InternalMed_Harrison

InternalMed_Harrison. seen with enzalutamide, for which an expanded indication is also anticipated. Alpharadin (radium-223 chloride), an alpha-emitting bone-seeking radioisotope, has been shown to prolong life in patients with symptoms related to osseous disease. The alpharadin result validated the bone microenvironment as a therapeutic target independent of direct effects on the tumor itself, as no declines in PSA were observed in the trial. Notable is that in addition to a survival benefit, the drug also reduced the development of significant skeletal events.


InternalMed_Harrison

InternalMed_Harrison. Other bone-targeted agents, such as the bisphosphonates and the RANK ligand inhibitor denosumab, protect against bone loss associated with androgen depletion and also reduce skeletal-related events by targeting bone osteoclasts. In one trial, denosumab was shown to be superior to zoledronic acid with respect to skeletal-related events, but had a slightly higher frequency of osteonecrosis of the jaw.


InternalMed_Harrison

InternalMed_Harrison. In clinical practice, most men seek to avoid chemotherapy and are first treated with a biologic agent and/or newer hormonal agent approved for this indication. It is crucial to the management of the individual patient to define therapeutic objectives before initiating treatment, as there are defined standards of care for different disease manifestations. For example, sipuleucel-T is not indicated for patients with symptoms or visceral disease because the effects on the disease occur late. Similarly, alpharadin is not indicated for patients with disease that is predominantly in soft tissue or who have osseous disease that is not causing symptoms.


InternalMed_Harrison

InternalMed_Harrison. Pain Management Management of pain secondary to osseous metastatic disease is a critical part of therapy. Optimal palliation requires assessing whether the symptoms are from metastases that threaten or that are already affecting the spinal cord, the cauda equina, or the base of the skull, which are best treated with external-beam radiation, as are single sites of pain. Neurologic symptoms require emergency evaluation because loss of function may be permanent if not addressed quickly. Because the disease is often diffuse, palliation at one site is often followed by the emergence of symptoms in a separate site that had not received radiation. In these cases, bone-seeking radioisotopes such as alpharadin or the beta emitter 153Sm-EDTMP (Quadramet) can be considered in addition to abiraterone acetate, docetaxel, and mitoxantrone, each of which is formally approved for the palliation of pain due to prostate cancer metastases.


InternalMed_Harrison

InternalMed_Harrison. BPH is a pathologic process that contributes to the development of lower urinary tract symptoms in men. Such symptoms, arising from lower urinary tract dysfunction, are further subdivided into obstructive symptoms (urinary hesitancy, straining, weak stream, terminal dribbling, prolonged voiding, incomplete emptying) and irritative symptoms (urinary frequency, urgency, nocturia, urge incontinence, small voided volumes). Lower urinary tract symptoms and other sequelae of BPH are not just due to a mass effect, but are also likely due to a combination of the prostatic enlargement and age-related detrusor dysfunction.


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InternalMed_Harrison. The symptoms are generally measured using a validated, reproducible index that is designed to determine disease severity and response to therapy—the AUA’s Symptom Index (AUASI), also adopted as the International Prostate Symptom Score (IPSS) (Table 115–2). Serial AUASI is particularly useful in following patients as they are treated with various forms of therapy. Asymptomatic patients do not require treatment regardless of the size of the gland, whereas patients with an inability to urinate, gross hematuria, recurrent infection, or bladder stones may require surgery. In patients with 587 symptoms, uroflowmetry can identify those with normal flow rates who are unlikely to benefit from treatment, and bladder ultrasound can identify those with high postvoid residuals who may need intervention. Pressure-flow (urodynamic) studies detect primary bladder dysfunction. Cystoscopy is recommended if hematuria is documented and to assess the urinary outflow tract before surgery. Imaging of the


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InternalMed_Harrison. Pressure-flow (urodynamic) studies detect primary bladder dysfunction. Cystoscopy is recommended if hematuria is documented and to assess the urinary outflow tract before surgery. Imaging of the upper tracts is advised for patients with hematuria, a history of calculi, or prior urinary tract problems.


InternalMed_Harrison

InternalMed_Harrison. Symptomatic relief is the most common reason men seek treatment for BPH, and therefore the goal of therapy for BPH is usually relief of these symptoms. Alpha-adrenergic receptor antagonists are thought to treat the dynamic aspect of BPH by reducing sympathetic tone of the bladder outlet, thereby decreasing resistance and improving urinary flow. 5ARIs are thought to treat the static aspect of BPH by reducing prostate volume and having a similar, albeit delayed effect. They have also proven to be beneficial in the prevention of BPH progression, as measured by prostate volume, the risk of developing acute urinary retention, and the risk of having BPH-related surgery. The use of an alpha-adrenergic receptor antagonist and a 5ARI as combination therapy seeks to provide symptomatic relief while preventing progression of BPH.


InternalMed_Harrison

InternalMed_Harrison. Another class of medications that has shown improvement in lower urinary tract symptoms secondary to BPH is PDE5 inhibitors, used currently in the treatment of erectile dysfunction. All three of the PDE5 inhibitors available in the United States, sildenafil, vardenafil, and tadalafil, appear to be effective in the treatment of symp toms secondary to BPH. The use of PDE5 inhibitors is not without controversy, however, given the fact that short-acting phosphodiesterase inhibitors such as sildenafil need to be dosed separately from alpha blockers such as tamsulosin because of potential hypotensive effects. Newer classes of pharmacologic agents have been used to treat symptoms secondary to BPH. Symptoms due to BPH often coexist with symptoms due to overactive bladder, and the most common pharmacologic agents for the treatment of overactive bladder symptoms are anticholinergics. This has led to multiple studies evaluating the efficacy of anticholinergics for the treatment of lower urinary


InternalMed_Harrison

InternalMed_Harrison. agents for the treatment of overactive bladder symptoms are anticholinergics. This has led to multiple studies evaluating the efficacy of anticholinergics for the treatment of lower urinary tract symptoms secondary to BPH. Surgical therapy is now considered second-line therapy and is usually reserved for patients after a trial of medical therapy. The goal of surgical therapy is to reduce the size of the prostate, effectively reducing resistance to urine flow.


InternalMed_Harrison

InternalMed_Harrison. Surgical approaches include TURP, transurethral incision, or removal of the gland via a retropubic, suprapubic, or perineal approach. Also used are transurethral ultrasound-guided laser-induced prostatectomy (TULIP), stents, and hyperthermia. Benign and Malignant Diseases of the Prostate Less Than Less Than About Half More Than Almost Questions to Be Answered Not at All 1 Time in 5 Half the Time the Time Half the Time Always Over the past month, how often have you had a sensation of not emptying your bladder completely after you finished urinating? Over the past month, how often have you had to urinate again less than 2 h after you finished urinating? Over the past month, how often have you found you stopped and started again several times when you urinated? Over the past month, how often have you found it difficult to postpone urination? Over the past month, how often have you had a weak urinary stream?


InternalMed_Harrison

InternalMed_Harrison. Over the past month, how often have you had a weak urinary stream? Over the past month, how often have you had to push or strain to begin urination? Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning? Sum of 7 circled numbers (AUA Symptom Score): ____ Abbreviation: AUA, American Urological Association. Source: MJ Barry et al: J Urol 148:1549, 1992. Used with permission.


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InternalMed_Harrison. Source: MJ Barry et al: J Urol 148:1549, 1992. Used with permission. 588 testicular Cancer Robert J. Motzer, Darren R. Feldman, George J. Bosl Primary germ cell tumors (GCTs) of the testis arising by the malig-nant transformation of primordial germ cells constitute 95% of all testicular neoplasms. Infrequently, GCTs arise from an extragonadal site, including the mediastinum, retroperitoneum, and, very rarely, the 116 pineal gland. This disease is notable for the young age of the afflicted patients, the totipotent capacity for differentiation of the tumor cells, and its curability; approximately 95% of newly diagnosed patients are cured. Experience in the management of GCTs leads to improved outcome.


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InternalMed_Harrison. The incidence of testicular GCT is now approximately 8000 cases annually in the United States, resulting in nearly 400 deaths. The tumor occurs most frequently in men between the ages of 20 and 40 years. A testicular mass in a male ≥50 years should be regarded as a lymphoma until proved otherwise. GCT is at least four to five times more common in white than in African-American males, and a higher incidence has been observed in Scandinavia and New Zealand than in the United States.


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InternalMed_Harrison. Cryptorchidism is associated with a several-fold higher risk of GCT. Abdominal cryptorchid testes are at a higher risk than inguinal crypt-orchid testes. Orchiopexy should be performed before puberty, if possible. Early orchiopexy reduces the risk of GCT and improves the ability to save the testis. An abdominal cryptorchid testis that cannot be brought into the scrotum should be removed. Approximately 2% of men with GCTs of one testis will develop a primary tumor in the other testis. Testicular feminization syndromes and family history increase the risk of testicular GCT, and Klinefelter’s syndrome is associated with mediastinal GCT. An isochromosome of the short arm of chromosome 12 [i(12p)] is pathognomonic for GCT. Excess 12p copy number, either in the form of i(12p) or as increased 12p on aberrantly banded marker chromosomes, occurs in nearly all GCTs, but the gene(s) on 12p involved in the pathogenesis are not yet defined.


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InternalMed_Harrison. A painless testicular mass is pathognomonic for a testicular malignancy. More commonly, patients present with testicular discomfort or swelling suggestive of epididymitis and/or orchitis. In this circumstance, a trial of antibiotics is reasonable. However, if symptoms persist or a residual abnormality remains, then testicular ultrasound examination is indicated. Ultrasound of the testis is indicated whenever a testicular malignancy is considered and for persistent or painful testicular swelling. If a testicular mass is detected, a radical inguinal orchiectomy should be performed. Because the testis develops from the gonadal ridge, its blood supply and lymphatic drainage originate in the abdomen and descend with the testis into the scrotum. An inguinal approach is taken to avoid breaching anatomic barriers and permitting additional pathways of spread.


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InternalMed_Harrison. Back pain from retroperitoneal metastases is common and must be distinguished from musculoskeletal pain. Dyspnea from pulmonary metastases occurs infrequently. Patients with increased serum levels of human chorionic gonadotropin (hCG) may present with gynecomastia. A delay in diagnosis is associated with a more advanced stage and possibly worse survival.


