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Melanoma Poorly Differentiated Cancer of Unknown Primary Site e Patients with cancer of unknown primary who have Poorly differentiated cancers are usually more aggressive than poorly differentiated carcinoma predominantly in the well-differentiated cancers, and metastatic poorly differenti- midline, such as those with large retroperitoneal or ated adenocarcinoma has a poor prognosis; however, some mediastinal lymphadenopathy, are likely to have a germ patients with poorly differentiated CUP that is not definitively cell tumor and should be treated for that possibility an adenocarcinoma may have specific treatment options. In with platinum-based chemotherapy. particular, young men with predominantly midline poorly e¢ Women with a cancer of unknown primary who have differentiated carcinoma, such as those with large retroperito- axillary lymphadenopathy and a negative breast MRI neal or mediastinal lymphadenopathy, should be carefully scan should be treated for presumptive stage II breast evaluated for the possibility of a germ cell tumor. Serum cancer. a-fetoprotein and B-human chorionic gonadotropin levels e Women with adenocarcinoma with abdominal carcino- should be measured, and a testicular examination and ultra- matosis and ascites should be treated for presumptive sonography should be performed. Even if these evaluations ovarian cancer. have negative findings, an unrecognized germ cell tumor may still exist, and these patients should be treated for this possi- e Patients with isolated or dominant cervical lymphade-

Poorly Differentiated Cancer of Unknown Primary Site e Patients with cancer of unknown primary who have Poorly differentiated cancers are usually more aggressive than poorly differentiated carcinoma predominantly in the well-differentiated cancers, and metastatic poorly differenti- midline, such as those with large retroperitoneal or ated adenocarcinoma has a poor prognosis; however, some mediastinal lymphadenopathy, are likely to have a germ patients with poorly differentiated CUP that is not definitively cell tumor and should be treated for that possibility an adenocarcinoma may have specific treatment options. In with platinum-based chemotherapy. particular, young men with predominantly midline poorly e¢ Women with a cancer of unknown primary who have differentiated carcinoma, such as those with large retroperito- axillary lymphadenopathy and a negative breast MRI neal or mediastinal lymphadenopathy, should be carefully scan should be treated for presumptive stage II breast evaluated for the possibility of a germ cell tumor. Serum cancer. a-fetoprotein and B-human chorionic gonadotropin levels e Women with adenocarcinoma with abdominal carcino- should be measured, and a testicular examination and ultra- matosis and ascites should be treated for presumptive sonography should be performed. Even if these evaluations ovarian cancer. have negative findings, an unrecognized germ cell tumor may still exist, and these patients should be treated for this possi- e Patients with isolated or dominant cervical lymphade- bility with a platinum-based chemotherapy regimen. nopathy and cancer of unknown primary should be Patients with poorly differentiated neuroendocrine treated along a head and neck cancer paradigm with tumors also warrant careful consideration. These tumors fre- chemotherapy and radiation therapy. quently both metastasize like small cell lung cancers and respond similarly to platinum-based chemotherapy. Nonfavorable Subgroups of Isolated Regional Lymphadenopathy Cancer of Unknown Primary Site Women found to have adenocarcinoma in isolated axillary Therapy for CUP that does not fall into one of the favorable lymphadenopathy have a more favorable CUP prognosis. These subgroups is empirically directed with chemotherapy and radi- patients should be presumptively considered to have locore- ation therapy based on the pattern of presentation. CUP pre- gional breast cancer. If mammography is unrevealing, breast senting above the diaphragm should be evaluated and managed MRI should be performed. If the MRI scan is negative, the as metastatic lung cancer. CUP that is predominantly below the patient is still assumed to have a presumptive stage II breast diaphragm should be managed as gastrointestinal cancer. cancer. Given the inability to identify the primary, a mastec- Chronic medical comorbidities and patient performance tomy or whole breast radiation therapy is recommended. These status greatly influence the range of treatment options. As patients should all receive adjuvant treatment consistent with with other solid tumors, patients with several comorbidities a stage II breast cancer diagnosis. Patients with isolated or and poor performance status are far less likely to benefit from dominant cervical lymphadenopathy should undergo full aggressive chemotherapy and are far more likely to experience endoscopic examination of the upper aerodigestive tract to serious or life-threatening toxicity. Palliative and hospice care evaluate for a head and neck primary. Even if a primary is not should be considered in such patients. identified, treatment along a head and neck paradigm with chemotherapy and radiation therapy is often appropriate. In particular, patients with high cervical lymphadenopathy with e Therapy for cancer of unknown primary that does not

