile Differential Diagnosis of CUPa aPatterns emerging from coexpression of stains are better than individual stains to suggest putative primary site. Even with optimization, no IHC panel is 100% sensitive or specific (e.g., ovarian mucinous carcinoma can exhibit positivity with intestinal markers). Abbreviations: AFP, α fetoprotein; β-hCG, β human chorionic gonadotropin; CUP, carcinoma of unknown primary; IHC, immunohistochemistry; PSA, prostate-specific antigen. promise of substantially increasing this yield. Gene expression profiles are most commonly generated using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or DNA microarray.


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InternalMed_Harrison. promise of substantially increasing this yield. Gene expression profiles are most commonly generated using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or DNA microarray. Neural network programs have been used to develop predictive algorithms from the gene expression profiles. Typically, a training set of gene profiles from known cancers (preferably from metastatic sites) is used to train the software. The program can then be used to predict the putative origin of a test tumor and presumably of true CUP. Comprehensive gene expression databases that have become available for common malignancies may also be useful in CUP. These approaches have been effective in testing against known primary cancers and their metastases.


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InternalMed_Harrison. mRNA-or microRNA-based tissue of origin molecular profiling assays have been studied in prospective and retrospective CUP trials. Most of the CUP studies have evaluated assay performance, although the challenge with validating the accuracy of an assay for CUP is that, by definition, the primary cancer diagnosis cannot be verified. Thus, current estimates of tissue of origin test accuracy have relied on indirect metrics including comparison with IHC, clinical presentation, and appearance of latent primaries. Using these measures, the assays suggest a plausible primary in ~70% of patients studied. The only out-comes-based study is a single-arm study reporting a median survival of 12.5 months for patients who received assay-directed site-specific therapy. Firm conclusions of therapeutic impact cannot be drawn from this study given the nonrandomized design, statistical biases, confounding variables including use of subsequent lines of (empiric) therapy, and the heterogeneity of the CUP


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InternalMed_Harrison. cannot be drawn from this study given the nonrandomized design, statistical biases, confounding variables including use of subsequent lines of (empiric) therapy, and the heterogeneity of the CUP cancers. Additional studies are needed to better understand the clinical influence of tissue of origin profiling tools and how these assays complement IHC and help guide therapy.


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InternalMed_Harrison. The treatment of CUP continues to evolve, albeit slowly. The median survival duration of most patients with disseminated CUP is ~6–10 months. Systemic chemotherapy is the primary treatment modality in most patients with disseminated disease, but the careful integra-120e-3 tion of surgery, radiation therapy, and even periods of observation is important in the overall management of this condition (Figs. 120e-2 and 120e-3). Prognostic factors include performance status, site and number of metastases, response to chemotherapy, and serum lactate dehydrogenase (LDH) levels. Culine and colleagues developed a prognostic model using performance status and serum LDH levels, which allowed the assignment of patients into two subgroups with divergent outcomes. Future prospective trials using this prognostic model are warranted. Clinically, some CUP diagnoses fall into a favorable prognostic subset. Others, including those with disseminated CUP, do not and have a more unfavorable prognosis.


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InternalMed_Harrison. TREATMENT OF FAVORABLE CUP SUBSETS Women with Isolated Axillary Adenopathy Women with isolated axillary adenopathy with adenocarcinoma or carcinoma are usually treated for stage II or III breast cancer based on pathologic findings. These patients should undergo a breast MRI if mammogram and ultrasound are negative. Radiation therapy to the ipsilateral breast is indicated if the breast MRI is positive. Chemotherapy and/or hormonal therapy are indicated based on patient’s age (premenopausal or postmenopausal), nodal disease bulk, and hormone receptor status (Chap. 108). It is important to verify that the pathology suggests a breast cancer profile (morphology, immunohistochemical breast markers including estrogen receptor, mammoglobin, GCDFP15, HER-2 gene expression) before embarking on a breast cancer therapeutic program.


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InternalMed_Harrison. The term primary peritoneal papillary serous carcinoma (PPSC) has been used to describe CUP with carcinomatosis with the pathologic and laboratory (elevated CA-125 antigen) characteristics of ovarian cancer but no ovarian primary tumor identified on transvaginal sonography or laparotomy. Studies suggest that ovarian cancer and PPSC, which are both of müllerian origin, have similar gene expression profiles. Similar to patients with ovarian cancer, patients with PPSC are candidates for cytoreductive surgery, followed by adjuvant taxaneand platinum-based chemotherapy. In one Chapter 120e Carcinoma of Unknown Primary


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InternalMed_Harrison. Chapter 120e Carcinoma of Unknown Primary Isolated axillary nodes in women Bone only metastases in men (blastic) Solitary site of metastasis Peritoneal carcinoma Disseminated cancer, 2 or more sites involved Breast MRI if mammogram and ultrasound are negative If PSA not elevated, C or RT as indicated MRI (+). Breast surgery or radiation. C and/or hormonal therapy for breast cancer. MRI (–). No surgery, consider radiation. C for breast cancer. Check PSA (in tumor and serum). If elevated, Rx as prostate cancer. If resectable, resect with or without prior C or CRT. If unresectable, C, RT, or CRT depending on location of tumor If not suggestive of primary peritoneal, GI workup for primary. C, if good performance status. If suggestive of primary peritoneal cancer, treat as ovarian cancer C, if good performance status FIGURE 120e-2 Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma of unknown primary (CUP).


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InternalMed_Harrison. FIGURE 120e-2 Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma of unknown primary (CUP). C, chemotherapy; CRT, chemoradiation; GI, gastrointestinal; IHC, immunohistochemistry; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; RT, radiation. Squamous cell CUP Disseminated, visceral metastases Metastatic inguinal adenopathy Metastatic cervical adenopathy Directed invasive tests as needed Perineal exam, anoscopy if needed. Pelvic examination in women. PET is optional. Triple endoscopy, consider tonsillectomy. CT neck and chest. PET is optional. C in good performance status patients. RT as indicated. If localized, lymph node dissection, followed by local RT in select patients If no extra-cervical disease—neck dissection followed by adjuvant RT vs. RT alone. C for bulky disease.


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InternalMed_Harrison. FIGURE 120e-3 Treatment algorithm for squamous cell carcinoma of unknown primary (CUP). C, chemotherapy; CT, computed tomography; PET, positron emission tomography; RT, radiation. retrospective study of 258 women with peritoneal carcinomatosis who had undergone cytoreductive surgery and chemotherapy, 22% of patients had a complete response to chemotherapy; the median survival duration was 18 months (range 11–24 months). However, not all peritoneal carcinomatosis in women is PPSC. Careful pathologic evaluation can help diagnose a colon cancer profile (CDX-2+, CK-20+, CK7−) or a pancreaticobiliary cancer or even a mislabeled peritoneal mesothelioma (calretinin positive).