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Oncology Inllammatory breast cancer is an aggressive and rapidly progressive type of cancer characterized by erythema and edema of the skin of the breast ("peau d'orange"). It is often mistaken fbr infectious mastitis' Inflammatory breast cancer is treated with neoadjuvant chemotherapy, followed by surgery and then radiation. Adjuvant hormone therapy for ER/PR positive nonmetastatic breast cancer is used to prevent or delay systemic recurrence for stages I to III invasive breast cancer and is associated with increased overall survival. In premenopausal women, a 5 to lO-year course of adjuvant tamoxifen is recommended. Premenopausal women who previ- ously completed 5 years of tamoxifen may benefit from taking an aromatase inhibitor for 5 years when they become postmenopausal. Postmenopausal women are treated with 5 years of an aromatase inhibitor (anastrozole, letrozole, exemestane) or 2 years of tamoxifen and 3 years of an aromatase inhibitor. Adjuvant chemotherapy is primarily indicated for patients with hormone receptor negative (triple-negative) tumors, HER2 positive tumors, or positive lymph nodes. Molecular prognostic profiles, such as the 21 gene recurrence score, which can be used in ER/PR-positive and HER2-negative tumors, help determine the benefit of adjuvant chemotherapy. Patients with high risk recurrence scores will benefit from adjuvant chemotherapy followed by antiestrogen therapy, whereas those with low risk scores do not benefit from adjuvant chemotherapy. HER2-positive breast cancer is treated with adjuvant trastuzumab and/or pertuzumab along with chemotherapy. Patients should undergo evaluation ol LV function befbre initiating and during trastuzumab treatment. Metastatic breast cancer that is hormone receptor positive can be treated with antiestrogen therapy. In HER2-positive metastatic breast cancer, treatment with trastuzumab, chemotherapy, or antiestrogen therapy is guided by hormone receptor status. Patients who have hormone receptor-negative disease or who do not respond to antiestrogen therapy are treated with chemo therapy. In patients with BRCA mutations, poly (ADP ribose) polymerase (PARP) inhibitors (olaparib, talazoparib) improve progression free survival relative to chemotherapy.

Metastatic breast cancer that is hormone receptor positive can be treated with antiestrogen therapy. In HER2-positive metastatic breast cancer, treatment with trastuzumab, chemotherapy, or antiestrogen therapy is guided by hormone receptor status. Patients who have hormone receptor-negative disease or who do not respond to antiestrogen therapy are treated with chemo therapy. In patients with BRCA mutations, poly (ADP ribose) polymerase (PARP) inhibitors (olaparib, talazoparib) improve progression free survival relative to chemotherapy. Lytic bone metastases are treated with bisphosphonates to decrease bone pain and skeletal related events. The monoclonal antibody denosumab is an alternate option. Painful skeletal disease is treated with radiation therapy. Follow-up Patientswithearly stagebreastcancershouldreceiveannualmammography.MRlofthebreastisreservedforpatientswhohave an especially high risk for subsequent breast cancer from BRCAI/2 mutations or a strong family history of breast cancer. Surveillance blood tests and other imaging studies are not recommended. DON'T BE TRICKED . Aromatase inhibitors are contraindicated in premenopausal women. . Ovarian ablation or suppression can be used for premenopausal women with contraindications to tamoxifen. . Do not select mastectomy in patients with metastatic disease unless required for local cancer control. . Pregnancy following breast cancer treatment does not increase the risk for breast cancer recurrence. STUDY TABLE: Breast Cancer Treatment Side Effects Drug Side Effect Aromatase inhibitors (anastrazole, Arthralgia, bone pain, hyperlipidemia, osteoporosis (DEX,A scan every 2 years; treat with letrozole, exemestane) bisphosphonate if T-score <-2.5) Tamoxifen Endometrial cancer, VTE disease Anthracyclines (doxorubicin, epirubicin) Cardiomyopathy, acute leu kemia Trastuzumab Cardiomyopathy, especially if used with an anthracycline (measure LVEF before initiation) Bisphosphonates Osteonecrosisof the jaw, particularly in patientswith dental disease Denosumab Hypoca lcemia and osteonecrosis of the jaw, particu larly in patients with dental disease 314

Oncology DOI{'T BE TRICKED o Biopsy new metastatic lesions; primary tumor and metastatic tumor ER and HER2 status differs in up to 15% of patients. TESTYOURSETF A 50 year-old premenopausal woman has a 1.S-cm moderately differentiated breast cancer. The lesion is completely excised (lumpectomy), and the surgical margins are negative. Three axillary lymph nodes are positive. The tumor is negative for ER and pR and highly positive for HER2/neu. ANSWER: For diagnosis, choose stage III HER2 positive, hormone receptor negative breast cancer. For management, select postop erative radiation therapy, adjuvant chemotherapy, and trastuzumab and/or perhrzumab, but not tamoxifen or aromatase inhibitors. Lung Cancer Screening and Prevention Smoking cessation is the most effective preventive measure for lung cancer. Annual screening with low-dose CT in patients aged 55 to 74 B0 years (guidelines vary) with a 3O-pack-year history of smoking, including those who quit smoking in the preceding 15 years, is associated with a decrease in lung cancer and all-cause mortality. DON'T BE TRICKED o Do not prescribe vitamin A derivatives (p-carotene and retinol) or vitamin E (cr-tocopherol) to prevent lung cancer Diagnosis The most characteristic finding is a mass lesion on chest x ray. Radiographic abnormalities should first be compared with previ ous chest imaging studies. A solid lung nodule that has been stable for 2 years or longer is highly unlikely to be cancer. Histologic confirmation is necessary for diagnosis. Testing Biopsy can distinguish tumors as either NSCLC or SCLC. Select the biopsy site that will simultaneously diagnose and stage the disease (peripheral lymph node, mediastinal node). Small Cell Lung Cancer SCLC is generally viewed as a systemic (metastatic) disease at the time of diagnosis. Limited stage disease is confined to one hemithorax, with hilar and mediastinal lymphadenopathy that can be encompassed within one tolerable radiotherapy portal. Extensive-stage disease consists of any disease that exceeds those boundaries, including malignant pleural effusion. Typical staging studies include CT of the chest, abdomen, and pelvis. Whole-body CT/PET scan and MRI of the brain should be done even in the absence of bone or CNS symptoms.