InternalMed_Harrison

InternalMed_Harrison. The staging evaluation for GCT includes a determination of serum levels of α fetoprotein (AFP), hCG, and lactate dehydrogenase (LDH). After orchiectomy, a computed tomography (CT) scan of the chest, abdomen, and pelvis is generally performed. Stage I disease is limited to the testis, epididymis, or spermatic cord. Stage II disease is limited to retroperitoneal (regional) lymph nodes. Stage III disease is disease outside the retroperitoneum, involving supradiaphragmatic nodal sites or viscera. The staging may be “clinical”—defined solely by physical examination, blood marker evaluation, and radiographs—or “pathologic”—defined by an operative procedure.


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InternalMed_Harrison. The regional draining lymph nodes for the testis are in the retro-peritoneum, and the vascular supply originates from the great vessels (for the right testis) or the renal vessels (for the left testis). As a result, the lymph nodes that are involved first by a right testicular tumor are the interaortocaval lymph nodes just below the renal vessels. For a left testicular tumor, the first involved lymph nodes are lateral to the aorta (para-aortic) and below the left renal vessels. In both cases, further retroperitoneal nodal spread is inferior, contralateral, and, less commonly, above the renal hilum. Lymphatic involvement can extend cephalad to the retrocrural, posterior mediastinal, and supraclavicular lymph nodes. Treatment is determined by tumor histology (seminoma versus nonseminoma) and clinical stage (Fig. 116-1).


InternalMed_Harrison

InternalMed_Harrison. GCTs are divided into nonseminoma and seminoma subtypes. Nonseminomatous GCTs are most frequent in the third decade of life and can display the full spectrum of embryonic and adult cellular differentiation. This entity comprises four histologies: embryonal carcinoma, teratoma, choriocarcinoma, and endodermal sinus (yolk sac) tumor. Choriocarcinoma, consisting of both cytotrophoblasts and syncytiotrophoblasts, represents malignant trophoblastic differentiation and is invariably associated with secretion of hCG. Endodermal sinus tumor is the malignant counterpart of the fetal yolk sac and is associated with secretion of AFP. Pure embryonal carcinoma may secrete AFP or hCG, or both; this pattern is biochemical evidence of differentiation. Teratoma is composed of somatic cell types derived from two or more germ layers (ectoderm, mesoderm, or endoderm). Each of these histologies may be present alone or in combination with others. Nonseminomatous GCTs tend to metastasize early to sites such


InternalMed_Harrison

InternalMed_Harrison. two or more germ layers (ectoderm, mesoderm, or endoderm). Each of these histologies may be present alone or in combination with others. Nonseminomatous GCTs tend to metastasize early to sites such as the retroperitoneal lymph nodes and lung parenchyma. Sixty percent of patients present with disease limited to the testis (stage I), 20% with retroperitoneal metastases (stage II), and 20% with more extensive supradiaphragmatic nodal or visceral metastases (stage III).


InternalMed_Harrison

InternalMed_Harrison. Seminoma represents approximately 50% of all GCTs, has a median age in the fourth decade, and generally follows a more indolent clinical course. Eighty percent of patients present with stage I disease, approximately 10% with stage II disease, and 10% with stage III disease; lung or other visceral metastases are rare. When a tumor contains both seminoma and nonseminoma components, patient management is directed by the more aggressive nonseminoma component.


InternalMed_Harrison

InternalMed_Harrison. Careful monitoring of the serum tumor markers AFP and hCG is essential in the management of patients with GCT, because these markers are important for diagnosis, as prognostic indicators, in monitoring treatment response, and in the early detection of relapse. Approximately 70% of patients presenting with disseminated nonseminomatous GCT have increased serum concentrations of AFP and/or hCG. Although hCG concentrations may be increased in patients with either nonseminoma or seminoma histology, the AFP concentration is increased only in patients with nonseminoma. The presence of an increased AFP level in a patient whose tumor shows only seminoma indicates that an occult nonseminomatous component exists, and the patient should be treated for nonseminomatous GCT. LDH levels are less specific than AFP or hCG but are increased in 50–60% patients with metastatic nonseminoma and in up to 80% of patients with advanced seminoma.


InternalMed_Harrison

InternalMed_Harrison. AFP, hCG, and LDH levels should be determined before and after orchiectomy. Increased serum AFP and hCG concentrations decay according to first-order kinetics; the half-life is 24–36 h for hCG and 5–7 days for AFP. AFP and hCG should be assayed serially during and after treatment. The reappearance of hCG and/or AFP or the failure of these markers to decline according to the predicted half-life is an indicator of persistent or recurrent tumor. Stage Extent of Disease Stage Extent of Disease Testis only,


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InternalMed_Harrison. Stage Extent of Disease Stage Extent of Disease Testis only, IIA IIC IB IIB Observation Chemotherapy or RT Observation Chemotherapy or RT Observation Retroperitoneal Nodes 2-5 cm RT or Chemotherapy RTRetroperitoneal Nodes < 2 cm RPLND +/– adjuvant Chemotherapy or Chemotherapy, often followed by RPLND Retroperitoneal Nodes > 5 cm Chemotherapy Chemotherapy, often followed by RPLND Testis only, with vascular/lymphatic invasion (T2), or extension through tunica albuginea (T2), or involvement of spermatic cord (T3) or scrotum (T4) RPLND or Chemotherapy Treatment Option Distant Metastases Nonseminoma Seminoma Chemotherapy, often followed by RPLND FIGURE 116-1 Germ cell tumor staging and treatment. RPLND, retroperitoneal lymph node dissection; RT, radiotherapy.


InternalMed_Harrison

InternalMed_Harrison. Patients with radiographs and physical examination showing no evidence of disease and serum AFP and hCG concentrations that are either normal or declining to normal according to the known half-life have clinical stage I disease. Approximately 20–50% of such patients will have retroperitoneal lymph node metastases (pathologic stage II) but will still be cured in over 95% of cases. Depending on risk of relapse, which is determined by the pathology (see below), surveillance, a nerve-sparing retroperitoneal lymph node dissection (RPLND), or adjuvant chemotherapy (one to two cycles of bleomycin, etoposide, and cisplatin [BEP]) may be appropriate choices depending on the availability of surgical expertise and patient and physician preference. If the primary tumor shows no evidence for lymphatic or vascular invasion and is limited to the testis (T1, clinical stage IA), then the risk of relapse is only 10–20%. Because over 80% of patients with clinical stage IA nonseminoma are cured with


InternalMed_Harrison

InternalMed_Harrison. or vascular invasion and is limited to the testis (T1, clinical stage IA), then the risk of relapse is only 10–20%. Because over 80% of patients with clinical stage IA nonseminoma are cured with orchiectomy alone and there is no survival advantage to RPLND (or adjuvant chemotherapy), surveillance is the preferred treatment option. This avoids overtreatment with the potential for both acute and long-term toxicities (see below). Surveillance requires patients to be carefully followed with periodic chest radiography, physical examination, CT scan of the abdomen, and serum tumor marker determinations. The median time to relapse is approximately 7 months, and late relapses (>2 years) are rare. Noncompliant patients can be considered for RPLND or adjuvant BEP.


InternalMed_Harrison

InternalMed_Harrison. If lymphatic or vascular invasion is present or the tumor extends through the tunica, spermatic cord, or scrotum (T2 through T4, clinical stage IB), then the risk of relapse is approximately 50%, and RPLND and adjuvant chemotherapy can be considered. Relapse rates are reduced to 3–5% after one to two cycles of adjuvant BEP. All three approaches (surveillance, RPLND, and adjuvant BEP) should cure >95% of patients with clinical stage IB disease.


InternalMed_Harrison

InternalMed_Harrison. RPLND is the standard operation for removal of the regional lymph nodes of the testis (retroperitoneal nodes). The operation removes the lymph nodes draining the primary site and the nodal groups adjacent to the primary landing zone. The standard (modified bilateral) RPLND removes all node-bearing tissue down to the bifurcation of the great vessels, including the ipsilateral iliac nodes. The major long-term effect of this operation is retrograde ejaculation with resultant infertility. Nerve-sparing RPLND can preserve anterograde ejaculation in ~90% of patients. Patients with pathologic stage I disease are observed, and only the <10% who relapse require additional therapy. If nodes are found to be involved at RPLND, then a decision regarding adjuvant chemotherapy is made on the basis of the extent of retroperitoneal disease (see “Stage II Nonseminoma” below). Hence, because less than 20% of patients require chemotherapy, of the three approaches, RPLND results in the lowest number of


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InternalMed_Harrison. the extent of retroperitoneal disease (see “Stage II Nonseminoma” below). Hence, because less than 20% of patients require chemotherapy, of the three approaches, RPLND results in the lowest number of patients at risk for the late toxicities of chemotherapy.


InternalMed_Harrison

InternalMed_Harrison. Patients with limited, ipsilateral retroperitoneal adenopathy ≤2 cm in largest diameter and normal levels of AFP and hCG can be treated with either a modified bilateral nerve-sparing RPLND or chemotherapy. The local recurrence rate after a properly performed RPLND is very low. Depending on the extent of disease, the postoperative management options include either surveillance or two cycles of adjuvant chemotherapy. Surveillance is the preferred approach for patients with resected “low-volume” metastases (tumor nodes ≤2 cm in diameter and <6 nodes involved) because the probability of relapse is one-third or less. For those who relapse, risk-directed chemotherapy is indicated (see section on advanced GCT below). Because relapse occurs in ≥50% of patients with “highvolume” metastases (>6 nodes involved, or any involved node >2 cm in largest diameter, or extranodal tumor extension), two cycles of adjuvant chemotherapy should be considered, as it results in a cure in ≥98% of patients.


InternalMed_Harrison

InternalMed_Harrison. nodes involved, or any involved node >2 cm in largest diameter, or extranodal tumor extension), two cycles of adjuvant chemotherapy should be considered, as it results in a cure in ≥98% of patients. Regimens consisting of etoposide plus cisplatin (EP) with or without bleomycin every 3 weeks are effective and well tolerated.


InternalMed_Harrison

InternalMed_Harrison. Increased levels of either AFP or hCG imply metastatic disease outside the retroperitoneum; full-dose (not adjuvant) chemotherapy is used in this setting. Primary management with chemotherapy is also favored for patients with larger (>2 cm) or bilateral retroperitoneal nodes (see section on advanced GCT below).


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InternalMed_Harrison. Inguinal orchiectomy followed by immediate retroperitoneal radiation therapy or surveillance with treatment at relapse both result in cure in nearly 100% of patients with stage I seminoma. Historically, radiation was the mainstay of treatment, but the reported association between radiation and secondary malignancies and the absence of a survival advantage of radiation over surveillance has led many to favor surveillance for compliant patients. Approximately 15% of patients relapse, which is usually treated with chemotherapy. Longterm follow-up is essential, because approximately 30% of relapses occur after 2 years and 5% occur after 5 years. A single dose of carboplatin has also been investigated as an alternative to radiation therapy; the outcome was similar, but long-term safety data are lacking, and the retroperitoneum remained the most frequent site of relapse.