bility with a platinum-based chemotherapy regimen. nopathy and cancer of unknown primary should be Patients with poorly differentiated neuroendocrine treated along a head and neck cancer paradigm with tumors also warrant careful consideration. These tumors fre- chemotherapy and radiation therapy. quently both metastasize like small cell lung cancers and respond similarly to platinum-based chemotherapy. Nonfavorable Subgroups of Isolated Regional Lymphadenopathy Cancer of Unknown Primary Site Women found to have adenocarcinoma in isolated axillary Therapy for CUP that does not fall into one of the favorable lymphadenopathy have a more favorable CUP prognosis. These subgroups is empirically directed with chemotherapy and radi- patients should be presumptively considered to have locore- ation therapy based on the pattern of presentation. CUP pre- gional breast cancer. If mammography is unrevealing, breast senting above the diaphragm should be evaluated and managed MRI should be performed. If the MRI scan is negative, the as metastatic lung cancer. CUP that is predominantly below the patient is still assumed to have a presumptive stage II breast diaphragm should be managed as gastrointestinal cancer. cancer. Given the inability to identify the primary, a mastec- Chronic medical comorbidities and patient performance tomy or whole breast radiation therapy is recommended. These status greatly influence the range of treatment options. As patients should all receive adjuvant treatment consistent with with other solid tumors, patients with several comorbidities a stage II breast cancer diagnosis. Patients with isolated or and poor performance status are far less likely to benefit from dominant cervical lymphadenopathy should undergo full aggressive chemotherapy and are far more likely to experience endoscopic examination of the upper aerodigestive tract to serious or life-threatening toxicity. Palliative and hospice care evaluate for a head and neck primary. Even if a primary is not should be considered in such patients. identified, treatment along a head and neck paradigm with chemotherapy and radiation therapy is often appropriate. In particular, patients with high cervical lymphadenopathy with e Therapy for cancer of unknown primary that does not squamous cell cancer occasionally achieve cure. Supraclavicular fall into one of the favorable subgroups should be man-

bility with a platinum-based chemotherapy regimen. nopathy and cancer of unknown primary should be Patients with poorly differentiated neuroendocrine treated along a head and neck cancer paradigm with tumors also warrant careful consideration. These tumors fre- chemotherapy and radiation therapy. quently both metastasize like small cell lung cancers and respond similarly to platinum-based chemotherapy. Nonfavorable Subgroups of Isolated Regional Lymphadenopathy Cancer of Unknown Primary Site Women found to have adenocarcinoma in isolated axillary Therapy for CUP that does not fall into one of the favorable lymphadenopathy have a more favorable CUP prognosis. These subgroups is empirically directed with chemotherapy and radi- patients should be presumptively considered to have locore- ation therapy based on the pattern of presentation. CUP pre- gional breast cancer. If mammography is unrevealing, breast senting above the diaphragm should be evaluated and managed MRI should be performed. If the MRI scan is negative, the as metastatic lung cancer. CUP that is predominantly below the patient is still assumed to have a presumptive stage II breast diaphragm should be managed as gastrointestinal cancer. cancer. Given the inability to identify the primary, a mastec- Chronic medical comorbidities and patient performance tomy or whole breast radiation therapy is recommended. These status greatly influence the range of treatment options. As patients should all receive adjuvant treatment consistent with with other solid tumors, patients with several comorbidities a stage II breast cancer diagnosis. Patients with isolated or and poor performance status are far less likely to benefit from dominant cervical lymphadenopathy should undergo full aggressive chemotherapy and are far more likely to experience endoscopic examination of the upper aerodigestive tract to serious or life-threatening toxicity. Palliative and hospice care evaluate for a head and neck primary. Even if a primary is not should be considered in such patients. identified, treatment along a head and neck paradigm with chemotherapy and radiation therapy is often appropriate. In particular, patients with high cervical lymphadenopathy with e Therapy for cancer of unknown primary that does not squamous cell cancer occasionally achieve cure. Supraclavicular fall into one of the favorable subgroups should be man- lymphadenopathy or adenocarcinoma makes a head and neck aged based on pattern of presentation; cancer present-

