InternalMed_Harrison

InternalMed_Harrison. Not every patient requires a SLNB. Patients whose melanomas are ≤0.75 mm thick have <5% risk of sentinel lymph node (SLN) disease and do not require a SLNB. Patients with tumors >1 mm thick generally undergo SLNB. For melanomas 0.76–1.0 mm thick, SLNB may be considered for lesions with high-risk features such as ulceration, high mitotic index, or lymphovascular invasion, but wide excision alone is the usual definitive therapy. Most other patients with clinically negative lymph nodes should undergo a SLNB. Patients whose SLNB is negative are spared a complete node dissection and its attendant morbidities, and can simply be followed or, based on the features of the primary melanoma, be considered for adjuvant therapy or a clinical trial. The current standard of care for all patients with a positive SLN is to perform a complete lymphadenectomy; however, ongoing clinical studies will determine whether patients with small-volume SLN metastases can be managed safely without additional


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InternalMed_Harrison. a positive SLN is to perform a complete lymphadenectomy; however, ongoing clinical studies will determine whether patients with small-volume SLN metastases can be managed safely without additional surgery. Patients with microscopically positive lymph nodes should be considered for adjuvant therapy with interferon or enrollment in a clinical trial.


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InternalMed_Harrison. Melanomas may recur at the edge of the scar or graft, as satellite metastases, which are separate from but within 2 cm of the scar; as in-transit metastases, which are recurrences >2 cm from the primary lesion but not beyond the regional nodal basin; or, most commonly, as metastasis to a draining lymph node basin. Each of these presentations is managed surgically, following which there 498 is the possibility of long-term disease-free survival. Isolated limb perfusion or infusion with melphalan and hyperthermia are options for patients with extensive cutaneous regional recurrences in an extremity. High complete response rates have been reported and significant palliation of symptoms can be achieved, but there is no change in overall survival. Patients rendered free of disease after surgery may be at high risk for a local or distant recurrence and should be considered for adjuvant therapy. Radiotherapy can reduce the risk of local recurrence after lymphadenectomy, but does not affect


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InternalMed_Harrison. may be at high risk for a local or distant recurrence and should be considered for adjuvant therapy. Radiotherapy can reduce the risk of local recurrence after lymphadenectomy, but does not affect overall survival. Patients with large nodes (>3–4 cm), four or more involved lymph nodes, or extranodal spread on microscopic examination should be considered for radiation. Systemic adjuvant therapy is indicated primarily for patients with stage III disease, but high-risk, node-negative patients (>4 mm thick or ulcerated lesions) and patients with completely resected stage IV disease also may benefit. Either interferon α2b (IFN-α2b), which is given at 20 million units/m2 IV 5 days a week for 4 weeks followed by 10 million units/m2 SC three times a week for 11 months (1 year total), or subcutaneous peginterferon α2b (6 μg/kg per week for 8 weeks followed by 3 μg/kg per week for a total of 5 years) is acceptable adjuvant therapy. Treatment is accompanied by significant toxicity, including a


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InternalMed_Harrison. peginterferon α2b (6 μg/kg per week for 8 weeks followed by 3 μg/kg per week for a total of 5 years) is acceptable adjuvant therapy. Treatment is accompanied by significant toxicity, including a flu-like illness, decline in performance status, and the development of depression. Side effects can be managed in most patients by appropriate treatment of symptoms, dose reduction, and treatment interruption. Sometimes IFN must be permanently discontinued before all of the planned doses are administered because of unacceptable toxicity. The high-dose regimen is significantly more toxic than peginterferon, but the latter requires 4 additional years of therapy. Adjuvant treatment with IFN improves disease-free survival, but its impact on overall survival remains controversial. Enrollment in a clinical trial is appropriate for these patients, many of whom will otherwise be observed without treatment either because they are poor candidates for IFN or because the patient (or their oncologist)


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InternalMed_Harrison. trial is appropriate for these patients, many of whom will otherwise be observed without treatment either because they are poor candidates for IFN or because the patient (or their oncologist) does not believe the beneficial effects of IFN outweigh the toxicity. The recently approved immunotherapy and targeted agents are being evaluated in the adjuvant setting.