InternalMed_Harrison

InternalMed_Harrison. Generally, nonbulky retroperitoneal disease (stage IIA and small IIB) is treated with retroperitoneal radiation therapy. Approximately 90% of patients achieve relapse-free survival with retroperitoneal masses <3 cm in diameter. Due to higher relapse rates after radiation for bulkier disease, initial chemotherapy is preferred for all stage IIC and some stage IIB patients. Chemotherapy has been studied as an alternative to radiation for stage IIA and small stage IIB seminoma with lower recurrence rates compared with historical controls. These results, combined with studies demonstrating a threefold increase in the incidence of secondary malignancies and cardiovascular disease among patients who receive both radiation and chemotherapy (patients relapsing after radiation fall into this category), have led some experts to prefer chemotherapy for all stage II seminomas.


InternalMed_Harrison

InternalMed_Harrison. Regardless of histology, all patients with stage IIC and stage III and most with stage IIB GCT are treated with chemotherapy. Combination chemotherapy programs based on cisplatin at doses of 100 mg/m2 plus etoposide at doses of 500 mg/m2 per cycle cure 70–80% of such patients, with or without bleomycin, depending on risk stratification (see below). A complete response (the complete disappearance of all clinical evidence of tumor on physical examination and radiography plus normal serum levels of AFP and hCG for ≥1 month) occurs after chemotherapy alone in ~60% of patients, and another 10–20% become disease free with surgical resection of residual masses containing viable GCT. Lower doses of cisplatin result in inferior survival rates.


InternalMed_Harrison

InternalMed_Harrison. The toxicity of four cycles of the BEP is substantial. Nausea, vomiting, and hair loss occur in most patients, although nausea and vomiting have been markedly ameliorated by modern antiemetic regimens. Myelosuppression is frequent, and symptomatic bleomycin pulmonary toxicity occurs in ~5% of patients. Treatment-induced mortality due to neutropenia with septicemia or bleomycin-induced pulmonary failure occurs in 1–3% of patients. Dose reductions for myelosuppression are rarely indicated. Long-term permanent toxicities include nephrotoxicity (reduced glomerular filtration and persistent magnesium wasting), ototoxicity, peripheral neuropathy, and infertility. When bleomycin is administered by weekly bolus injection, Raynaud’s phenomenon appears in 5–10% of patients. Other evidence of small blood vessel damage, such as transient ischemic attacks and myocardial infarction, is seen less often.


InternalMed_Harrison

InternalMed_Harrison. Because not all patients are cured and treatment may cause significant toxicities, patients are stratified into “good-risk,” “intermediaterisk,” and “poor-risk” groups according to pretreatment clinical features established by the International Germ Cell Cancer Consensus Group (Table 116-1). For good-risk patients, the goal is to achieve necessary. If viable tumor is present but is completely excised, two 591 additional cycles of chemotherapy are given. If the initial histology is pure seminoma, mature teratoma is Abbreviations: AFP, α fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase. Source: From International Germ Cell Cancer Consensus Group. maximum efficacy with minimal toxicity. For intermediateand poor-risk patients, the goal is to identify more effective therapy with tolerable toxicity.


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InternalMed_Harrison. maximum efficacy with minimal toxicity. For intermediateand poor-risk patients, the goal is to identify more effective therapy with tolerable toxicity. The marker cut offs are included in the TNM (primary tumor, regional nodes, metastasis) staging of GCT. Hence, TNM stage groupings are based on both anatomy (site and extent of disease) and biology (marker status and histology). Seminoma is either goodor intermediate-risk, based on the absence or presence of nonpulmonary visceral metastases. No poor-risk category exists for seminoma. Marker levels and primary site play no role in defining risk for seminoma. Nonseminomas have good-, intermediate-, and poor-risk categories based on the primary site of the tumor, the presence or absence of nonpulmonary visceral metastases, and marker levels.


InternalMed_Harrison

InternalMed_Harrison. For ~90% of patients with good-risk GCTs, four cycles of EP or three cycles of BEP produce durable complete responses, with minimal acute and chronic toxicity, and a low relapse rate. Pulmonary toxicity is absent when bleomycin is not used and is rare when therapy is limited to 9 weeks; myelosuppression with neutropenic fever is less frequent; and the treatment mortality rate is negligible. Approximately 75% of intermediate-risk patients and 50% of poor-risk patients achieve durable complete remission with four cycles of BEP, and no regimen has proved superior.


InternalMed_Harrison

InternalMed_Harrison. POSTCHEMOTHERAPY SURGERY Resection of residual metastases after the completion of chemotherapy is an integral part of therapy. If the initial histology is nonseminoma and the marker values have normalized, all sites of residual disease should be resected. In general, residual retroperitoneal disease requires a modified bilateral RPLND. Thoracotomy (unilateral or bilateral) and neck dissection are less frequently required to remove residual mediastinal, pulmonary parenchymal, or cervical nodal disease. Viable tumor (seminoma, embryonal carcinoma, yolk sac tumor, or choriocarcinoma) will be present in 15%, mature teratoma in 40%, and necrotic debris and fibrosis in 45% of resected specimens. The frequency of teratoma or viable disease is highest in residual mediastinal tumors. If necrotic debris or mature teratoma is present, no further chemotherapy is rarely present, and the most frequent finding is necrotic debris. For residual retroperitoneal disease, a complete RPLND is technically


InternalMed_Harrison

InternalMed_Harrison. or mature teratoma is present, no further chemotherapy is rarely present, and the most frequent finding is necrotic debris. For residual retroperitoneal disease, a complete RPLND is technically difficult due to extensive postchemotherapy fibrosis. Observation is recommended when no radiographic abnormality exists on CT scan. Positive findings on a positron emission tomography (PET) scan correlate with viable seminoma in residua and mandate surgical excision or biopsy.


InternalMed_Harrison

InternalMed_Harrison. Of patients with advanced GCT, 20–30% fail to achieve a durable complete response to first-line chemotherapy. A combination of vinblastine, ifosfamide, and cisplatin (VeIP) will cure approximately 25% of patients as a second-line therapy. Patients are more likely to achieve a durable complete response if they had a testicular primary tumor and relapsed from a prior complete remission to first-line cisplatin-containing chemotherapy. Substitution of paclitaxel for vinblastine (TIP) in this setting was associated with durable remission in nearly two-thirds of patients. In contrast, for patients with a primary mediastinal nonseminoma or who did not achieve a complete response with first-line chemotherapy, then VeIP standard-dose salvage therapy is rarely beneficial. Such patients are usually managed with high-dose chemotherapy and/or surgical resection.


InternalMed_Harrison

InternalMed_Harrison. Chemotherapy consisting of dose-intensive, high-dose carboplatin plus high-dose etoposide, with peripheral blood stem cell support, induces a complete response in 25–40% of patients who have progressed after ifosfamide-containing salvage chemotherapy. Approximately one-half of the complete responses will be durable. High-dose therapy is standard of care for this patient population and has been suggested as the treatment of choice for all patients with relapsed or refractory disease. Paclitaxel is active when incorporated into high-dose combination programs. Cure is still possible in some relapsed patients.


InternalMed_Harrison

InternalMed_Harrison. The prognosis and management of patients with extragonadal GCT depends on the tumor histology and site of origin. All patients with a diagnosis of extragonadal GCT should have a testicular ultrasound examination. Nearly all patients with retroperitoneal or mediastinal seminoma achieve a durable complete response to BEP or EP. The clinical features of patients with primary retroperitoneal nonseminoma GCT are similar to those of patients with a primary tumor of testis origin, and careful evaluation will find evidence of a primary testicular GCT in about two-thirds of cases. In contrast, a primary mediastinal nonseminomatous GCT is associated with a poor prognosis; one-third of patients are cured with standard therapy (four cycles of BEP). Patients with newly diagnosed mediastinal nonseminoma are considered to have poor-risk disease and should be considered for clinical trials testing regimens of possibly greater efficacy. In addition, mediastinal nonseminoma is associated with


InternalMed_Harrison

InternalMed_Harrison. are considered to have poor-risk disease and should be considered for clinical trials testing regimens of possibly greater efficacy. In addition, mediastinal nonseminoma is associated with hematologic disorders, including acute myelogenous leukemia, myelodysplastic syndrome, and essential thrombocytosis unrelated to previous chemotherapy. These hematologic disorders are very refractory to treatment. Nonseminoma of any primary site may change into other malignant histologies such as embryonal rhabdomyosarcoma or adenocarcinoma. This is called malignant transformation. i(12p) has been identified in the transformed cell type, indicating GCT clonal origin.


InternalMed_Harrison

InternalMed_Harrison. A group of patients with poorly differentiated tumors of unknown histogenesis, midline in distribution, and not associated with secretion of AFP or hCG has been described; a few (10–20%) are cured by standard cisplatin-containing chemotherapy. An i(12p) is present in ~25% of such tumors (the fraction that are cisplatin-responsive), confirming their origin from primitive germ cells. This finding is also predictive of the response to cisplatin-based chemotherapy and resulting long-term survival. These tumors are heterogeneous; neuroepithelial tumors and lymphoma may also present in this fashion.


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InternalMed_Harrison. 592 FERTILITY Infertility is an important consequence of the treatment of GCTs. Preexisting infertility or impaired fertility is often present. Azoospermia and/or oligospermia are present at diagnosis in at least 50% of patients with testicular GCTs. Ejaculatory dysfunction is associated with RPLND, and germ cell damage may result from cisplatin-containing chemotherapy. Nerve-sparing techniques to preserve the retroperitoneal sympathetic nerves have made retrograde ejaculation less likely in the subgroups of patients who are candidates for this operation. Spermatogenesis does recur in some patients after chemotherapy. However, because of the significant risk of impaired reproductive capacity, semen analysis and cryopreservation of sperm in a sperm bank should be recommended to all patients before treatment.