bility with a platinum-based chemotherapy regimen. nopathy and cancer of unknown primary should be Patients with poorly differentiated neuroendocrine treated along a head and neck cancer paradigm with tumors also warrant careful consideration. These tumors fre- chemotherapy and radiation therapy. quently both metastasize like small cell lung cancers and respond similarly to platinum-based chemotherapy. Nonfavorable Subgroups of Isolated Regional Lymphadenopathy Cancer of Unknown Primary Site Women found to have adenocarcinoma in isolated axillary Therapy for CUP that does not fall into one of the favorable lymphadenopathy have a more favorable CUP prognosis. These subgroups is empirically directed with chemotherapy and radi- patients should be presumptively considered to have locore- ation therapy based on the pattern of presentation. CUP pre- gional breast cancer. If mammography is unrevealing, breast senting above the diaphragm should be evaluated and managed MRI should be performed. If the MRI scan is negative, the as metastatic lung cancer. CUP that is predominantly below the patient is still assumed to have a presumptive stage II breast diaphragm should be managed as gastrointestinal cancer. cancer. Given the inability to identify the primary, a mastec- Chronic medical comorbidities and patient performance tomy or whole breast radiation therapy is recommended. These status greatly influence the range of treatment options. As patients should all receive adjuvant treatment consistent with with other solid tumors, patients with several comorbidities a stage II breast cancer diagnosis. Patients with isolated or and poor performance status are far less likely to benefit from dominant cervical lymphadenopathy should undergo full aggressive chemotherapy and are far more likely to experience endoscopic examination of the upper aerodigestive tract to serious or life-threatening toxicity. Palliative and hospice care evaluate for a head and neck primary. Even if a primary is not should be considered in such patients. identified, treatment along a head and neck paradigm with chemotherapy and radiation therapy is often appropriate. In particular, patients with high cervical lymphadenopathy with e Therapy for cancer of unknown primary that does not squamous cell cancer occasionally achieve cure. Supraclavicular fall into one of the favorable subgroups should be man- lymphadenopathy or adenocarcinoma makes a head and neck aged based on pattern of presentation; cancer present- primary far less likely, and therapy is less efficacious. ing above the diaphragm should be treated as metastatic

squamous cell cancer occasionally achieve cure. Supraclavicular fall into one of the favorable subgroups should be man- lymphadenopathy or adenocarcinoma makes a head and neck aged based on pattern of presentation; cancer present- primary far less likely, and therapy is less efficacious. ing above the diaphragm should be treated as metastatic Isolated inguinal lymphadenopathy should prompt anos- lung cancer, and cancer presenting below the dia- copy and careful examination of the perineal and genital phragm should be treated as gastrointestinal cancer. regions. Even in the absence of a defined primary tumor, e Palliative or hospice care is appropriate for patients with definitive resection or irradiation to inguinal or other isolated an unfavorable subtype of cancer of unknown primary solitary or regional lymph nodes may provide long-term site who have comorbidities and poor performance status. tumor control and cures in rare circumstances. Peritoneal Carcinomatosis in Women Women who have adenocarcinoma with abdominal carcino- Melanoma matosis and ascites should be presumptively treated for ovar- Melanoma has been steadily increasing in incidence world- ian cancer, including initial cytoreductive surgery and ovarian wide, with risk related to sun exposure. Most melanomas cancer chemotherapy regimens. begin in and present with cutaneous disease, but they can also 40