Small Cell Lung Cancer SCLC is generally viewed as a systemic (metastatic) disease at the time of diagnosis. Limited stage disease is confined to one hemithorax, with hilar and mediastinal lymphadenopathy that can be encompassed within one tolerable radiotherapy portal. Extensive-stage disease consists of any disease that exceeds those boundaries, including malignant pleural effusion. Typical staging studies include CT of the chest, abdomen, and pelvis. Whole-body CT/PET scan and MRI of the brain should be done even in the absence of bone or CNS symptoms. SCLC is associated with paraneoplastic syndromes such as hyponatremia from the SIADH and hypercortisolism through secretion of ACTH. Neurologic symptoms, such as the Lambert-Eaton syndrome, cortical cerebellar degeneration, limbic encephalitis, and peripheral neuropathy, may rarely occur. 315

Oncology STUDY TABLE: Screening for Colorectal Cancer in lndividuals at Elevated Risk (Continued) Risk Category Criteria Screening Recommendations lnterval) High Familial adenomatous polyposis Begin at age 10-12 years; flexible sigmoidoscopy or colonoscopy; repeat every 1-2years until colectomy Lynch syndrome Begin at age 20-25 years or 1 0 years earlier than youngest cancer in family; colonoscopy; repeat every 1-2years lnflammatory bowel disease (Crohn Begin after 8 years of chronic colitis; colonoscopy with biopsies; disease or ulcerative colitis) every 1-2 rS CRC = colorectal cancer; FDR = first-degree relative (parent, sibling, or child). "lf baseline examination is normal. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 201 5 Feb;110\2):223-62; quiz 263. IPMID: 2564557 4l; Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG cli nical guideline: ulcerative colitis in adults. Am J Gastroenterol. 20.1 9;1 1 4:384-41 3. I PMI D: 30840605] doi:1 0.1 4309/aj9.0000000000000 1 52 DO]iI'T BE TRICKED . A single positive FOBT flnding constitutes a positive screening test and requires prompt follow-up colonoscopy Diagnosis Colonoscopy is the diagnostic procedure of choice. Testing All cancers should undergo molecular testing to determine whether it has evidence of defective mismatch repair (dMMR) gene deficiency manifesting as DNA microsatellite instability. Patients whose tumors test positive should be screened for Lynch syndrome. Staging also consists of contrast enhanced CT of the abdomen, chest, and pelvis and a serum CEA level. Rectal cancers also require a rectal MRL DON'I BE TRICKED . Do not obtain a serum CEA level to screen for or diagnose colon cancer . Do not obtain a PET scan for initial staging ofcolorectal cancer.

Testing All cancers should undergo molecular testing to determine whether it has evidence of defective mismatch repair (dMMR) gene deficiency manifesting as DNA microsatellite instability. Patients whose tumors test positive should be screened for Lynch syndrome. Staging also consists of contrast enhanced CT of the abdomen, chest, and pelvis and a serum CEA level. Rectal cancers also require a rectal MRL DON'I BE TRICKED . Do not obtain a serum CEA level to screen for or diagnose colon cancer . Do not obtain a PET scan for initial staging ofcolorectal cancer. Treatment General rules for colon cancer therapy: . confined to colon (stage I) or local invasion (stage II) -+ resection for cure o metastatic to regional lymph nodes (stage III) J resection and adjuvant chemotherapy o distant metastases (stage IV) + molecular analysis flor K ros, N ros, and BRAFgene mutation stafus and dMMR determination Patients with an oligometastatic lesion to a single organ may be cured with surgical removal of the primary tumor and the metastasis. S-FU based adjuvant chemotherapy improves survival for patients with stage III colon cancer. 5 FU based adjuvant chemotherapy is efficacious for metastatic colon cancer. The addition of bevacizumab, a monoclonal antibody against VEGII, increases the efficacy of first- and second-line chemotherapy. The anti_EGFR monoclonal antibody cetuximab or panitumumab may also be a useful addition to chemotherapy, but these agents are inactive in patients with K_ ros, N ros, or BRAFmutations. 318