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InternalMed_Harrison. part 7 gynecologic malignancies Michael V. Seiden OVARIAN CANCER INCIDENCE AND PATHOLOGY Cancer arising in or near the ovary is actually a collection of diverse malignancies. This collection of malignancies, often referred to as 117 “ovary cancer,” is the most lethal gynecologic malignancy in the United States and other countries that routinely screen women for cervical neoplasia. In 2014, it was estimated that there were 21,980 cases of ovarian cancer with 14,270 deaths in the United States. The ovary is a complex and dynamic organ and, between the ages of approximately 11 and 50 years, is responsible for follicle maturation associated with egg maturation, ovulation, and cyclical sex steroid hormone production. These complex and linked biologic functions are coordinated through a variety of cells within the ovary, each of which possesses neoplastic potential. By far the most common and most lethal of the ovarian neoplasms arise from the ovarian epithelium or, alternatively, the


InternalMed_Harrison

InternalMed_Harrison. of cells within the ovary, each of which possesses neoplastic potential. By far the most common and most lethal of the ovarian neoplasms arise from the ovarian epithelium or, alternatively, the neighboring specialized epithelium of the fallopian tube, uterine corpus, or cervix. Epithelial tumors may be benign (50%), malignant (33%), or of borderline malignancy (16%). Age influences risk of malignancy; tumors in younger women are more likely benign. The most common of the ovarian epithelial malignancies are serous tumors (50%); tumors of mucinous (25%), endometrioid (15%), clear cell (5%), and transitional cell histology or Brenner tumor (1%) represent smaller proportions of epithelial ovarian tumors. In contrast, stromal tumors arise from the steroid hormone–producing cells and likewise have different phenotypes and clinical presentations largely dependent on the type and quantity of hormone production. Tumors arising in the germ cell are most similar in biology and behavior to


InternalMed_Harrison

InternalMed_Harrison. have different phenotypes and clinical presentations largely dependent on the type and quantity of hormone production. Tumors arising in the germ cell are most similar in biology and behavior to testicular tumors in males (Chap. 116).


InternalMed_Harrison

InternalMed_Harrison. Tumors may also metastasize to the ovary from breast, colon, appendiceal, gastric, and pancreatic primaries. Bilateral ovarian masses from metastatic mucin-secreting gastrointestinal cancers are termed Krukenberg tumors.


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InternalMed_Harrison. OVARIAN CANCER OF EPITHELIAL ORIGIN Epidemiology and Pathogenesis A female has approximately a 1 in 72 lifetime risk (1.6%) of developing ovarian cancer, with the majority of affected women developing epithelial tumors. Each of the histologic variants of epithelial tumors is distinct with unique molecular features. As a group of malignancies, epithelial tumors of the ovary have a peak incidence in women in their sixties, although age at presentation can range across the extremes of adult life, with cases being reported in women in their twenties to nineties. Each histologic subtype of ovarian cancer likely has its own associated risk factors. Serous cancer, the most common type of epithelial ovarian cancer, is seen with increased frequency in women who are nulliparous or have a history of use of talc agents applied to the perineum; other risk factors include obesity and probably hormone replacement therapy. Protective factors include the use of oral contraceptives, multiparity, and


InternalMed_Harrison

InternalMed_Harrison. of use of talc agents applied to the perineum; other risk factors include obesity and probably hormone replacement therapy. Protective factors include the use of oral contraceptives, multiparity, and breast-feeding. These protective factors are thought to work through suppression of ovulation and perhaps the associated reduction of ovulation associated inflammation of the ovarian epithelium or, alternatively, the serous epithelium located within the fimbriae of the fallopian tube. Other protective factors, such as fallopian tube ligation, are thought to protect the ovarian epithelium (or perhaps the distal fallopian tube fimbriae) from carcinogens that migrate from the vagina to the tubes and ovarian surface epithelium. Mucinous tumors are more frequent in women with a history of cigarette smoking, whereas endometrioid and clear cell tumors are more frequent in women with a history of endometriosis.


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InternalMed_Harrison. Considerable evidence now suggests that the precursor cell to serous carcinoma of the ovary might actually arise in the fimbria of the fallopian tube with extension or metastasis to the ovarian surface or capture of preneoplastic or neoplastic exfoliating tubal cells into an involuting ovarian follicle around the time of ovulation. Careful histologic and molecular analysis of tubal epithelium demonstrates molecular and histologic abnormalities, termed serous tubular intraepithelial carcinoma (STIC) lesions, in a high proportion of women undergoing risk-reducing salpingo-oophorectomies in the context of high-risk germline mutations in BRCA1 and BRCA2, as well as a modest proportion of women with ovarian cancer in the absence of such mutations. Genetic Risk Factors A variety of genetic syndromes substan tially increase a woman’s risk of developing ovarian cancer.


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InternalMed_Harrison. Approximately 10% of women with ovarian cancer have a germline mutation in one of two DNA repair genes: BRCA1 (chromosome 17q12-21) or BRCA2 (chromosome 13q12-13). Individuals inheriting a single copy of a mutant allele have a very high incidence of breast and ovarian cancer. Most of these women have a family history that is notable for multiple cases of breast and/or ovarian cancer, although inheritance through male members of the family can camouflage this genotype through several generations. The most common malignancy in these women is breast carcinoma, although women harboring germline BRCA1 mutations have a marked increased risk of developing ovarian malignancies in their forties and fifties with a 30–50% lifetime risk of developing ovarian cancer. Women harboring a mutation in BRCA2 have a lower penetrance of ovarian cancer with perhaps a 20–40% chance of developing this malignancy, with onset typically in their fifties or sixties. Women with a BRCA2 mutation also are at


InternalMed_Harrison

InternalMed_Harrison. BRCA2 have a lower penetrance of ovarian cancer with perhaps a 20–40% chance of developing this malignancy, with onset typically in their fifties or sixties. Women with a BRCA2 mutation also are at slightly increased risk of pancreatic cancer. Likewise women with mutations in the DNA mismatch repair genes associated with Lynch syndrome, type 2 (MSH2, MLH1, MLH6, PMS1, PMS2) may have a risk of ovarian cancer as high as 1% per year in their forties and fifties. Finally, a small group of women with familial ovarian cancer may have mutations in other BRCA-associated genes such as RAD51, CHK2, and others. Screening studies in this select population suggest that current screening techniques, including serial evaluation of the CA-125 tumor marker and ultrasound, are insufficient at detecting early-stage and curable disease, so women with these germline mutations are advised to undergo prophylactic removal of ovaries and fallopian tubes typically after completing childbearing and ideally


InternalMed_Harrison

InternalMed_Harrison. early-stage and curable disease, so women with these germline mutations are advised to undergo prophylactic removal of ovaries and fallopian tubes typically after completing childbearing and ideally before age 35–40 years. Early prophylactic oophorectomy also protects these women from subsequent breast cancer with a reduction of breast cancer risk of approximately 50%.


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InternalMed_Harrison. Presentation Neoplasms of the ovary tend to be painless unless they undergo torsion. Symptoms are therefore typically related to compression of local organs or due to symptoms from metastatic disease. Women with tumors localized to the ovary do have an increased incidence of symptoms including pelvic discomfort, bloating, and perhaps changes in a woman’s typical urinary or bowel pattern. Unfortunately, these symptoms are frequently dismissed by either the woman or her health care team. It is believed that high-grade tumors metastasize early in the neoplastic process. Unlike other epithelial malignancies, these tumors tend to exfoliate throughout the peritoneal cavity and thus present with symptoms associated with disseminated intraperitoneal tumors. The most common symptoms at presentation include a multimonth period of progressive complaints that typically include some combination of heartburn, nausea, early satiety, indigestion, constipation, and abdominal pain. Signs include the


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InternalMed_Harrison. include a multimonth period of progressive complaints that typically include some combination of heartburn, nausea, early satiety, indigestion, constipation, and abdominal pain. Signs include the rapid increase in abdominal girth due to the accumulation of ascites that typically alerts the patient and her physician that the concurrent gastrointestinal symptoms are likely associated with serious pathology. Radiologic evaluation typically demonstrates a complex adnexal mass and ascites. Laboratory evaluation usually demonstrates a markedly elevated CA-125, a shed mucin (Muc 16) associated with, but not specific for, ovarian cancer. Hematogenous and lymphatic spread are seen but are not the typical presentation. Ovarian cancers are divided into four stages, with stage I tumors confined to the ovary, stage II malignancies confined to the pelvis, and stage III tumors confined to the peritoneal cavity (Table 117-1). These three stages are subdivided, with the most common presentation, stage


InternalMed_Harrison

InternalMed_Harrison. ovary, stage II malignancies confined to the pelvis, and stage III tumors confined to the peritoneal cavity (Table 117-1). These three stages are subdivided, with the most common presentation, stage IIIC, defined as tumors with bulky intraperitoneal disease. About 60% of women present with stage IIIC disease. Stage IV disease includes women with parenchymal metastases (liver, lung, spleen) or, alternatively, abdominal wall or pleural disease. The 40% not presenting with stage IIIC disease are roughly evenly distributed among the other stages, although mucinous and clear cell tumors are overrepresented in stage I tumors.


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InternalMed_Harrison. Screening Ovarian cancer is the fifth most lethal malignancy in women in the United States. It is curable in early stages, but seldom curable in advanced stages; hence, the development of effective screening strategies is of considerable interest. Furthermore, the ovary is well visualized with a variety of imaging techniques, most notably trans-vaginal ultrasound. Early-stage tumors often produce proteins that can be measured in the blood such as CA-125 and HE-4. Nevertheless, the incidence of ovarian cancer in the middle-aged female population is low, with only approximately 1 in 2000 women between the ages of 50 and 60 carrying an asymptomatic and undetected tumor. Thus effective screening techniques must be sensitive but, more importantly, highly specific to minimize the number of false-positive results. Even a screening test with 98% specificity and 50% sensitivity would have a positive predictive value of only about 1%. A large randomized study of active screening versus usual


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InternalMed_Harrison. results. Even a screening test with 98% specificity and 50% sensitivity would have a positive predictive value of only about 1%. A large randomized study of active screening versus usual standard care demonstrated that a screening program consisting of six annual CA-125 measurements and four annual transvaginal ultrasounds in a population of women age 55–74 was not effective at reducing death from ovarian cancer and was associated with significant morbidity in the screened arm due to complications associated with diagnostic testing in the screened group. Although ongoing studies are evaluating the utility of alternative screening strategies, currently screening of normal-risk women is not recommended outside of a clinical trial.