Melanoma begin in mucosal and ocular sites. About half of cutaneous and on the use of immune checkpoint inhibitors of pro- melanomas arise in preexisting nevi, but many begin in appar- grammed cell death transmembrane proteins. ently normal skin. Melanoma can also present in nodal or Approximately one half of melanomas harbor a BRAF visceral sites without a known cutaneous or mucosal primary. gene mutation (most commonly V600E), and another 20% Only 10% of patients with melanoma have a familial history, have an MEK or NRAS mutation; all of these mutations and mutations in certain genes, such as CDKN2A, have been activate the mitogen-activated protein kinase pathway. identified in some families. Ocular melanoma is the most Melanomas with BRAF V600E or V600K may respond to oral common cancer of the eye, and these melanomas have a dis- therapy with the available BRAF/MEK inhibitor combina- tinct biology and behavior. tions (dabrafenib/trametinib; vemurafenib/cobimetinib; Advances in systemic therapy during the past decade have encorafenib/binimetinib). Combining BRAF inhibitors with resulted in significant improvements in survival for patients MEK inhibitors improves the rate and duration of response with metastatic melanoma. These advances include the use of over BRAF inhibitors alone. molecular therapy targeted at specific gene mutations and In addition to the efficacy of BRAF inhibitors, the use of immunotherapy, including the use of immune checkpoint immune checkpoint inhibitors has revolutionized the therapy inhibitors. and prognosis of patients with metastatic melanoma. Cellular immunity is based on T cells recognizing peptide fragments

begin in mucosal and ocular sites. About half of cutaneous and on the use of immune checkpoint inhibitors of pro- melanomas arise in preexisting nevi, but many begin in appar- grammed cell death transmembrane proteins. ently normal skin. Melanoma can also present in nodal or Approximately one half of melanomas harbor a BRAF visceral sites without a known cutaneous or mucosal primary. gene mutation (most commonly V600E), and another 20% Only 10% of patients with melanoma have a familial history, have an MEK or NRAS mutation; all of these mutations and mutations in certain genes, such as CDKN2A, have been activate the mitogen-activated protein kinase pathway. identified in some families. Ocular melanoma is the most Melanomas with BRAF V600E or V600K may respond to oral common cancer of the eye, and these melanomas have a dis- therapy with the available BRAF/MEK inhibitor combina- tinct biology and behavior. tions (dabrafenib/trametinib; vemurafenib/cobimetinib; Advances in systemic therapy during the past decade have encorafenib/binimetinib). Combining BRAF inhibitors with resulted in significant improvements in survival for patients MEK inhibitors improves the rate and duration of response with metastatic melanoma. These advances include the use of over BRAF inhibitors alone. molecular therapy targeted at specific gene mutations and In addition to the efficacy of BRAF inhibitors, the use of immunotherapy, including the use of immune checkpoint immune checkpoint inhibitors has revolutionized the therapy inhibitors. and prognosis of patients with metastatic melanoma. Cellular immunity is based on T cells recognizing peptide fragments Treatment of Melanoma expressed on the surface of antigen-presenting cells when bound to histocompatibility complex molecules. Cytotoxic Melanoma has the potential to behave quite aggressively, but it T-lymphocyte-associated protein 4 is a potent down-regulator is a highly curable disease when detected and treated early of this process. The antibody against cytotoxic T-lymphocyte- with a wide local excision. For localized melanomas, prognosis associated protein 4, ipilimumab, can result in dramatic tumor is related to the depth of invasion by Breslow depth. A high response, albeit in a small percentage of patients. Tumor mitotic rate, lymphovascular invasion, and the presence of response is independent of BRAF status. ulceration are poor prognostic signs. Surgical resection mar- Nivolumab and pembrolizumab are both anti-pro- gins for melanomas do not have to be excessive: 1-cm margins grammed cell death protein 1 antibodies that can result in are acceptable for lesions that are less than 1 mm in thickness. significant melanoma response rates with sometimes durable Patients with melanomas between 1 mm and 2 mm in thick- response and dramatic survival improvement. Ipilimumab ness should be resected with a 2-cm margin provided that a alone has a relatively low response rate (20%) and is associated skin graft is not required for closure. A 1- to 2-cm margin may with considerable toxicity, with various immune-related be selected if wound closure is not feasible without creating a adverse effects that can include rash, colitis, hepatitis, pneu- cosmetic deformity or impairing function. Patients with lesions that are greater than 2 mm in thickness should be monitis, myocarditis, and endocrine insufficiency syndromes. Similar adverse effects can occur with nivolumab and pem- resected with 2-cm margins. Patients with early-stage disease can be assessed clinically and do not need radiographic staging brolizumab but are less frequent, and these antibodies are