L L L Oncology t t General rules for rectal cancer therapy: t o Rectal cancers that do not penetrate the full thickness of the bowel and do not involve regional lymph nodes are resected for cure. t o Full-thickness tumors and/or those with involved lymph nodes are treated with radiation, chemotherapy, and surgery. L t Follow-up L Recommended follow up includes: L o CEA measurement every 6 months for 5 years t o colonoscopy I year later, 3 years later, and then every 5 years t . CT of the abdomen, chest, and pelvis annually for 5 years I t I DO]{'T BE TRICKED : o Do not use PET scans to follow patients for recurrent colorectal cancer. t . Anti-VEGF and anti-EGFR monoclonal antibodies should not be used together : o Do not institute therapy for metastatic disease based on CEA elevation alone. TESTYOURSELF A 71-year-old man is evaluated for stage II colon cancer that was resected 3 years ago. A surveillance CT scan shows three small metastatic Iesions in the left lobe of the liver. No other abnormal findings are noted. ANSWER: For management, select resection of all lesions. Hepatocellular Ca rcinoma Prevention The most important preventive measure for HCC is hepatitis B vaccination. Screening Guidelines recommend that all patients with cirrhosis be screened with abdominal ultrasonography every 6 months. DOil'T BE TRICKED . Serum AFP measurement alone is not recommended for HCC screening or surveillance. Testing Order contrast-enhanced CT or MRI of the liver when the abdominal ultrasound is abnormal. Because the advanced imaging findings of HCC are fairly characteristic (arterial phase enhancement), biopsy for confirmation is usually unnecessary. Treatment Surgical resection or liver transplantation is first-line therapy. Patients with CTP class A cirrhosis, without significant portal hypertension or jaundice, and with a singular lesion <5 cm should be considered for curative resection. Other patients should be considered for liver transplantation. 319

Oncology STUDY TABLE: Other Hepatic Tumors and Cysts TyPe Characteristics Hepatic adenoma Adenomas are typically heterogeneous in appearance because of regions of hemorrhage or necrosis. Oral contraceptives should be discontinued. Selea resection if >5 cm. Focal nodular hyperplasia Many larger focal nodular hyperplasias have a central stellate scar. No therapy is required. Metastatic tumors Single or multiple hypoechoic lesions on ultrasonography that are hypovascular on contrast-enhanced CT scans. lsolated lesions may be amenable to resection. TEST YOURSELF A 60 year old man with chronic hepatitis C and decompensated cirrhosis is found to have a 4 cm liver mass on screening ultra sonography. A CT scan showed the mass enhances on arterial phase. ANSWER: For diagnosis, choose hepatocellular carcinoma. For management, select liver transplantation. Pancreatic Cancer Diagnosis Symptoms are influenced by tumor site and extent and may include: . upper abdominal discomfort and lumbar back pain o anorexia and weight loss . obstructive jaundice . vascular thromboses (Trousseau syndrome) Physical examination findings may include a palpable gallbladder and jaundice. Testing Contrast enhanced multidetector CT has 90'l. sensitivity for detecting pancreatic cancer. Encloscopic ultrasonography is more sensitive in detecting small cancers (<Z cm) and guides fine needle aspiration when needed. Germline testing fbr BRCA and mismatch repair deficiency is recommended for all patients. :: : DOil'T BE TRICKED : . PET scans do not add value in pancreatic cancer management. . Serum tumor markers are not used to diagnose pancreatic cancer. o AIP can be mistaken for pancreatic cancer; look for elevated serum levels of IgG4. Treatment Surgical resection is appropriate for patients with resectable pancreatic cancer followed by combined chemotherapy. :

DOil'T BE TRICKED : . PET scans do not add value in pancreatic cancer management. . Serum tumor markers are not used to diagnose pancreatic cancer. o AIP can be mistaken for pancreatic cancer; look for elevated serum levels of IgG4. Treatment Surgical resection is appropriate for patients with resectable pancreatic cancer followed by combined chemotherapy. : Metastatic disease is treated with combined chemotherapy. palliative measures to alleviate pain in patients with unresectable or metastatic disease include optimization of analgesic medications, radiation therapy, chemical splanchnicectomy, or celiac nerve blocks. Palliation of biliary obstruction may be achieved with surgical biliary bypass, percutaneous radiologr biliary stent place ment, or endoscopic biliary stent placement. 320

Oncology Ovarian Cancer Prevention Oophorectomy after childbearing or at age 35 years can be offered to women with BRCA1/2 and mismatch repair genetic muta tions or >2 first-degree relatives with ovarian cancer. Screening Screening women at average risk for ovarian cancer is not indicated. Screening women with high risk genetic mutations has no proven benefit. Diagnosis Patients may have a family history of breast, ovarian, or colon cancer. Characteristic findings are abdominal swelling, ascites, and pain, as well as abnormal vaginal bleeding and dyspareunia. A pelvic mass or nodularity may be present in the cul de sac. Tiesting If ovarian cancer is suspected, CT or MRI of the abdomen and pelvis and chest imaging are performed to assess disease extent. In patients with an adnexal mass without ascites, surgical removal of the mass without biopsy is associated with a survival beneflt. In patients with advanced disease, diagnosis may be made by cytologic examination of ascites or pleural effusion or biopsy of peritoneal masses. DO]iI'T BE TRICKED o Do not obtain biopsy for early ovarian cancer. . Women with peritoneal CUP have ovarian cancer until proven otherwise. Treatment Surgery is indicated to remove the ovaries and any evidence of grossly visible disease within the abdomen. Neoadjuvant therapy can be given for patients with initially unresectable disease to shrink the tumor for possible resection. Most patients with stage IA and IB disease with grade I (well-differentiated) histolory do not receive adjuvant chemotherapy. Other patients are treated with adjuvant platinum based chemotherapy. Intraperitoneal chemotherapy shows a survival benefit in patients with small amounts of residual disease confined to the peritoneal cavity following surgery. DON'T BE TRICKED . Do not opt for "second look surgery'following completion of chemotherapy . All women should undergo BRCAII2testing. Follow-up Limit follow up to physical examination with pelvic examination and serum CA 125 measurement (if initially elevated) TESTYOURSETF A 60 year-old woman has a 3-month history of increasing abdominal girth, constipation, and pain. Physical examination is normal except for ascites. Pelvic ultrasound is normal. Laparoscopy shows diffuse peritoneal carcinomatosis. ANSWER: For diagnosis, select adenocarcinoma of unknown primary site. For management, select ovarian cancer treatment. 322