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InternalMed_Harrison. In women presenting with a localized ovarian mass, the principal diagnostic and therapeutic maneuver is to determine if the tumor is benign or malignant and, in the event that the tumor is malignant, whether the tumor arises in the ovary or is a site of metastatic disease. Metastatic disease to the ovary can be seen from primary tumors of the colon, appendix, stomach (Krukenberg tumors), and breast. Typically women undergo a unilateral salpingo-oophorectomy, and if pathology reveals a primary ovarian malignancy, then the procedure is followed by a hysterectomy, removal of the remaining tube and ovary, omentectomy, and pelvic node sampling along with some random biopsies of the peritoneal cavity. This extensive surgical procedure is performed because approximately 30% of tumors that by visual inspection appear to be confined to the ovary have already disseminated to the peritoneal cavity and/or surrounding lymph nodes.


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InternalMed_Harrison. If there is evidence of bulky intraabdominal disease, a comprehensive attempt at maximal tumor cytoreduction is attempted even if it involves partial bowel resection, splenectomy, and in certain cases more extensive upper abdominal surgery. The ability to debulk metastatic ovarian cancer to minimal visible disease is associated with an improved prognosis compared with women left with visible disease. Patients without gross residual disease after resection have a median survival of 39 months, compared with 17 months for those left with macroscopic tumor. Once tumors have been surgically debulked, women receive therapy with a platinum agent, typically a taxane. Debate continues as to whether this therapy should be delivered intravenously or, alternatively, whether some of the therapy should be delivered directly into the peritoneal cavity via a catheter. Three randomized studies have demonstrated improved survival with intraperitoneal therapy, but this approach is still not widely


InternalMed_Harrison

InternalMed_Harrison. be delivered directly into the peritoneal cavity via a catheter. Three randomized studies have demonstrated improved survival with intraperitoneal therapy, but this approach is still not widely accepted due to technical challenges associated with this delivery route and increased toxicity. In women who present with bulky intraabdominal disease, an alternative approach is to treat with platinum plus a taxane for several cycles before attempting a surgical debulking procedure (neoadjuvant therapy). Subsequent surgical procedures are more effective at leaving the patient without gross residual tumor and appear to be less morbid. Two studies have demonstrated that the neoadjuvant approach is associated with an overall survival that is comparable to the traditional approach of primary surgery followed by chemotherapy.


InternalMed_Harrison

InternalMed_Harrison. With optimal debulking surgery and platinum-based chemotherapy (usually carboplatin dosed to an area under the curve [AUC] of 6 plus paclitaxel 175 mg/m2 by 3-h infusion in 21-day cycles), 70% of women who present with advanced-stage tumors respond, and 40–50% experience a complete remission with normalization of their CA-125, computed tomography (CT) scans, and physical examination. Unfortunately, a small proportion of women who obtain a complete response to therapy will remain in remission. Disease recurs within 1–4 years from the completion of their primary therapy in 75% of the complete responders. CA-125 levels often increase as a first sign of relapse; however, data are not clear that early intervention in relapsing patients influences survival. Recurrent disease is effectively managed, but not cured, with a variety of chemotherapeutic agents. Eventually all women with recurrent disease develop chemotherapy-refractory disease at which point refractory ascites, poor bowel


InternalMed_Harrison

InternalMed_Harrison. managed, but not cured, with a variety of chemotherapeutic agents. Eventually all women with recurrent disease develop chemotherapy-refractory disease at which point refractory ascites, poor bowel motility, and obstruction or pseudoobstruction due to a 594 tumor-infiltrated aperistaltic bowel are common. Limited surgery to relieve intestinal obstruction, localized radiation therapy to relieve pressure or pain from masses, or palliative chemotherapy may be helpful. Agents with >15% response rates include gemcitabine, topotecan, liposomal doxorubicin, pemetrexed, and bevacizumab. Approximately 10% of ovarian cancers are HER2/neu positive, and trastuzumab may induce responses in this subset. Five-year survival correlates with the stage of disease: stage I, 85–90%; stage II, 70–80%; stage III, 20–50%; and stage IV, 1–5% (Table 117-1). Low-grade serous tumors are molecularly distinct from high-grade serous tumors and are, in general, poorly responsive to chemotherapy. Targeted therapies


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InternalMed_Harrison. 20–50%; and stage IV, 1–5% (Table 117-1). Low-grade serous tumors are molecularly distinct from high-grade serous tumors and are, in general, poorly responsive to chemotherapy. Targeted therapies focused on inhibiting kinases downstream of RAS and BRAF are being tested. Patients with tumors of low malignant potential are managed by surgery; chemotherapy and radiation therapy do not improve survival.


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InternalMed_Harrison. OVARIAN SEX CORD AND STROMAL TUMORS Epidemiology, Presentation, and Predisposing Syndromes Approximately 7% of ovarian neoplasms are stromal or sex cord tumors, with approximately 1800 cases expected each year in the United States. Ovarian stromal tumors or sex cord tumors are most common in women in their fifties or sixties, but tumors can present in the extremes of age, including the pediatric population. These tumors arise from the mesenchymal components of the ovary, including steroid-producing cells as well as fibroblasts. Essentially all of these tumors are of low malignant potential and present as unilateral solid masses. Three clinical presentations are common: the detection of an abdominal mass; abdominal pain due to ovarian torsion, intratumoral hemorrhage, or rupture; or signs and symptoms due to hormonal production by these tumors.


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InternalMed_Harrison. The most common hormone-producing tumors include thecomas, granulosa cell tumor, or juvenile granulosa tumors in children. These estrogen-producing tumors often present with breast tenderness as well as isosexual precocious pseudopuberty in children, menometrorrhagia, oligomenorrhea, or amenorrhea in premenopausal women, or alternatively as postmenopausal bleeding in older women. In some women, estrogen-associated secondary malignancies, such as endometrial or breast cancer, may present as synchronous malignancies. Alternatively, endometrial cancer may serve as the presenting malignancy with evaluation subsequently identifying a unilateral solid ovarian neoplasm that proves to be an occult granulosa cell tumor. Sertoli-Leydig tumors often present with hirsutism, virilization, and occasionally Cushing’s syndrome due to increased production of testosterone, androstenedione, or other 17-ketosteroids. Hormonally inert tumors include fibroma that presents as a solitary mass often in


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InternalMed_Harrison. Cushing’s syndrome due to increased production of testosterone, androstenedione, or other 17-ketosteroids. Hormonally inert tumors include fibroma that presents as a solitary mass often in association with ascites and occasionally hydrothorax also known as Meigs’ syndrome. A subset of these tumors present in individuals with a variety of inherited disorders that predispose them to mesenchymal neoplasia. Associations include juvenile granulosa cell tumors and perhaps Sertoli-Leydig tumors with Ollier’s disease (multiple enchondromatosis) or Maffucci’s syndrome, ovarian sex cord tumors with annular tubules with Peutz-Jeghers syndrome, and fibromas with Gorlin’s disease. Essentially all granulosa tumors and a minority of juvenile granulosa cell tumors and thecomas have a defined somatic point mutation in the FOXL2 gene at C134W generated by replacement of cysteine with a guanine at position 402. About 30% of Sertoli-Leydig tumors harbor a mutation in the RNA-processing gene DICER in the


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InternalMed_Harrison. mutation in the FOXL2 gene at C134W generated by replacement of cysteine with a guanine at position 402. About 30% of Sertoli-Leydig tumors harbor a mutation in the RNA-processing gene DICER in the RNAIIIb domain.


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InternalMed_Harrison. The mainstay of treatment for sex cord tumors is surgical resection. Most women present with tumors confined to the ovary. For the small subset of women who present with metastatic disease or develop evidence of tumor recurrence after primary resection, survival is still typically long, often in excess of a decade. Because these tumors are slow growing and relatively refractory to chemotherapy, women with metastatic disease are often debulked because disease is usually peritoneal-based (as with epithelial ovarian cancer). Definitive data that surgical debulking of metastatic or recurrent disease prolongs survival are lacking, but ample data document women who have survived years or, in some cases, decades after resection of recurrent disease. In addition, large peritoneal-based metastases also have a proclivity for hemorrhage, sometimes with catastrophic complications. Chemotherapy is occasionally effective, and women tend to receive regimens designed to treat epithelial or germ cell


InternalMed_Harrison

InternalMed_Harrison. also have a proclivity for hemorrhage, sometimes with catastrophic complications. Chemotherapy is occasionally effective, and women tend to receive regimens designed to treat epithelial or germ cell tumors. Bevacizumab has some activity in clinical trials but is not approved for this specific indication. These tumors often produce high levels of müllerian inhibiting substance (MIS), inhibin, and, in the case of Sertoli-Leydig tumors, α fetoprotein (AFP). These proteins are detectable in serum and can be used as tumor markers to monitor women for recurrent disease because the increase or decrease of these proteins in the serum tends to reflect the changing bulk of systemic tumor.


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InternalMed_Harrison. Germ cell tumors, like their counterparts in the testis, are cancers of germ cells. These totipotent cells contain the programming for differentiation to essentially all tissue types, and hence the germ cell tumors include a histologic menagerie of bizarre tumors, including benign teratomas and a variety of malignant tumors, such as immature teratomas, dysgerminomas, yolk sac malignancies, and choriocarcinomas. Benign teratoma (or dermoid cyst) is the most common germ cell neoplasm of the ovary and often presents in young woman. These tumors include a complex mixture of differentiated tissue including tissues from all three germ layers. In older women, these differentiated tumors can develop malignant transformation, most commonly squamous cell carcinomas. Malignant germ cell tumors include dysgerminomas, yolk sac tumors, immature teratomas, and embryonal carcinoma and choriocarcinomas. There are no known genetic abnormalities that unify these tumors. A subset of dysgerminomas harbor


InternalMed_Harrison

InternalMed_Harrison. dysgerminomas, yolk sac tumors, immature teratomas, and embryonal carcinoma and choriocarcinomas. There are no known genetic abnormalities that unify these tumors. A subset of dysgerminomas harbor mutations in c-Kit oncogenes (as seen in gastrointestinal stromal tumors [GIST]), whereas a subset of germ cell tumors have isochromosome 12 abnormalities, as seen in testicular malignancies. In addition, a subset of dysgerminomas is associated with dysgenetic ovaries. Identification of a dysgerminoma arising in genotypic XY gonads is important in that it highlights the need to identify and remove the contralateral gonad due to risk of gonadoblastoma.


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InternalMed_Harrison. Presentation Germ cell tumors can present at all ages, but the peak age of presentation tends to be in females in their late teens or early twenties. Typically these tumors will become large ovarian masses, which eventually present as palpable low abdominal or pelvic masses. Like sex cord tumors, torsion or hemorrhage may present urgently or emergently as acute abdominal pain. Some of these tumors produce elevated levels of human chorionic gonadotropin (hCG), which can lead to isosexual precocious puberty when tumors present in younger girls. Unlike epithelial ovarian cancer, these tumors have a higher proclivity for nodal or hematogenous metastases. As with testicular tumors, some of these tumors tend to produce AFP (yolk sac tumors) or hCG (embryonal carcinoma, choriocarcinomas, and some dysgerminomas) that are reliable tumor markers.