Treatment of Melanoma expressed on the surface of antigen-presenting cells when bound to histocompatibility complex molecules. Cytotoxic Melanoma has the potential to behave quite aggressively, but it T-lymphocyte-associated protein 4 is a potent down-regulator is a highly curable disease when detected and treated early of this process. The antibody against cytotoxic T-lymphocyte- with a wide local excision. For localized melanomas, prognosis associated protein 4, ipilimumab, can result in dramatic tumor is related to the depth of invasion by Breslow depth. A high response, albeit in a small percentage of patients. Tumor mitotic rate, lymphovascular invasion, and the presence of response is independent of BRAF status. ulceration are poor prognostic signs. Surgical resection mar- Nivolumab and pembrolizumab are both anti-pro- gins for melanomas do not have to be excessive: 1-cm margins grammed cell death protein 1 antibodies that can result in are acceptable for lesions that are less than 1 mm in thickness. significant melanoma response rates with sometimes durable Patients with melanomas between 1 mm and 2 mm in thick- response and dramatic survival improvement. Ipilimumab ness should be resected with a 2-cm margin provided that a alone has a relatively low response rate (20%) and is associated skin graft is not required for closure. A 1- to 2-cm margin may with considerable toxicity, with various immune-related be selected if wound closure is not feasible without creating a adverse effects that can include rash, colitis, hepatitis, pneu- cosmetic deformity or impairing function. Patients with lesions that are greater than 2 mm in thickness should be monitis, myocarditis, and endocrine insufficiency syndromes. Similar adverse effects can occur with nivolumab and pem- resected with 2-cm margins. Patients with early-stage disease can be assessed clinically and do not need radiographic staging brolizumab but are less frequent, and these antibodies are (for example, CT and PET). associated with a higher response rate (30%-40%). Combining

Treatment of Melanoma expressed on the surface of antigen-presenting cells when bound to histocompatibility complex molecules. Cytotoxic Melanoma has the potential to behave quite aggressively, but it T-lymphocyte-associated protein 4 is a potent down-regulator is a highly curable disease when detected and treated early of this process. The antibody against cytotoxic T-lymphocyte- with a wide local excision. For localized melanomas, prognosis associated protein 4, ipilimumab, can result in dramatic tumor is related to the depth of invasion by Breslow depth. A high response, albeit in a small percentage of patients. Tumor mitotic rate, lymphovascular invasion, and the presence of response is independent of BRAF status. ulceration are poor prognostic signs. Surgical resection mar- Nivolumab and pembrolizumab are both anti-pro- gins for melanomas do not have to be excessive: 1-cm margins grammed cell death protein 1 antibodies that can result in are acceptable for lesions that are less than 1 mm in thickness. significant melanoma response rates with sometimes durable Patients with melanomas between 1 mm and 2 mm in thick- response and dramatic survival improvement. Ipilimumab ness should be resected with a 2-cm margin provided that a alone has a relatively low response rate (20%) and is associated skin graft is not required for closure. A 1- to 2-cm margin may with considerable toxicity, with various immune-related be selected if wound closure is not feasible without creating a adverse effects that can include rash, colitis, hepatitis, pneu- cosmetic deformity or impairing function. Patients with lesions that are greater than 2 mm in thickness should be monitis, myocarditis, and endocrine insufficiency syndromes. Similar adverse effects can occur with nivolumab and pem- resected with 2-cm margins. Patients with early-stage disease can be assessed clinically and do not need radiographic staging brolizumab but are less frequent, and these antibodies are (for example, CT and PET). associated with a higher response rate (30%-40%). Combining As the depth of invasion increases, the risk of nodal and ipilimumab with nivolumab improves response rates com-