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InternalMed_Harrison. At diagnosis, most patients with melanoma will have early-stage disease; however, some will present with metastases, and others will develop metastases after initial therapy. Patients with a history of melanoma who develop signs or symptoms suggesting recurrent disease should undergo restaging that includes physical examination, CBC, complete metabolic panel, LDH, and appropriate diagnostic imaging that may include a magnetic resonance image (MRI) of the brain and total-body PET/CT or CT scans of the chest, abdomen, and pelvis. Distant metastases (stage IV), which may involve any organ, commonly involve the skin and lymph nodes as well as viscera, bone, or the brain. Historically, metastatic melanoma was considered incurable; median survival ranges from 6 to 15 months, depending on the organs involved. The prognosis is better for patients with skin and subcutaneous metastases (M1a) than for lung (M1b) and worst for those with metastases to liver, bone, and brain (M1c). An elevated


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InternalMed_Harrison. organs involved. The prognosis is better for patients with skin and subcutaneous metastases (M1a) than for lung (M1b) and worst for those with metastases to liver, bone, and brain (M1c). An elevated serum LDH is a poor prognostic factor and places the patient in stage M1c regardless of the site of the metastases (Table 105-3). Although historical data suggest that the 15-year survival of patients with M1a, M1b, and M1c disease is less than 10%, there is optimism that newer therapies will increase the number of melanoma patients with long-term survival, especially patients with M1a and M1b disease.


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InternalMed_Harrison. The treatment for patients with stage IV melanoma has changed dramatically in the past 2 years. Two new classes of therapeutic agents for melanoma have been approved by the U.S. Food and Drug Administration (FDA). The immune T cell checkpoint inhibitor, ipilimumab, and three new oral agents that target the MAP kinase pathway: the BRAF inhibitors, vemurafenib and dabrafenib, and the Surgery: Metastasectomy for small number of lesions Immunotherapy: Anti-CTLA-4: ipilimumab Anti-PD-1: nivolumab, lambrolizumab Molecular targeted therapy: BRAF inhibitor: vemurafenib, dabrafenib MEK inhibitor: trametinib Chemotherapy: dacarbazine, temozolomide, paclitaxel, albumin-bound paclitaxel (Abraxane), carboplatin MEK inhibitor, trametinib, are now available, so patients with stage IV disease now have multiple therapeutic options (Table 105-4).


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InternalMed_Harrison. MEK inhibitor, trametinib, are now available, so patients with stage IV disease now have multiple therapeutic options (Table 105-4). Patients with oligometastatic disease should be referred to a surgical oncologist for consideration of metastasectomy, because they may experience long-term disease-free survival after surgery. Patients with solitary metastases are the best candidates, but surgery increasingly is being used even for patients with metastases at more than one site. Patients rendered free of disease can be considered for IFN therapy or a clinical trial because their risk of developing additional metastases is very high. Surgery can also be used as an adjunct to immunotherapy when only a few of many metastatic lesions prove resistant to systemic therapy.


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InternalMed_Harrison. The cytokine interleukin 2 (IL-2 or aldesleukin) has been approved to treat patients with melanoma since 1995. IL-2 is used to treat stage IV patients who have a good performance status and is administered at centers with experience managing IL-2-related toxicity. Patients require hospitalization in an intensive care unit– like setting to receive high-dose IL-2 600,000 or 720,000 IU every 8 h for up to 14 doses (one cycle). Patients continue treatment until they achieve maximal benefit, usually 4–6 cycles. Treatment is associated with long-term disease-free survival (probable cures) in 5% of treated patients. The mechanism by which IL-2 causes tumor regression has not been identified, but it is presumed that IL-2 induces melanoma-specific T cells that eliminate tumor cells by recognizing specific antigens. Rosenberg and his colleagues at the National Cancer Institute (NCI) have combined adoptive transfer of in vitro–expanded tumor-infiltrating lymphocytes with high-dose IL-2 in


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InternalMed_Harrison. specific antigens. Rosenberg and his colleagues at the National Cancer Institute (NCI) have combined adoptive transfer of in vitro–expanded tumor-infiltrating lymphocytes with high-dose IL-2 in patients who were preconditioned with nonmyeloablative chemotherapy (sometimes combined with total-body irradiation). Tumor regression was observed in more than 50% of patients with IL-2-refractory metastatic melanoma.