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InternalMed_Harrison. Germ cell tumors typically present in women who are still of childbearing age, and because bilateral tumors are uncommon (except in dysgerminoma, 10–15%), the typical treatment is unilateral oophorectomy or salpingo-oophorectomy. Because nodal metastases to pelvic and para-aortic nodes are common and may affect treatment choices, these nodes should be carefully inspected and, if enlarged, should be resected if possible. Women with malignant germ cell tumors typically receive bleomycin, etoposide, and cisplatin (BEP) chemotherapy. In the majority of women, even those with advanced-stage disease, cure is expected. Close follow-up without adjuvant therapy of women with stage I tumors is reasonable if there is high confidence that the patient and health care team are committed to compulsive and careful follow-up, as chemotherapy at the time of tumor recurrence is likely to be curative.


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InternalMed_Harrison. Dysgerminoma is the ovarian counterpart of testicular seminoma. The 5-year disease-free survival is 100% in early-stage patients and 61% in stage III disease. Although the tumor is highly radiation-sensitive, radiation produces infertility in many patients. BEP chemotherapy is as effective or more so without causing infertility. The use of BEP following incomplete resection is associated with a 2-year disease-free survival rate of 95%. This chemotherapy is now the treatment of choice for dysgerminoma.


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InternalMed_Harrison. Transport of the egg to the uterus occurs via transit through the fallopian tube, with the distal ends of these tubes composed of fimbriae that drape about the ovarian surface and capture the egg as it erupts from the ovarian cortex. Fallopian tube malignancies are typically serous tumors. Previous teaching was that these malignancies were rare, but more careful histologic examination suggests that many “ovarian malignancies” might actually arise in the distal fimbria of the fallopian tube (see above). These women often present with adnexal masses, and like ovarian cancer, these tumors spread relatively early throughout the peritoneal cavity and respond to platinum and taxane therapy and have a natural history that is essentially identical to ovarian cancer (Table 117-1).


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InternalMed_Harrison. Cervical cancer is the second most common and most lethal malignancy in women worldwide likely due to the widespread infection with high-risk strains of human papillomavirus (HPV) and limited utilization of or access to Pap smear screening in many nations throughout the world. Nearly 500,000 cases of cervical cancer are expected worldwide, with approximately 240,000 deaths annually. Cancer incidence is particularly high in women residing in Central and South America, the Caribbean, and southern and eastern Africa. Mortality rate is disproportionately high in Africa. In the United States, 12,360 women were diagnosed with cervical cancer and 4020 women died in 2014. Developed countries have looked at high-technology screening techniques for HPV involving automated polymerase chain reaction in thin preps that identify dysplastic cytology as well as high-risk HPV genetic material. Visual inspection of the cervix coated with acetic acid has demonstrated the ability to reduce mortality from


InternalMed_Harrison

InternalMed_Harrison. thin preps that identify dysplastic cytology as well as high-risk HPV genetic material. Visual inspection of the cervix coated with acetic acid has demonstrated the ability to reduce mortality from cervical cancer with potential broad applicability in low-resource environments. The development of effective vaccines for high-risk HPV types makes it imperative to determine economical, socially acceptable, and logistically feasible strategies to deliver and distribute this vaccine to girls and boys before their engagement in sexual activity.


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InternalMed_Harrison. HPV is the primary neoplastic-initiating event in the vast majority of women with invasive cervical cancer. This double-strand DNA virus infects epithelium near the transformation zone of the cervix. More than 60 types of HPV are known, with approximately 20 types having the ability to generate high-grade dysplasia and malignancy. HPV16 and -18 are the types most frequently associated with high-grade dysplasia and targeted by both U.S. Food and Drug Administration– approved vaccines. The large majority of sexually active adults are exposed to HPV, and most women clear the infection without specific intervention. The 8-kilobase HPV genome encodes seven early genes, most notably E6 and E7, which can bind to RB and p53, respectively. High-risk types of HPV encode E6 and E7 molecules that are particularly effective at inhibiting the normal cell cycle checkpoint functions of these regulatory proteins, leading to immortalization but not full transformation of cervical epithelium. A minority


InternalMed_Harrison

InternalMed_Harrison. particularly effective at inhibiting the normal cell cycle checkpoint functions of these regulatory proteins, leading to immortalization but not full transformation of cervical epithelium. A minority of woman will fail 595 to clear the infection with subsequent HPV integration into the host genome. Over the course of as short as months but more typically years, some of these women develop high-grade dysplasia. The time from dysplasia to carcinoma is likely years to more than a decade and almost certainly requires the acquisition of other poorly defined genetic mutations within the infected and immortalized epithelium.


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InternalMed_Harrison. Risk factors for HPV infection and, in particular, dysplasia include a high number of sexual partners, early age of first intercourse, and history of venereal disease. Smoking is a cofactor; heavy smokers have a higher risk of dysplasia with HPV infection. HIV infection, especially when associated with low CD4+ T cell counts, is associated with a higher rate of high-grade dysplasia and likely a shorter latency period between infection and invasive disease. The administration of highly active antiretroviral therapy reduces the risk of high-grade dysplasia associated with HPV infection.


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InternalMed_Harrison. Currently approved vaccines include the recombinant proteins to the late proteins, L1 and L2, of HPV-16 and -18. Vaccination of women before the initiation of sexual activity dramatically reduces the rate of HPV-16 and -18 infection and subsequent dysplasia. There is also partial protection against other HPV types, although vaccinated women are still at risk for HPV infection and still require standard Pap smear screening. Although no randomized trial data demonstrate the utility of Pap smears, the dramatic drop in cervical cancer incidence and death in developed countries employing wide-scale screening provides strong evidence for its effectiveness. In addition, even visual inspection of the cervix with preapplication of acetic acid using a “see and treat” strategy has demonstrated a 30% reduction in cervical cancer death. The incorporation of HPV testing by polymerase chain reaction or other molecular techniques increases the sensitivity of detecting cervical pathology but at the


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InternalMed_Harrison. reduction in cervical cancer death. The incorporation of HPV testing by polymerase chain reaction or other molecular techniques increases the sensitivity of detecting cervical pathology but at the cost of identifying many women with transient infections who require no specific medical intervention.


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InternalMed_Harrison. The majority of cervical malignancies are squamous cell carcinomas associated with HPV. Adenocarcinomas are also HPV-related and arise deep in the endocervical canal; they are typically not seen by visual inspection of the cervix and thus are often missed by Pap smear screening. A variety of rarer malignancies including atypical epithelial tumors, carcinoids, small cell carcinomas, sarcomas, and lymphomas have also been reported.


InternalMed_Harrison

InternalMed_Harrison. The principal role of Pap smear testing is the detection of asymptomatic preinvasive cervical dysplasia of squamous epithelial lining. Invasive carcinomas often have symptoms or signs including post-coital spotting or intermenstrual cycle bleeding or menometrorrhagia. Foul-smelling or persistent yellow discharge may also be seen. Presentations that include pelvic or sacral pain suggest lateral extension of the tumor into pelvic nerve plexus by either the primary tumor or a pelvic node and are signs of advanced-stage disease. Likewise, flank pain from hydronephrosis from ureteral compression or deep venous thrombosis from iliac vessel compression suggests either extensive nodal disease or direct extension of the primary tumor to the pelvic sidewall. The most common finding of physical exam is a visible tumor on the cervix.


InternalMed_Harrison

InternalMed_Harrison. Scans are not part of the formal clinical staging of cervical cancer yet are very useful in planning appropriate therapy. CT can detect hydronephrosis indicative of pelvic sidewall disease but is not accurate at evaluating other pelvic structures. Magnetic resonance imaging (MRI) is more accurate at estimating uterine extension and paracervical extension of disease into soft tissues typically bordered by broad and cardinal ligaments that support the uterus in the central pelvis. Positron emission tomography (PET) scan is the most accurate technique for evaluating the pelvis and more importantly nodal (pelvic, para-aortic, and scalene) sites for disease. Staging of cervix cancer Extent of Carcinoma Confined Disease Disease Invades bladder, tumor in-situ to cervix beyond cervix to pelvic rectum or but not to pelvic wall or metastasis wall or lower lower 1/3 1/3 of vagina vagina


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InternalMed_Harrison. FIGURE 117-1 Anatomic display of the stages of cervix cancer defined by location, extent of tumor, frequency of presentation, and 5-year survival. This technique seems more prognostic and accurate than CT, MRI, or lymphangiogram, especially in the para-aortic region.


InternalMed_Harrison

InternalMed_Harrison. Stage I cervical tumors are confined to the cervix, whereas stage II tumors extend into the upper vagina or paracervical soft tissue (Fig. 117-1). Stage III tumors extend to the lower vagina or the pelvic sidewalls, whereas stage IV tumors invade the bladder or rectum or have spread to distant sites. Very small stage I cervical tumors can be treated with a variety of surgical procedures. In young women desiring to maintain fertility, radical trachelectomy removes the cervix with subsequent anastomosis of the upper vagina to the uterine corpus. Larger cervical tumors confined to the cervix can be treated with either surgical resection or radiation therapy in combination with cisplatin-based chemotherapy with a high chance of cure. Larger tumors that extend regionally down the vagina or into the paracervical soft tissues or the pelvic sidewalls are treated with combination chemotherapy and radiation therapy. The treatment of recurrent or metastatic disease is unsatisfactory due to the


InternalMed_Harrison

InternalMed_Harrison. the paracervical soft tissues or the pelvic sidewalls are treated with combination chemotherapy and radiation therapy. The treatment of recurrent or metastatic disease is unsatisfactory due to the relative resistance of these tumors to chemotherapy and currently available biological agents, although bevacizumab, a monoclonal antibody that is said to inhibit tumor-associated angiogenesis, has demonstrated clinically meaningful activity in the management of metastatic disease.