L t L Oncology t I t Endometrial Cancer t t Diagnosis I L Characteristic findings include irregular vaginal bleeding after age 40 years or in perimenopausal women, persistent pink or brown vaginal discharge, postmenopausal bleeding, and a Pap smear revealing atlpical glandular cells of undetermined signifi- t cance or containing endometrial cells. The diagnosis is made by endometrial biopsy. t L Treatment L Surgical resection of the uterus, cervix, and adnexa is first line treatment; radiation therapy and/or chemotherapy may be added for higher risk disease. Radiation therapy alone is an alternative for high-risk surgical patients. t t DOil'T BE TRICKED L o Do not screen for endometrial cancer; screening does not reduce mortality. t o Women taking tamoxifen are at increased risk for endometrial cancer. I . Symptom monitoring and physical examination are as effective as imaging for diagnosing recurrent endometrial t cancer. I L L t Prostate Cancer L Prevention L Finasteride reduces the incidence of prostate cancer but not cancer mortality rates and is not recommended for prevention. L Diagnosis I 5 I L I Prostate cancer is most commonly diagnosed after identification of an elevated serum PSA level during screening and in the absence of symptoms. In men with metastatic disease at the time of initial presentation, bone pain or back pain may be the I ! presenting symptom. ! Testing Select transrectal ultrasonography-guided prostate biopsy for a significantly elevated or rapidly rising PSA level or a nodule or firmness on digital rectal examination. Serum PSA, Grade Group (based on Gleason score), TNM cancer staging, and digital rectal examination determine prognosis and treatment options. Imaging studies are not done in patients at very low or low risk but should be obtained in others to evaluate regional lymph node involvement and metastatic disease. Testing for BRCA gene mutation should be done in all men with high-risk disease and patients with positive lymph nodes or metastatic disease.

Imaging studies are not done in patients at very low or low risk but should be obtained in others to evaluate regional lymph node involvement and metastatic disease. Testing for BRCA gene mutation should be done in all men with high-risk disease and patients with positive lymph nodes or metastatic disease. DOil'T BE TRICKED . Acute urinary retention significantly increases the PSA level regardless of the cause of obstruction. 323

Oncology Renal Cell Carcinoma Diagnosis Patients with renal cell carcinoma are often asymptomatic until they have advanced disease, but possible symptoms and signs include hematuria, abdominal pain, and abdominal mass. Renal cell carcinoma has been associated with various paraneoplastic syndromes, including erythrocytosis, AA amyloidosis, polymyalgia rheumatica, and hepatic dysfunction (unrelated to metastatic disease). Testing Ultrasonography can be used to differentiate benign cysts from complex cysts or solid masses. If a lesion is not clearly a benign cyst, CT is indicated for further evaluation. CT of the abdomen, pelvis, and chest is performed to evaluate the local disease extent and assess for metastatic disease. A suspicious solitary renal mass <4 cm does not necessarily require treatment. Active surveil- Iance is an option for such lesions. DOil'T BE TRICKED o Patients with CT findings pathognomonic for renal cell cancer do not need a conflrmatory kidney biopsy Treatment Manage early-stage localized renal cancer with partial or radical nephrectomy. Adjuvant therapy is not recommended. Patients with limited metastatic disease and good functional status are candidates for debulking nephrectomy, which improves survival. Surgery also has a role in the treatment of isolated or several easily resected areas of metastatic disease. Various agents, including immune checkpoint inhibitors and tyrosine kinase inhibitors, have been shown to be effective in metastatic disease. TESTYOURSELF A 50 year old woman is diagnosed with renal cell carcinoma and a 1.2-cm single pulmonary nodule. ANSWER: For management, select nephrectomy and pulmonary metastasectomy. Thyroid Cancer Diagnosis Characteristic findings are a very firm nodule with fixation to adjacent structures, vocal cord paralysis, and enlarged regional lymph nodes. Consider medullary thyroid cancer and MEN syndrome in a patient with: . headache, sweating, palpitations, and hypertension (pheochromoc5rtoma) o kidney stones and hypercalcemia (hyperparathyroidism) Testing FNAB is the diagnostic study for thyroid nodules >1 cm. The aspirate should be anallzed for the BRAFgene mutation when the diag- nosis is indeterminate. The BRAFgene mutation is specific for papillary carcinoma and more aggressive forms of thy.oid cancer. 326