Treatment of Melanoma expressed on the surface of antigen-presenting cells when bound to histocompatibility complex molecules. Cytotoxic Melanoma has the potential to behave quite aggressively, but it T-lymphocyte-associated protein 4 is a potent down-regulator is a highly curable disease when detected and treated early of this process. The antibody against cytotoxic T-lymphocyte- with a wide local excision. For localized melanomas, prognosis associated protein 4, ipilimumab, can result in dramatic tumor is related to the depth of invasion by Breslow depth. A high response, albeit in a small percentage of patients. Tumor mitotic rate, lymphovascular invasion, and the presence of response is independent of BRAF status. ulceration are poor prognostic signs. Surgical resection mar- Nivolumab and pembrolizumab are both anti-pro- gins for melanomas do not have to be excessive: 1-cm margins grammed cell death protein 1 antibodies that can result in are acceptable for lesions that are less than 1 mm in thickness. significant melanoma response rates with sometimes durable Patients with melanomas between 1 mm and 2 mm in thick- response and dramatic survival improvement. Ipilimumab ness should be resected with a 2-cm margin provided that a alone has a relatively low response rate (20%) and is associated skin graft is not required for closure. A 1- to 2-cm margin may with considerable toxicity, with various immune-related be selected if wound closure is not feasible without creating a adverse effects that can include rash, colitis, hepatitis, pneu- cosmetic deformity or impairing function. Patients with lesions that are greater than 2 mm in thickness should be monitis, myocarditis, and endocrine insufficiency syndromes. Similar adverse effects can occur with nivolumab and pem- resected with 2-cm margins. Patients with early-stage disease can be assessed clinically and do not need radiographic staging brolizumab but are less frequent, and these antibodies are (for example, CT and PET). associated with a higher response rate (30%-40%). Combining As the depth of invasion increases, the risk of nodal and ipilimumab with nivolumab improves response rates com- ultimately distant metastasis increases. Nodal metastases are pared with either ipilimumab or nivolumab alone but results

(for example, CT and PET). associated with a higher response rate (30%-40%). Combining As the depth of invasion increases, the risk of nodal and ipilimumab with nivolumab improves response rates com- ultimately distant metastasis increases. Nodal metastases are pared with either ipilimumab or nivolumab alone but results uncommon in thin melanomas, and nodes are typically not in significantly more immune-related toxicities. This immu- assessed if the melanoma has a Breslow depth of less than notherapy combination is effective whether or not the patient 0.8 mm and is without uiceration. Assessing for lymph node has BRAF-mutated melanoma. Durable benefit in terms of metastasis with lymphatic mapping and sentinel lymph node survival is possible in a substantial fraction of patients with biopsy is often recommended for intermediate and thicker metastatic melanoma treated with checkpoint inhibitors. melanomas. Even if the sentinel node is positive, a completion In addition to their use in metastatic disease, immune

metastasis with lymphatic mapping and sentinel lymph node survival is possible in a substantial fraction of patients with biopsy is often recommended for intermediate and thicker metastatic melanoma treated with checkpoint inhibitors. melanomas. Even if the sentinel node is positive, a completion In addition to their use in metastatic disease, immune lymph node dissection is no longer routinely performed, as checkpoint inhibitors and BRAF/MEK inhibitors (in patients there is no improvement in survival. Patients with positive with the BRAF mutation) have shown survival benefits in the sentinel lymph node biopsies (stage III) may be followed by adjuvant setting in patients with resected stage III (nodal) clinical examination and serial ultrasounds of the nodal basin disease. involved to detect nodal recurrences. These patients are also Although prophylactic lymphadenectomies or comple- eligible for adjuvant systemic treatment. tion node dissections for those with positive sentinel nodes Systemic therapies for metastatic disease have advanced have not definitively shown an overall survival benefit, node significantly over the past decade. Conventional cytotoxic dissections can be curative in 20% to 50% of patients who pre- chemotherapy has little role in current management. Although sent with or develop regional nodal disease. For some patients interferon and interleukin-2 have some activity in the adju- with distant metastatic disease, surgery may still play a signifi- vant and metastatic setting, respectively, the current focus is cant role. Melanoma can present with solitary or oligometa- on targeted therapy for patients with specific gene mutations static disease amenable to resection that is curable in some 41