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InternalMed_Harrison. Immune checkpoint blockade with monoclonal antibodies to the inhibitory immune receptors CTLA-4 and PD-1 has shown promising clinical efficacy. An array of inhibitory receptors are upregulated during an immune response. An absolute requirement to ensure proper regulation of a normal immune response, the continued expression of inhibitory receptors during chronic infection (hepatitis, HIV) and in cancer patients denotes exhausted T cells with limited potential for proliferation, cytokine production, or cytotoxicity (Fig. 105-3). Checkpoint blockade with a monoclonal antibody results in improved T cell function with eradication of tumor cells in preclinical animal models. Ipilimumab, a fully human IgG antibody that binds CTLA-4 and blocks inhibitory signals, was the first treatment of any kind to improve survival in patients with metastatic melanoma. A full course of therapy is four IV outpatient infusions of ipilimumab 3 mg/kg every 3 weeks. Although response rates were low (∼10%) in


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InternalMed_Harrison. kind to improve survival in patients with metastatic melanoma. A full course of therapy is four IV outpatient infusions of ipilimumab 3 mg/kg every 3 weeks. Although response rates were low (∼10%) in randomized clinical trials, survival of both previously treated and untreated patients was improved, and ipilimumab was approved by the FDA in March 2011.


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InternalMed_Harrison. FIGURE 105-3 Inhibitory regulatory pathways that influence T cell function, memory, and lifespan after engagement of the T cell receptor by antigen presented by antigen-presenting cells in the context of MHC I/II. CTLA-4 and PD-1 are part of the CD28 family and have inhibitory effects that can be mitigated by antagonistic antibodies to the receptors or ligand, resulting in enhanced T cell function and antitumor effects. CTLA-4, cytotoxic T lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PD-L2, programmed death ligand-2; TCR, T cell receptor.


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InternalMed_Harrison. In addition to its antitumor effects, ipilimumab’s interference with normal regulatory mechanisms produced a novel spectrum of side effects that resembled autoimmunity. The most common immune-related adverse events were skin rash and diarrhea (sometimes severe, life-threatening colitis), but toxicity could involve most any organ (e.g., hypophysitis, hepatitis, nephritis, pneumonitis, myocarditis, neuritis). Vigilance and early treatment with steroids that do not appear to interfere with the antitumor effects are required to manage these patients safely. Widespread use of ipilimumab has not been completely embraced by the oncology community because of the low objective response rate, significant toxicity (including death), and high cost (drug cost alone for a course of therapy is approximately $120,000 in 2013). Despite these reservations, ipilimumab’s overall survival benefit (17% of patients alive at 7 years) indicates that treatment should be strongly considered for all eligible


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InternalMed_Harrison. $120,000 in 2013). Despite these reservations, ipilimumab’s overall survival benefit (17% of patients alive at 7 years) indicates that treatment should be strongly considered for all eligible patients.


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InternalMed_Harrison. Chronic T cell activation also leads to induction of PD-1 on the surface of T cells. Expression of one of its ligands, PD-L1, on tumor cells can protect them from immune destruction (Fig. 105-3). Early trials attempting to block the PD-1:PD-L1 axis by IV administration of anti-PD-1 or anti-PD-L1 have shown substantial clinical activity in patients with advanced melanoma (and lung cancer) with significantly less toxicity than ipilimumab. Anti-PD-1 therapy looks promising, but is not currently available except by participation in clinical trials. Intriguingly, preliminary results from a clinical trial indicate that blocking both inhibitory pathways with ipilimumab and anti-PD-1 leads to superior antitumor activity than treatment with either agent alone. The main benefit to patients from immune-based therapy (IL-2, ipilimumab, and anti-PD-1) is the durability of the responses achieved. Although the percentage of patients whose tumors regress following immunotherapy is lower than the


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InternalMed_Harrison. immune-based therapy (IL-2, ipilimumab, and anti-PD-1) is the durability of the responses achieved. Although the percentage of patients whose tumors regress following immunotherapy is lower than the response rate after targeted therapy (see below), the durability of immunotherapy-induced responses (>10 years in some cases) appears to be superior to responses after targeted therapy and suggests that many of these patients have been cured.