Oncology Medullary thyroid cancer is associated with elevated serum calcitonin. Inherited forms of medullary thyroid cancer are associ- ated with germline mutations in the RET proto-oncogene. Screen family members for disease when a patient presents with a new diagnosis of medullary thyroid cancer. Treatment Treat papillary thyroid cancer and follicular thyroid cancer with total thyroidectomy followed by radioiodine therapy in most cases. Medullary thyroid cancer is treated with total thyroidectomy and varying degrees of neck dissection to remove involved lymph nodes. DOil'T BE TRICKED o Radioiodine is not taken up by C cells and is not a treatment option for medullary thyroid cancer. r Chemotherapy does not prolong or improve the quality of life for patients with metastatic thyroid carcinoma. 'ESTYOURSELF A 37-year-old woman has a 2-cm right-sided thyroid nodule that is firm and nontender and moves when she swallows. Serum TSH is 1.8 pU/mL and serum calcium is 11.8 mg/dl. AI{SWER: For diagnosis, choose medullary thyroid cancer. For management, select serum calcitonin measurement. Lymphoma Patients with soft, small, freely moveable lymph nodes that are limited to one or tvvo adjacent sites and who have no other sig- nificant history or physical examination Iindings may be followed over 6 to 8 weeks and require no other blood work or imaging. Persistent or enlarging lymphadenopathy, particularly when associated with fever, night sweats, or weight loss, requires further evaluation. To establish a diagnosis of lymphoma, perform an excisional biopsy. Core needle biopsy may be used for deep lymph nodes, but fine-needle aspiration should be avoided. Flow cytometry can suggest monoclonality and demonstrate B cell or T-cell markers. After a diagnosis of lymphoma is made, total-body CT with PET scan and a bone marrow biopsy are performed to complete staging. Bone marrow biopsy is not needed in patients with Hodgkin lymphoma and large cell lymphoma if PET scan and CBC are normal. Lymphomas are divided into Hodgkin and non Hodgkin lymphomas. Lymphomas are further classified into three prognostic groups: indolent, aggressive, and highly aggressive. lndolent Non-Hodgkin Lymphomas These lymphomas may not require therapy for decades but are difficult to cure. The most common indolent lymphomas are follicular lymphoma, MALI lymphoma, CLL, and hairy cell leukemia.

Lymphomas are divided into Hodgkin and non Hodgkin lymphomas. Lymphomas are further classified into three prognostic groups: indolent, aggressive, and highly aggressive. lndolent Non-Hodgkin Lymphomas These lymphomas may not require therapy for decades but are difficult to cure. The most common indolent lymphomas are follicular lymphoma, MALI lymphoma, CLL, and hairy cell leukemia. Diagnosis of follicular lymphoma is confirmed by cytogenetic analysis identi$ring a translocation [t(r+,ra)] that causes an overexpression of the BCL2 oncogene. Therapy is withheld until patients become symptomatic. Localized disease can be potentially cured with involved-field radiation and/or rituximab. Symptomatic, systemic disease is treated with rituximab plus multiagent chemotherapy. Allogeneic HSCT is curative therapy but is associated with significant morbidity and mortality. 327

l I l Oncology j I I The clinical course of MALT lymphoma is usually indolent, and -a presentation is usually localized. Gastric MALI lymphoma occurs : most commonly and is caused by chronic infection with Helicobacter pylori. Complete remissions are achieved in most l .\ patients after completion of H. pylori eradication therapy (e.g', l clarithromycin, amoxicillin, and omeprazole). j Patients with chronic lymphocytic leukemia are usually asymp I tomatic and are identified by a relative lymphocytosis. Smudge : cells may be seen on the peripheral blood smear. Diagnosis is confirmed by flow cytometry demonstrating B cell surface 1

Patients with chronic lymphocytic leukemia are usually asymp I tomatic and are identified by a relative lymphocytosis. Smudge : cells may be seen on the peripheral blood smear. Diagnosis is confirmed by flow cytometry demonstrating B cell surface 1 antigens. . Patients with low stage, asymptomatic CLL can often be observed for years without therapy. Several treatment options are available. ; Concomitant autoimmune disease, including immune thrombo- CIL "Smudge Cell": Peripheral blood smear showing a "smudge cell," which is a i lymphocyte that appears flattened or distorted and is characteristic of CLL. cytopenia and hemolytic anemia, is common among patients with CLL. Low serum IgG levels require replacement therapy to 1 prevent infection. Patients are at increased risk for transforma- : l tion from CLL to a large cell lymphoma requiring aggressive I chemotherapy. ,g* kdv .,

antigens. . Patients with low stage, asymptomatic CLL can often be observed for years without therapy. Several treatment options are available. ; Concomitant autoimmune disease, including immune thrombo- CIL "Smudge Cell": Peripheral blood smear showing a "smudge cell," which is a i lymphocyte that appears flattened or distorted and is characteristic of CLL. cytopenia and hemolytic anemia, is common among patients with CLL. Low serum IgG levels require replacement therapy to 1 prevent infection. Patients are at increased risk for transforma- : l tion from CLL to a large cell lymphoma requiring aggressive I chemotherapy. ,g* kdv ., Hairy cell leukemia is characterized by pancytopenia and pro- gressive splenomegaly without lymphadenopathy. Typically, an ) a: attempt at bone marrow aspiration is unsuccessful. The circulat- I