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InternalMed_Harrison. Several different tumor types arise in uterine corpus. Most tumors arise in the glandular lining and are endometrial adenocarcinomas. Tumors can also arise in the smooth muscle; most are benign (uterine leiomyoma), with a small minority of tumors being sarcomas. The endometrioid histologic subtype of endometrial cancer is the most common gynecologic malignancy in the United States. In 2014, an estimated 52,630 women were diagnosed with cancer of the uterine corpus, with 8590 deaths from the disease. Development of these tumors is a multistep process, with estrogen playing an important early role in driving endometrial gland proliferation. Relative overexposure to this class of hormones is a risk factor for the subsequent development of endometrioid tumors. In contrast, progestins drive glandular maturation and are protective. Hence, women with high endogenous or pharmacologic exposure to estrogens, especially if unopposed by progesterone, are at high risk for endometrial cancer.


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InternalMed_Harrison. Obese women, women treated with unopposed estrogens, or women with estrogen-producing tumors (such as granulosa cell tumors of the ovary) are at higher risk for endometrial cancer. In addition, treatment with tamoxifen, which has antiestrogenic effects in breast tissue but estrogenic effects in uterine epithelium, is associated with an increased risk of endometrial cancer. Events such as the loss of the PTEN tumor suppressor gene with activation and often additional mutations in the PIK-3CA/AKT pathways likely serve as secondary events in carcinogenesis. The Cancer Genome Atlas Research Network has demonstrated that endometrioid tumors can be divided into four subgroups: ultramutated, microsatellite instability hypermutated, copy number low, and copy number high subgroups. These groups have different natural histories; therapy for these subgroups may eventually be individualized. Serous tumors of the uterine corpus represent approximately 5–10% of epithelial tumors of the uterine


InternalMed_Harrison

InternalMed_Harrison. have different natural histories; therapy for these subgroups may eventually be individualized. Serous tumors of the uterine corpus represent approximately 5–10% of epithelial tumors of the uterine corpus and possess distinct molecular characteristics that are most similar to those seen in serous tumors arising in the ovary or fallopian tube.


InternalMed_Harrison

InternalMed_Harrison. Women with a mutation in one of a series of DNA mismatch repair genes associated with the Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), are at increased risk for endometrioid endometrial carcinoma. These individuals have germline mutations in MSH2, MLH1, and in rare cases PMS1 and PMS2, with resulting microsatellite instability and hypermutation. Individuals who carry these mutations typically have a family history of cancer and are at markedly increased risk for colon cancer and modestly increased risk for ovarian cancer and a variety of other tumors. Middle-aged women with HNPCC carry a 4% annual risk of endometrial cancer and a relative overall risk of approximately 200-fold as compared to age-matched women without HNPCC.


InternalMed_Harrison

InternalMed_Harrison. The majority of women with tumors of the uterine corpus present with postmenopausal vaginal bleeding due to shedding of the malignant endometrial lining. Premenopausal women often will present with atypical bleeding between typical menstrual cycles. These signs typically bring a woman to the attention of a health care professional, and hence the majority of women present with early-stage disease with the tumor confined to the uterine corpus. Diagnosis is typically established by endometrial biopsy. Epithelial tumors may spread to pelvic or para-aortic lymph nodes. Pulmonary metastases can appear later in the natural history of this disease but are very uncommon at initial presentation. Serous tumors tend to have patterns of spread much more reminiscent of ovarian cancer with many patients presenting with disseminated peritoneal disease and sometimes ascites. Some women presenting with uterine sarcomas will present with pelvic pain. Nodal metastases are uncommon with sarcomas, which


InternalMed_Harrison

InternalMed_Harrison. presenting with disseminated peritoneal disease and sometimes ascites. Some women presenting with uterine sarcomas will present with pelvic pain. Nodal metastases are uncommon with sarcomas, which are more likely to present with either intraabdominal disease or pulmonary metastases.


InternalMed_Harrison

InternalMed_Harrison. Most women with endometrial cancer have disease that is localized to the uterus (75% are stage I, Table 117-1), and definitive treatment typically involves a hysterectomy with removal of the ovaries and fallopian tubes. The resection of lymph nodes does not improve outcome but does provide prognostic information. Node involvement defines stage III disease, which is present in 13% of patients. Tumor grade and depth of invasion are the two key prognostic variables in early-stage tumors, and women with low-grade and/ or minimally invasive tumors are typically observed after definitive surgical therapy. Patients with high-grade tumors or tumors that are deeply invasive (stage IB, 13%) are at higher risk for pelvic recurrence or recurrence at the vaginal cuff, which is typically prevented by vaginal vault brachytherapy.


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InternalMed_Harrison. Women with regional metastases or metastatic disease (3% of patients) with low-grade tumors can be treated with progesterone. Poorly differentiated tumors are typically resistant to hormonal manipulation and thus are treated with chemotherapy. The role of chemotherapy in the adjuvant setting is currently under investigation. Chemotherapy for metastatic disease is delivered with palliative intent. Drugs that effectively target and inhibit signaling of the AKT-mTOR pathway are currently under investigation. Five-year survival is 89% for stage I, 73% for stage II, 52% for stage III, and 17% for stage IV disease (Table 117-1).


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InternalMed_Harrison. Five-year survival is 89% for stage I, 73% for stage II, 52% for stage III, and 17% for stage IV disease (Table 117-1). Gestational trophoblastic diseases represent a spectrum of neo plasia from benign hydatidiform mole to choriocarcinoma due to persistent trophoblastic disease associated most commonly with molar pregnancy but occasionally seen after normal gestation. The most common presentations of trophoblastic tumors are partial and complete molar pregnancies. These represent approximately 1 in 1500 conceptions in developed Western countries. The incidence widely varies globally, with areas in Southeast Asia having a much higher incidence of molar pregnancy. Regions with high molar pregnancy rates are often associated with diets low in carotene and animal fats.


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InternalMed_Harrison. Trophoblastic tumors result from the outgrowth or persistence of placental tissue. They arise most commonly in the uterus but can also arise in other sites such as the fallopian tubes due to ectopic pregnancy. Risk factors include poorly defined dietary and environmental factors as well as conceptions at the extremes of reproductive age, with the incidence particularly high in females conceiving younger than age 16 or older than age 50. In older women, the incidence of molar pregnancy might be as high as one in three, likely due to increased risk of abnormal fertilization of the aged ova. Most trophoblastic neoplasms are associated with complete moles, diploid tumors with all genetic material from the paternal donor (known as parental disomy). This is thought to occur when a single sperm fertilizes an enucleate egg that subsequently duplicates the paternal DNA. Trophoblastic proliferation occurs with exuberant villous stroma. If pseudopregnancy extends out past the 12th week, fluid


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InternalMed_Harrison. fertilizes an enucleate egg that subsequently duplicates the paternal DNA. Trophoblastic proliferation occurs with exuberant villous stroma. If pseudopregnancy extends out past the 12th week, fluid progressively accumulates within the stroma, leading to “hydropic changes.” There is no fetal development in complete moles.


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InternalMed_Harrison. Partial moles arise from the fertilization of an egg with two sperm; 597 hence two-thirds of genetic material is paternal in these triploid tumors. Hydropic changes are less dramatic, and fetal development can often occur through late first trimester or early second trimester at which point spontaneous abortion is common. Laboratory findings will include excessively high hCG and high AFP. The risk of persistent gestational trophoblastic disease after partial mole is approximately 5%. Complete and partial moles can be noninvasive or invasive. Myometrial invasion occurs in no more than one in six complete moles and a lower portion of partial moles.


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InternalMed_Harrison. The clinical presentation of molar pregnancy is changing in developed countries due to the early detection of pregnancy with home pregnancy kits and the very early use of Doppler and ultrasound to evaluate the early fetus and uterine cavity for evidence of a viable fetus. Thus, in these countries, the majority of women presenting with trophoblastic disease have their moles detected early and have typical symptoms of early pregnancy including nausea, amenorrhea, and breast tenderness. With uterine evacuation of early complete and partial moles, most women experience spontaneous remission of their disease as monitored by serial hCG levels. These women require no chemotherapy. Patients with persistent elevation of hCG or rising hCG after evacuation have persistent or actively growing gestational trophoblastic disease and require therapy. Most series suggest that between 15 and 25% of women will have evidence of persistent gestational trophoblastic disease after molar evacuation.


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InternalMed_Harrison. In women who lack access to prenatal care, presenting symptoms can be life threatening including the development of preeclampsia or even eclampsia. Hyperthyroidism can also be seen. Evacuation of large moles can be associated with life-threatening complications including uterine perforation, volume loss, high-output cardiac failure, and adult respiratory distress syndrome (ARDS). For women with evidence of rising hCG or radiologic confirmation of metastatic or persistent regional disease, prognosis can be estimated through a variety of scoring algorithms that identify those women at low, intermediate, and high risk for requiring multiagent chemotherapy. In general, women with widely metastatic nonpulmonary disease, very elevated hCG, and prior normal antecedent term pregnancy are considered at high risk and typically require multiagent chemotherapy for cure.


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InternalMed_Harrison. The management for a persistent and rising hCG after evacuation of a molar conception is typically chemotherapy, although surgery can play an important role for disease that is persistently isolated in the uterus (especially if childbearing is complete) or to control hemorrhage. For women wishing to maintain fertility or with metastatic disease, the preferred treatment is chemotherapy. Chemotherapy is guided by the hCG level, which typically drops to undetectable levels with effective therapy. Single-agent treatment with methotrexate or dactinomycin cures 90% of women with low-risk disease. Patients with high-risk disease (high hCG levels, presentation 4 or more months after pregnancy, brain or liver metastases, failure of methotrexate therapy) are typically treated with multiagent chemotherapy (e.g., etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine [EMA-CO]), which is typically curative even in women with extensive metastatic disease.


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InternalMed_Harrison. chemotherapy (e.g., etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine [EMA-CO]), which is typically curative even in women with extensive metastatic disease. Cisplatin, bleomycin, and either etoposide or vinblastine are also active combinations. Survival in high-risk disease exceeds 80%. Cured women may get pregnant again without evidence of increased fetal or maternal complications.