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InternalMed_Harrison. RAF and MEK inhibitors of the MAP kinase pathway are a new and exciting approach for patients whose melanomas harbor a BRAF mutation. The high frequency of oncogenic mutations in the RASRAF-MEK-ERK pathway, which delivers proliferation and survival signals from the cell surface to the cytoplasm and nucleus, has led to the development of inhibitors to BRAF and MEK. Two BRAF inhibitors, vemurafenib and dabrafenib, have been approved for the treatment of stage IV patients whose melanomas harbor a mutation at position 600 in the gene for BRAF. The oral BRAF inhibitors cause 499 tumor regression in approximately 50% of patients, and overall survival is improved compared to treatment with chemotherapy. Treatment is accompanied by manageable side effects that differ from those following immunotherapy or chemotherapy. A class-specific complication of BRAF inhibition is the development of numerous skin lesions, some of which are well-differentiated squamous cell skin cancers (seen in up to a


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InternalMed_Harrison. or chemotherapy. A class-specific complication of BRAF inhibition is the development of numerous skin lesions, some of which are well-differentiated squamous cell skin cancers (seen in up to a quarter of patients). Patients should be co-managed with a dermatologist as these skin cancers will need excision. Metastases have not been reported, and treatment can be continued safely following simple excision. Long-term results following treatment with BRAF inhibitors are not yet available, but the current concern is that over time the vast majority of patients will relapse and eventually die from drug-resistant disease. There are a number of mechanisms by which resistance develops, usually via maintenance of MAP kinase signaling; however, mutations in the BRAF gene that affect binding of the inhibitor are not among them. The MEK inhibitor trametinib has activity as a single agent, but appears to be less effective than either of the BRAF inhibitors. Combined therapy with the BRAF inhibitor


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InternalMed_Harrison. are not among them. The MEK inhibitor trametinib has activity as a single agent, but appears to be less effective than either of the BRAF inhibitors. Combined therapy with the BRAF inhibitor and MEK inhibitor showed improved progression-free survival compared to BRAF inhibitor therapy alone; and, interestingly, the neoplastic skin lesions that were so troubling with BRAF inhibition alone did not occur. Although the durability of responses following combined therapy remains to be determined, its use in metastatic melanoma is FDA approved. Activating mutations in the c-kit receptor tyrosine kinase are found in a minority of cutaneous melanomas with chronic sun damage, but more commonly in mucosal and acral lentiginous subtypes. Overall, the number of patients with c-kit mutations is exceedingly small, but when present, they are largely identical to mutations found in gastrointestinal stromal tumors (GISTs); melanomas with activating c-kit mutations can have clinically meaningful


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InternalMed_Harrison. exceedingly small, but when present, they are largely identical to mutations found in gastrointestinal stromal tumors (GISTs); melanomas with activating c-kit mutations can have clinically meaningful responses to imatinib.


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InternalMed_Harrison. No chemotherapy regimen has ever been shown to improve survival in metastatic melanoma, and the advances in immunotherapy and targeted therapy have relegated chemotherapy to the palliation of symptoms. Drugs with antitumor activity include dacarbazine (DTIC) or its orally administered analog temozolomide (TMZ), cisplatin and carboplatin, the taxanes (paclitaxel alone or albumin-bound and docetaxel), and carmustine (BCNU), which have reported response rates of 12–20%.


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InternalMed_Harrison. Upon diagnosis of stage IV disease, whether by biopsy or diagnostic imaging, a sample of the patient’s tumor needs to undergo molecular testing to determine whether a druggable mutation (e.g., BRAF) is present. Analysis of a metastatic lesion is preferred, but any biopsy will suffice because there is little discordance between primary and metastatic lesions. Treatment algorithms start with the tumor’s BRAF status. For BRAF “wild-type” tumors, immunotherapy is recommended. For patients whose tumors harbor a BRAF mutation, initial therapy with either a BRAF inhibitor or immunotherapy is acceptable. Molecular testing may also include N-RAS and c-kit in appropriate tumors.