Hairy cell leukemia is characterized by pancytopenia and pro- gressive splenomegaly without lymphadenopathy. Typically, an ) a: attempt at bone marrow aspiration is unsuccessful. The circulat- I ing cells have the classic appearance of thread-like projections emanating from the cell surface ("hairy" cells). Treatment is not necessary in asymptomatic patients. Treatment with purine .t..tl ic nucleoside agents, such as cladribine, results in complete and durable remission in most patients. :.?fiit&r' .r ' ,&i Hairy Cell leukemia: Atypical lymphocytes with cytoplasmic projections charac- Aggressive Non-Hod g kin teristic of hairy cell leukemia. B-Cell Lymphomas The most aggressive forms ol lymphoma are dilfuse large cell lymphoma (DLCL), mantle cell lymphoma, and Burkitt lymphoma. Patients with DLCL typically have symptomatic enlarging lymphadenopathy and advanced disease at presentation and are treated with combined chemotherapy. Patients with mantle cell lymphoma present with widely disseminated disease, including the GI tract and bone marrow, and : are treated with combined chemotherapy. Burkitt lymphoma is remarkable fbr its extremely rapid growth. The endemic form occurs primarily in Afiica, is a common cause of childhood cancer, and is associated with Epstein Barr virus inflection. The sporadic form seen in the United States is more likely to present with abdominal or pelvic involvement. A third variety occurs in patients with HIV. Early signs of the tumor lysis syndrome are often present in patients with Burkitt lymphoma at diagnosis and should be anticipated during treatment. DOil'T BE TRICKED . Prophylaxis for tumor lysis syndrome should be started before initiation of chemotherapy for Burkitt lymphoma. 328

I i I I I Oncology I L i I I Hodgkin Lymphoma t Hodgkin lymphoma commonly presents locally, with palpable, firm lymphadenopathy or a mediastinal mass on chest x-ray. I Some patients may have B symptoms, splenomegaly, and hepatomegaly. I t Hodgkin lymphoma is curable in most patients. The staging evaluation consists of PET scanning. Routine bone marrow biopsy, ; in the absence of unexplained blood abnormalities, is not indicated. i I I ABVD followed by radiation therapy is used for all patients regardless of prognosis. Options for patients with early stage disease L are two chemotherapy cycles and involved-field radiation. Patients with early stage disease who have a negative PET scan after I two cycles of chemotherapy have >90% likelihood of long term disease response, and these patients may forgo radiation therapy. Patients with advanced disease or those with B symptoms usually require a full course of chemotherapy. Patients with recurrent, chemotherapy-sensitive disease are candidates for autologous HSCT, whereas those with resistant disease can achieve long term remissions with allogeneic HSCT. ' Patients are at risk for secondary cancers (breast, Iung, skin) and MDS. Women who were treated with radiation to the medi astinum should be screened for breast cancer with MRI, mammography, or a combination of both beginning at age 25 years or 8 years after completion of radiation therapy, whichever occurs last. DOil'T BE TRICKED e All patients with Hodgkin lymphoma previously treated with mediastinal radiation who present with chest pain should be evaluated for CAD, regardless ofage. Cutaneous T-Cell Non-Hodgkin Lymphoma Mycosis fungoides and Sezary syndrome are the two major sub q types of cutaneous T-cell lymphoma. The skin findings in mycosis fungoides range fiom maculopapular plaques, to skin tumors with ulceration. The Sdzary syndrome is a more aggressive form of cutaneous T cell lymphoma in which diffuse erythroderma characterizes the skin involvement and malignant T cells circulate in the blood. Early stage disease limited to the skin is treated with topical gluco corticoids. Advanced-stage disease is often treated with electron beam radiation therapy and systemic chemotherapy.

Cutaneous T-Cell Non-Hodgkin Lymphoma Mycosis fungoides and Sezary syndrome are the two major sub q types of cutaneous T-cell lymphoma. The skin findings in mycosis fungoides range fiom maculopapular plaques, to skin tumors with ulceration. The Sdzary syndrome is a more aggressive form of cutaneous T cell lymphoma in which diffuse erythroderma characterizes the skin involvement and malignant T cells circulate in the blood. Early stage disease limited to the skin is treated with topical gluco corticoids. Advanced-stage disease is often treated with electron beam radiation therapy and systemic chemotherapy. Carcinoma of Unknown Cutaneous I-Cell lymphoma: Cutaneous T-cell lymphoma (mycosis fungoides) is characterized by scaling or nonscaling plaques of different red hues. ln early Primary Origin stages, the condition is superficial and may not be well defined, but as the disease progresses, the lesions become thicker, round, oval, arciform, or annular. Diagnosis Patients with metastatic cancer who do not have an identified primary site are classifled as having CUP Diagnostic efforts should fbcus on identifying patients with CUP who have a more favorable prognosis and who can benefit from a specific treatment strateS/. Ihe clinical evaluation in patients with CUP should not involve an exhaustive search for a primary site, because flnding an asymptomatic and occult primary site does not improve outcome. Favorable subgroups include those with isolated regional lymphadenopathy, women with peritoneal carcinomatosis, and patients with poorly differentiated nonadenocarcinoma. 329