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InternalMed_Harrison. 598 primary and metastatic tumors of the nervous system Lisa M. DeAngelis, Patrick Y. Wen Primary brain tumors are diagnosed in approximately 52,000 people each year in the United States. At least one-half of these tumors are 118 malignant and associated with a high mortality. Glial tumors account for about 30% of all primary brain tumors, and 80% of those are malignant. Meningiomas account for 35%, vestibular schwannomas 10%, and central nervous system (CNS) lymphomas about 2%. Brain metastases are three times more common than all primary brain tumors combined and are diagnosed in approximately 150,000 people each year. Metastases to the leptomeninges and epidural space of the spinal cord each occur in approximately 3–5% of patients with systemic cancer and are also a major cause of neurologic disability. APPROACH TO THE PATIENT: primary and metastatic tumors of the nervous system


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InternalMed_Harrison. Brain tumors of any type can present with a variety of symptoms and signs that fall into two categories: general and focal; patients often have a combination of the two (Table 118-1). General or nonspecific symptoms include headache, with or without nausea or vomiting, cognitive difficulties, personality change, and gait disorder. Generalized symptoms arise when the enlarging tumor and its surrounding edema cause an increase in intracranial pressure or direct compression of cerebrospinal fluid (CSF) circulation leading to hydrocephalus. The classic headache associated with a brain tumor is most evident in the morning and improves during the day, but this particular pattern is actually seen in a minority of patients. Headaches are often holocephalic but can be ipsilateral to the side of a tumor. Occasionally, headaches have features of a typical migraine with unilateral throbbing pain associated with visual scotoma. Personality changes may include apathy and withdrawal from social


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InternalMed_Harrison. a tumor. Occasionally, headaches have features of a typical migraine with unilateral throbbing pain associated with visual scotoma. Personality changes may include apathy and withdrawal from social circumstances, mimicking depression. Focal or lateralizing findings include hemiparesis, aphasia, or visual field defect. Lateralizing symptoms are typically subacute and progressive. A visual field defect is often unnoticed by the patient; its presence may only be revealed after it leads to an injury such as an automobile accident occurring in the blind visual field. Language difficulties may be mistaken for confusion. Seizures are a common presentation of brain tumors, occurring in about 25% of patients with brain metastases or malignant gliomas but can be the presenting symptom in up to 90% of patients with a low-grade glioma. All seizures that arise from a brain tumor will have a focal onset whether or not it is apparent clinically.


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InternalMed_Harrison. Cranial MRI is the preferred diagnostic test for any patient suspected of having a brain tumor and should be performed with gadolinium contrast administration. Computed tomography (CT) scan should be reserved for those patients unable to undergo magnetic resonance imaging (MRI; e.g., pacemaker). Malignant brain tumors—whether primary or metastatic—typically enhance with gadolinium and may have central areas of necrosis; they are characteristically surrounded by edema of the neighboring white matter. Low-grade gliomas usually do not enhance with gadolinium and are best appreciated on fluid-attenuated inversion recovery (FLAIR) MRIs. Meningiomas have a characteristic appearance on MRI because they are duralbased with a dural tail and compress but do not invade the brain. Dural metastases or a dural lymphoma can have a similar appearance. Imaging is characteristic for many primary and metastatic tumors and sometimes will suffice to establish a diagnosis when the location precludes


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InternalMed_Harrison. or a dural lymphoma can have a similar appearance. Imaging is characteristic for many primary and metastatic tumors and sometimes will suffice to establish a diagnosis when the location precludes surgical intervention (e.g., brainstem glioma). Functional MRI is useful in presurgical planning to define eloquent sensory, motor, or language cortex. Positron emission tomography (PET) is useful in determining the metabolic activity of the lesions seen on MRI; MR perfusion and spectroscopy can provide information on blood flow or tissue composition. These techniques may help distinguish tumor progression from necrotic tissue as a consequence of treatment with radiation and chemotherapy or identify foci of high-grade tumor in an otherwise low-grade-appearing glioma.


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InternalMed_Harrison. Neuroimaging is the only test necessary to diagnose a brain tumor. Laboratory tests are rarely useful, although patients with metastatic disease may have elevation of a tumor marker in their serum that reflects the presence of brain metastases (e.g., β human chorionic gonadotropin [β-hCG] from testicular cancer). Additional testing such as cerebral angiogram, electroencephalogram (EEG), or lumbar puncture is rarely indicated or helpful.


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InternalMed_Harrison. Therapy of any intracranial malignancy requires both symptomatic and definitive treatments. Definitive treatment is based on the specific tumor type and includes surgery, radiotherapy, and chemotherapy. However, symptomatic treatments apply to brain tumors of any type. Most high-grade malignancies are accompanied by substantial surrounding edema, which contributes to neurologic disability and raised intracranial pressure. Glucocorticoids are highly effective at reducing perilesional edema and improving neurologic function, often within hours of administration. Dexamethasone has been the glucocorticoid of choice because of its relatively low mineralocorticoid activity. Initial doses are typically 12–16 mg/d in divided doses given orally or IV (both are equivalent). Although glucocorticoids rapidly ameliorate symptoms and signs, their long-term use causes substantial toxicity including insomnia, weight gain, diabetes mellitus, steroid myopathy, and personality changes. Consequently, a


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InternalMed_Harrison. rapidly ameliorate symptoms and signs, their long-term use causes substantial toxicity including insomnia, weight gain, diabetes mellitus, steroid myopathy, and personality changes. Consequently, a taper is indicated as definitive treatment is administered and the patient improves.


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InternalMed_Harrison. Patients with brain tumors who present with seizures require antiepileptic drug therapy. There is no role for prophylactic antiepileptic drugs in patients who have not had a seizure. The agents of choice are those drugs that do not induce the hepatic microsomal enzyme system. These include levetiracetam, topiramate, lamotrigine, valproic acid, and lacosamide (Chap. 445). Other drugs, such as phenytoin and carbamazepine, are used less frequently because they are potent enzyme inducers that can interfere with both glucocorticoid metabolism and the metabolism of chemotherapeutic agents needed to treat the underlying systemic malignancy or the primary brain tumor. Venous thromboembolic disease occurs in 20–30% of patients with high-grade gliomas and brain metastases. Therefore, prophylactic anticoagulants should be used during hospitalization and in nonambulatory patients. Those who have had either a deep vein thrombosis or pulmonary embolus can receive therapeutic doses of


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InternalMed_Harrison. prophylactic anticoagulants should be used during hospitalization and in nonambulatory patients. Those who have had either a deep vein thrombosis or pulmonary embolus can receive therapeutic doses of anticoagulation safely and without increasing the risk for hemorrhage into the tumor. Inferior vena cava filters are reserved for patients with absolute contraindications to anticoagulation such as recent craniotomy.


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InternalMed_Harrison. No underlying cause has been identified for the majority of primary brain tumors. The only established risk factors are exposure to ionizing radiation (meningiomas, gliomas, and schwannomas) and immunosuppression (primary CNS lymphoma). Evidence for an association with exposure to electromagnetic fields including cellular telephones, head injury, foods containing N-nitroso compounds, or occupational risk factors are unproven. A small minority of patients have a family history of brain tumors. Some of these familial cases are associated with genetic syndromes (Table 118-2).


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InternalMed_Harrison. As with other neoplasms, brain tumors arise as a result of a multi-step process driven by the sequential acquisition of genetic alterations. These include loss of tumor-suppressor genes (e.g., p53 and phosphatase and tensin homolog on chromosome 10 [PTEN]) and amplification and overexpression of protooncogenes such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptors (PDGFR). The accumulation of these genetic abnormalities results in uncontrolled cell growth and tumor formation.


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InternalMed_Harrison. Important progress has been made in understanding the molecular pathogenesis of several types of brain tumors, including glioblastoma and medulloblastoma. Morphologically indistinguishable glioblastomas can be separated into four subtypes defined by molecular profiling: (1) classical, characterized by overactivation of the EGFR pathway; (2) proneural, characterized by overexpression of PDGFRA, mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes, and expression 599 of neural markers; (3) mesenchymal, defined by expression of mesenchymal markers and loss of NF1; and (4) neural, characterized by overactivity of EGFR and expression of neural markers. The clinical implications of these subtypes are under study. Medulloblastoma is the other primary brain tumor that has been highly analyzed, and four molecular subtypes have also been identified: (1) the Wnt subtype is defined by a mutation in β-catenin and has an excellent prognosis; (2) the SHH subtype has mutations in PTCH1, SMO,


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InternalMed_Harrison. and four molecular subtypes have also been identified: (1) the Wnt subtype is defined by a mutation in β-catenin and has an excellent prognosis; (2) the SHH subtype has mutations in PTCH1, SMO, GLI2, or SUFU and has an intermediate prognosis; (3) group 3 has elevated MYC expression and has the worst prognosis; and (4) group 4 is characterized by isochromosome 17q. Targeted therapeutics are under development for some of the medulloblastoma subtypes, especially the SHH group.


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InternalMed_Harrison. These are infiltrative tumors with a presumptive glial cell of origin. The World Health Organization (WHO) classifies astrocytomas into four prognostic grades based on histologic features: grade I (pilocytic astrocytoma, subependymal giant cell astrocytoma); grade II (diffuse astrocytoma); grade III (anaplastic astrocytoma); and grade IV (glioblastoma). Grades I and II are considered low-grade astrocytomas, and grades III and IV are considered high-grade astrocytomas. most common tumor of childhood. They occur typically in the cerebellum but may also be found elsewhere in the neuraxis, including the optic nerves and brainstem. Frequently they appear as cystic lesions Primary and Metastatic Tumors of the Nervous System aVarious DNA mismatch repair gene mutations may cause a similar clinical phenotype, also referred to as Turcot syndrome, in which there is a predisposition to nonpolyposis colon cancer and brain tumors.


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InternalMed_Harrison. Abbreviations: AD, autosomal dominant; APC, adenomatous polyposis coli; AR, autosomal recessive; ch, chromosome; PTEN, phosphatase and tensin homologue; TSC, tuberous sclerosis complex. FIGURE 118-1 Fluid-attenuated inversion recovery (FLAIR) MRI of a left frontal low-grade astrocytoma. This lesion did not enhance. FIGURE 118-2 Postgadolinium T1 MRI of a large cystic left frontal glioblastoma. with an enhancing mural nodule. These are well-demarcated lesions that are potentially curable if they can be resected completely. Giant-cell subependymal astrocytomas are usually found in the ventricular wall of patients with tuberous sclerosis. They often do not require intervention but can be treated surgically or with inhibitors of the mammalian target of rapamycin (mTOR).


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InternalMed_Harrison. grade ii astrocytomas These are infiltrative tumors that usually present with seizures in young adults. They appear as nonenhancing tumors with increased T2/FLAIR signal (Fig. 118-1). If feasible, patients should undergo maximal surgical resection, although complete resection is rarely possible because of the invasive nature of the tumor. Radiation therapy (RT) is helpful, but there is no difference in overall survival between RT administered postoperatively or delayed until the time of tumor progression. There is increasing evidence that chemotherapeutic agents such as temozolomide, an oral alkylating agent, can be helpful in some patients. The tumor transforms to a malignant astrocytoma in the majority of patients, leading to variable survival with a median of about 5 years.