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InternalMed_Harrison. The majority of patients still die from their melanoma, despite improvements in therapy. Therefore, enrollment in a clinical trial is always an important consideration, even for previously untreated patients. Most patients with stage IV disease will eventually progress despite advances in therapy, and many, because of disease burden, poor performance status, or concomitant illness, will be unsuitable for therapy. Therefore, a major focus of care should be the timely integration of palliative care and hospice. Skin examination and surveillance at least once a year are recommended for all patients with melanoma. The National Comprehensive Cancer Network (NCCN) guidelines for patients with stage IA–IIA


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InternalMed_Harrison. Cancer of the Skin 500 melanoma recommend a comprehensive history and physical examination every 6–12 months for 5 years, and then annually as clinically indicated. Particular attention should be paid to the draining lymph nodes in stage I–III patients as resection of lymph node recurrences may still be curative. A CBC, LDH, and chest x-ray are recommended at the physician’s discretion, but are ineffective tools for the detection of occult metastases. Routine imaging for metastatic disease is not recommended at this time. For patients with higher stage disease (IIB–IV), imaging (chest x-ray, CT, and/or PET/CT scans) every 4–12 months can be considered. Because no discernible survival benefit has been demonstrated for routine surveillance, it is reasonable to perform scans only if clinically indicated.


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InternalMed_Harrison. Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States. Although tumor registries do not routinely gather data on the incidence of basal cell and squamous cell skin cancers, it is estimated that the annual incidence is 1.5–2 million cases in the United States. Basal cell carcinomas (BCCs) account for 70–80% of NMSCs. Squamous cell carcinomas (SCCs), which comprise ∼20% of NMSCs, are more significant because of their ability to metastasize and account for 2400 NMSC deaths annually. There has also been an increase in the incidence of nonepithelial skin cancer, especially Merkel cell carcinoma, with nearly 5000 new diagnoses and 3000 deaths annually.


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InternalMed_Harrison. The most significant cause of BCC and SCC is UV exposure, whether through direct exposure to sunlight or by artificial UV light sources (tanning beds). Both UVA and UVB can induce DNA damage through free radical formation (UVA) or induction of pyrimidine dimers (UVB). The sun emits energy across the UV spectrum, whereas tanning bed equipment typically emits 97% UVA and 3% UVB. DNA damage induced by UV irradiation can result in cell death or repair of damaged DNA by nucleotide excision repair (NER). Inherited disorders of NER, such as xeroderma pigmentosum, are associated with a greatly increased incidence of skin cancer and help to establish the link between UV-induced DNA damage, inadequate DNA repair, and skin cancer. The genes damaged most commonly by UV in BCC involve the Hedgehog pathway (Hh). In SCC, p53 and N-RAS are commonly affected. There is a dose-response relationship between tanning bed use and the incidence of skin cancer. As few as four tanning bed visits per year


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InternalMed_Harrison. pathway (Hh). In SCC, p53 and N-RAS are commonly affected. There is a dose-response relationship between tanning bed use and the incidence of skin cancer. As few as four tanning bed visits per year confers a 15% increase in BCC and an 11% increase in SCC and melanoma. Tanning bed use as a teenager or young adult confers greater risk than comparable exposure in older individuals. Other associations include blond or red hair, blue or green eyes, a tendency to sunburn easily, and an outdoor occupation. The incidence of NMSC increases with decreasing latitude. Most tumors develop on sun-exposed areas of the head and neck. The risk of lip or oral SCC is increased with cigarette smoking. Human papillomaviruses and UV radiation may act as cocarcinogens.


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InternalMed_Harrison. Solid organ transplant recipients on chronic immunosuppression have a 65-fold increase in SCC and a 10-fold increase in BCC. The frequency of skin cancer is proportional to the level and duration of immunosuppression and the extent of sun exposure before and after transplantation. SCCs in this population also demonstrate higher rates of local recurrence, metastasis, and mortality. There is increasing use of tumor necrosis factor (TNF) antagonists to treat inflammatory bowel disease and autoimmune disorders such as rheumatoid and psoriatic arthritis. TNF antagonists may also confer an increased risk of NMSC. BRAF-targeted therapy can induce SCCs including keratoacanthoma-type SCCs in keratinocytes, with preexisting H-RAS overexpression present in approximately 60% of patients.