Oncology STUOY TABLE: Examples of Favorable Subgroups and Management Axillary lymphadenopathy in women Obtain breast MRl. lf positive, treat according to stage. lf negative, treat as if stage ll breast cancer. lsolated cervical lymphadenopathy Obtain upper endoscopy, bronchoscopy, and laryngoscopy. lf negative, treat with chemotherapy and radiation as for head and neck cancer. lsolated inguinal lymphadenopathy Anorectal, genital, and perineal examination. lf negative, lymph node resection or locoregional radiation. Peritoneal carcinomatosis and ascites Treat as ovarian carcinoma with cytoreductive surgery and chemotherapy. Midline nonadenocarcinoma of mediastinum or Measure serum AFP and p-hCG, perform testicular exam and testicular retroperitoneum ultrasonography; treat with platinum-containing germ cell tumor regimens. DO]I'T BE TRICKED o Do not select routine radiographic contrast studies ofthe GI tract. . Do not measure CA-19 9, CA-15-3, and CA-125, because they are rarely helpful and virtually never diagnostic. . Do not order PET scans, because the findings are rarely definitive and do not improve long-term outcome. TESTYOURSELF A 45 year-old woman has an axillary lymph node that is positive for adenocarcinoma. Bilateral mammogram, breast MRI, and CT scans ofthe chest and abdomen are normal. She has never smoked. ANSWER: For diagnosis, choose CUP For management, select treatment for stage II breast cancer. Melanoma Diagnosis The identification and diagnosis of melanoma is discussed in the General Internal Medicine chapter. Treatment Complete excision is the preferred biopsy technique for most varieties of melanoma, and sentinel lymph node biopsy is indi- cated for melanomas >1 mm thick. The extent of the surgical excision depends on the thickness of the primary melanoma. In patients with metastatic melanoma, look for a BRAFmutation, which may respond to the BRAF inhibitors combined with MEK inhibitors. Anti-PD-l antibodies can result in signiflcant response rates with sometimes dramatic survival improvement.

Treatment Complete excision is the preferred biopsy technique for most varieties of melanoma, and sentinel lymph node biopsy is indi- cated for melanomas >1 mm thick. The extent of the surgical excision depends on the thickness of the primary melanoma. In patients with metastatic melanoma, look for a BRAFmutation, which may respond to the BRAF inhibitors combined with MEK inhibitors. Anti-PD-l antibodies can result in signiflcant response rates with sometimes dramatic survival improvement. Effects of Cancer Therapy STUDY TABLE: Short- and Long-Term Effects of Cancer Therapy Potential Complications Cardiovascular Doxorubicin: dose-related HF (irreversible) Tamoxifen:WE Trastuzumab: non-dose-related HF (reversible) Mediastinal radiation: myocardial, valvulal pericardial fibrosis, and premature CAD Checkpoint inhibitors: myocarditis, pericarditis Pulmonary Bleomycin: pulmonary toxicity, most commonly bleomycin-induced pneumonitis Radiation: radiation-induced pneumonitis lmmunotherapy: pneumonitis (Continued on the nert page) 330

L L L Oncology STUDY TABIE: Short- and Long'Term Elfects of Cancer Therapy (Continued) L Category Potential Complications I I Reproductive Chemotherapy: premature ovarian failure, male infertility Tamoxifen: endometrial cancer i t Endocrine Radiation therapy to head and neck: hypothyroidism I 5 lmmunotherapy: thyroiditis, adrenalitis, hypophysitis Musculoskeletal Aromatase inhibitors: osteoporosis Leu prol ide, goserelin, castration : osteoporosis Cancer Mantle radiation: breast, lung, and esophageal cancer Chemotherapy (breast cancer): MDS and acute leukemia Kidney and bladder Cisplatin and ifosfamide: renaltubular damage and CKD Cyclophosphamide and ifosfamide: hemorrhage cystitis Dermatology Fluoropyrimidines: hand-foot syndrome (red ness, peeling, tenderness) EGFR inhibitors and monoclonal antibodies: pustular acneiform eruptions Gastrointestinal Fluoropyrimidines: stomatitis, colitis lmmunotherapy: colitis, hepatitis ?EST YOURSETF A 44-year old man is evaluated for cough and dyspnea 2 weeks after he completed his ABVD therapy for Hodgkin lymphoma. The chest x-ray shows bilateral interstitial infiltrates. ANSWER: For diagnosis, choose bleomycin-induced lung injury. Cancers of lnfectious Origin SIUDY TABLE; Malignancies With lnfectious Causes Cancer Associated lnfection Cervical and anal cancers HPV lncreased incidence in HIV infection Risk proportional to number of sexual partners

Cancers of lnfectious Origin SIUDY TABLE; Malignancies With lnfectious Causes Cancer Associated lnfection Cervical and anal cancers HPV lncreased incidence in HIV infection Risk proportional to number of sexual partners Kaposi sarcoma Human herpesvirus 8 Primarily in younger HIV-infected men who have sex with men May be mistaken for bacillary angiomatosis (bartonellosis) Hodgkin lymphoma EBV Burkitt lymphoma EBV t(8;1 4!positive lncreased incidence in HIV infection (AIDS-defining cancer) Presents as oral and nasopharyngeal cancer in China and Southeast Asia and as posttransplantation lymphoma in immunosuppressed patients MALT lymphoma Helicobacter pylori Usually involves the Gl tract, particularly the stomach Treat early disease with antibiotics and PPls (localized radiation th erapy for H. pylori-negative disease) HCC Cirrhosis and HCV infection or HBV infection with or without cirrhosis Non-Hodgkin lymphoma lncreased incidence in HIV infection (AIDS-defining cancer) Head and neck (nasopharynx) EBV Head and neck (oropharynx) HPV 331

Oncology Diagnosis: Characteristic symptoms: . dyspnea on exertion o chest pain . cough Obtain chest x ray or chest CT to establish a diagnosis and then perform thoracentesis for diagnosis. Treatment: To reduce the incidence ofrecurrence, standard therapies include chest tube placement, prolonged drainage (over the course of a few to several days), and pleurodesis. Placement of indwelling pleural catheters is an option. Tumor Lysis Syndrome Prevention: Tumor lysis syndrome is prevented and managed by aggressive hydration and use of allopurinol or rasburicase. IV rasburicase is indicated for patients at high risk for tumor lysis syndrome or when rapid reduction of serum urate levels is indicated (e.g., emergently administered chemotherapy). Factors defining high risk include bulky disease, a high leukocyte count, high pretreatment levels of LDH or urate, compromised kidney function, and use of nephrotoxic agents. Diagnosis: Tumor lysis syndrome is the result of the rapid breakdown of malignant cells, resulting in dangerous increases in serum urate, potassium, and phosphate concentrations. Typically, tumor lysis syndrome occurs within 1to 5 days of treatment and develops most commonly in patients with hemato logic malignancies or other rapidly dividing tumors, such as acute leukemia and high-grade lymphoma. Spontaneous (pretreat- ment) tumor lysis syndrome occurs commonly in patients with leukemia and Burkitt lymphoma. Treatment: Tumor lysis syndrome is treated with IV hydration, rasburicase, and furosemide, if needed, to enhance urine flow. Hyperkalemia is also aggressively treated. If acute kidney failure develops, hemodialysis may be indicated. Febrile Neutropenia Diagnosis Fever is defined as a single oral temperature >38.3 "C (101.0 oF) or a temperature >38.0 'C (100.4 'F) sustained over a l-hour period. The first step in managing febrile neutropenia is identigring high- and low risk patients. . High risk is defined as neutropenia for >7 days with an absolute neutrophil count <100/pL and/or significant comorbidities (e.g., hypotension, pneumonia, abdominal pain, neurologic changes). o Low risk is defined as anticipated neutropenia for <7 days and no or few comorbidities. Obtain at least two sets of blood cultures, and culture any obvious source of infection. Signs and symptoms guide imaging; no routine imaging tests exist.

. High risk is defined as neutropenia for >7 days with an absolute neutrophil count <100/pL and/or significant comorbidities (e.g., hypotension, pneumonia, abdominal pain, neurologic changes). o Low risk is defined as anticipated neutropenia for <7 days and no or few comorbidities. Obtain at least two sets of blood cultures, and culture any obvious source of infection. Signs and symptoms guide imaging; no routine imaging tests exist. Treatment Management of high risk febrile neutropenia . Admit all high-risk patients to the hospital for empiric IV antibiotics. . Begin empiric monotherapy with an antipseudomonal B-lactam (e.g., cefepime), a carbapenem (e.g., imipenem-cilastatin), or piperacillin-tazobactam. Management of low-risk febrile neutropenia: o Low risk patients may be candidates for outpatient empiric antibiotic therapy. . Begin oral or IV antibiotics in the clinic or hospital setting, with transition to the outpatient setting if the patient remains stable during a 4 to 24-hour period ofobservation. 334

Oncology Modiff the initial therapy for patients at high risk for antibiotic-resistant organisms (e.g., unstable patient, ear$ suggestive blood culture results): o Add vancomycin, linezolid, or daptomycin for suspected MRSA infection. . Add linezolid or daptomycin for suspected vancomycin resistant enterococci. r Begin empiric antifungal therapy for persistent fever despite 4 to 7 days of empiric antibiotics and anticipated neutrope nia for >7 days. Continue antibiotics until the absolute neutrophil count is >500/pL or longer, depending on clinical circumstances. DOil'T BE TRICKED DoB: i:dy ?-q l'l i I tll !l: . Vancomycin is not recommended as standard initial BrI therapy for febrile neutropenia. o Do not use myeloid colony stimulating factors for treatment of febrile neutropenia. . Antiviral treatment is indicated only for clinical evidence -l of active viral infection. . Typhlitis (necrotizing enterocolitis) should be suspected in patients with neutropenia and even minimal RLQ abdominal pain; obtain an abdominal CT scan. . Diagnose angioinvasive aspergillosis fur neutropenic patients with leukemia receiving prolonged antibiotic 2ilf therapy. lnvasiue Aspergillosis: CT scan showing a dense infiltrate sunounded by a TESTYOURSELF ground-glas-appearing halo ("halo sign") suggestive, but not diagnostic, of inva' A 73-year old man with AML develops febrile neutropenia on the sive aspergillosis. eighth day of chemotherapy. Ceftazidime is begun, but after 5 days of therapy he remains febrile and neutropenic. Blood cultures are negative, and he has no localizing signs of infection. ANSWER: For management, add amphotericin B or itraconazole. 335