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InternalMed_Harrison. Other risk factors include HIV infection, ionizing radiation, thermal burn scars, and chronic ulcerations. Albinism, xeroderma pigmentosum, Muir-Torre syndrome, Rombo’s syndrome, BazexDupré-Christol syndrome, dyskeratosis congenita, and basal cell nevus syndrome (Gorlin syndrome) also increase the incidence of NMSC. Mutations in Hh genes encoding the tumor-suppressor patched


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InternalMed_Harrison. FIGURE 105-4 Influence of vismodegib on the hedgehog (Hh) pathway. Normally, one of three Hh ligands (sonic [SHh], Indian, or desert) binds to patched homolog 1 (PTCH1), causing its degradation and release of smoothened homolog (SMO). The downstream events of SMO release are the activation of Gli1, Gli2, and Gli3 through the transcriptional regulator known as SUFU. Gli1 and Gli2 translocate to the nucleus and promote gene transcription. Vismodegib is an SMO antagonist that decreases the interaction between SMO and PTCH1, resulting in decreased Hh pathway signaling, gene transcription, and cell division. The downstream Hh pathway events inhibited by vismodegib are indicated in red.


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InternalMed_Harrison. homolog 1 (PTCH1) and smoothened homolog (SMO) occur in BCC. Aberrant PTCH1 signaling is propagated by the nuclear transcription factors Gli1 and Gli2, which are salient in the development of BCC and have led to the FDA approval of an oral SMO inhibitor, vismodegib, to treat advanced inoperable or metastatic BCC (Fig. 105-4). Vismodegib also reduces the incidence of BCC in patients with basal cell nevus syndrome who have PTCH1 mutations, affirming the importance of Hh in the onset of BCC.


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InternalMed_Harrison. CLINICAL PRESENTATION Basal Cell Carcinoma BCC arises from epidermal basal cells. The least invasive of BCC subtypes, superficial BCC, consists of often subtle, erythematous scaling plaques that slowly enlarge and are most commonly seen on the trunk and proximal extremities (Fig. 105-5). This BCC subtype may be confused with benign inflammatory dermatoses, especially nummular eczema and psoriasis. BCC also can present as a small, slowly growing pearly nodule, often with tortuous telangiectatic vessels on its surface, rolled borders, and a central crust (nodular BCC). The occasional presence of melanin in this variant of nodular BCC (pigmented BCC) may lead to confusion with melanoma. Morpheaform (fibrosing), infiltrative, and micronodular BCC, the most invasive and potentially aggressive subtypes, manifest as solitary, flat or slightly depressed, indurated whitish, yellowish, or pink scar-like plaques. Borders are typically indistinct, and lesions can be subtle; thus, delay in


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InternalMed_Harrison. subtypes, manifest as solitary, flat or slightly depressed, indurated whitish, yellowish, or pink scar-like plaques. Borders are typically indistinct, and lesions can be subtle; thus, delay in treatment is common, and tumors can be more extensive than expected clinically.


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InternalMed_Harrison. Squamous Cell Carcinoma Primary cutaneous SCC is a malignant neoplasm of keratinizing epidermal cells. SCC has a variable clinical course, ranging from indolent to rapid growth kinetics, with the potential for metastasis to regional and distant sites. Commonly, SCC appears as an ulcerated erythematous nodule or superficial erosion on sun-exposed skin of the head, neck, trunk, and extremities (Fig. 105-5). It may also appear as a banal, firm, dome-shaped papule or rough-textured plaque. It is commonly mistaken for a wart or callous when the inflammatory response to the lesion is minimal. Clinically visible overlying telangiectasias are uncommon, although dotted or coiled vessels are a hallmark of SCC when viewed through a dermatoscope. FIGURE 105-5 Cutaneous neoplasms. A. Non-Hodgkin’s lymphoma involves the skin with typical violaceous, “plum-colored” nodules.


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InternalMed_Harrison. FIGURE 105-5 Cutaneous neoplasms. A. Non-Hodgkin’s lymphoma involves the skin with typical violaceous, “plum-colored” nodules. B. Squamous cell carcinoma is seen here as a hyperkeratotic crusted and somewhat eroded plaque on the lower lip. Sun-exposed skin in areas such as the head, neck, hands, and arms represent other typical sites of involvement. C. Actinic keratoses consist of hyperkeratotic erythematous papules and patches on sun-exposed skin. They arise in middle-aged to older adults and have some potential for malignant transformation. D. Metastatic carcinoma to the skin is characterized by inflammatory, often ulcerated dermal nodules. E. Mycosis fungoides is a cutaneous T cell lymphoma, and plaque-stage lesions are seen in this patient. F. Keratoacanthoma is a low-grade squamous cell carcinoma that presents as an exophytic nodule with central keratinous debris. G. This basal cell carcinoma shows central ulceration and a pearly, rolled telangiectatic tumor border.


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InternalMed_Harrison. Cancer of the Skin The margins of this tumor may be ill defined, and fixation to underlying structures may occur (“tethering”). A very rapidly growing but low-grade form of SCC, called keratoacanthoma (KA), typically appears as a large dome-shaped papule with a central keratotic crater. Some KAs regress spontaneously without therapy, but because progression to metastatic SCC has been documented, KAs should be treated in the same manner as other types of cutaneous SCC. KAs are also associated with medications that target BRAF mutations and occur in 15–25% of patients receiving these medications.


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InternalMed_Harrison. Actinic keratoses and cheilitis (actinic keratoses occurring on the lip), both premalignant forms of SCC, present as hyperkeratotic papules on sun-exposed areas. The potential for malignant degeneration in untreated lesions ranges from 0.25 to 20%. SCC in situ, also called Bowen’s disease, is the intraepidermal form of SCC and usually presents as a scaling, erythematous plaque. As with invasive SCC, SCC in situ most commonly arises on sun-damaged skin, but can occur anywhere on the body. Bowen’s disease forming secondary to infection with human papillomavirus (HPV) can arise on skin with minimal or no prior sun exposure, such as the buttock or posterior thigh. Treatment of premalignant and in situ lesions reduces the subsequent risk of invasive disease.


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InternalMed_Harrison. NATURAL HISTORY Basal Cell Carcinoma The natural history of BCC is that of a slowly enlarging, locally invasive neoplasm. The degree of local destruction and risk of recurrence vary with the size, duration, location, and histologic subtype of the tumor. Location on the central face, ears, or scalp may portend a higher risk. Small nodular, pigmented, cystic, or superficial BCCs respond well to most treatments. Large lesions and micronodular, infiltrative, and morpheaform subtypes may be more aggressive. The metastatic potential of BCC is low (0.0028–0.1% in immunocompetent patients), but the risk of recurrence or a new primary NMSC is about 40% over 5 years.


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InternalMed_Harrison. Squamous Cell Carcinoma The natural history of SCC depends on tumor and host characteristics. Tumors arising on sun-damaged skin have a lower metastatic potential than do those on non-sunexposed areas. Cutaneous SCC metastasizes in 0.3–5.2% of individuals, most frequently to regional lymph nodes. Tumors occurring on the lower lip and ear develop regional metastases in 13 and 11% of patients, respectively, whereas the metastatic potential of SCC arising in scars, chronic ulcerations, and genital or mucosal surfaces is higher. Recurrent SCC has a much higher potential for metastatic disease, approaching 30%. Large, poorly differentiated, deep tumors with perineural or lymphatic invasion, multifocal tumors, and those arising in immunosuppressed patients often behave aggressively.


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InternalMed_Harrison. Treatments used for BCC include electrodesiccation and curettage (ED&C), excision, cryosurgery, radiation therapy (RT), laser therapy, Mohs micrographic surgery (MMS), topical 5-fluorouracil, photo-dynamic therapy (PDT), and topical immunomodulators such as imiquimod. The therapy chosen depends on tumor characteristics including depth and location, patient age, medical status, and patient preference. ED&C remains the most commonly employed method for superficial, minimally invasive nodular BCCs and low-risk tumors (e.g., a small tumor of a less aggressive subtype in a favorable location). Wide local excision with standard margins is usually selected for invasive, ill-defined, and more aggressive subtypes of tumors, or for cosmetic reasons. MMS, a specialized type of surgical excision that provides the best method for tumor removal while preserving uninvolved tissue, is associated with cure rates >98%. It is the preferred modality for lesions that are recurrent, in high-risk or


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InternalMed_Harrison. that provides the best method for tumor removal while preserving uninvolved tissue, is associated with cure rates >98%. It is the preferred modality for lesions that are recurrent, in high-risk or cosmetically sensitive locations (including recurrent tumors in these locations), and in which maximal tissue conservation is critical (e.g., the eyelids, lips, ears, nose, and digits). RT can cure patients not considered surgical candidates and can be used as a surgical adjunct in high-risk tumors. Younger patients may not be good candidates 502 for RT because of the risks of long-term carcinogenesis and radio-dermatitis. Imiquimod can be used to treat superficial and smaller nodular BCCs, although it is not FDA-approved for nodular BCC. Topical 5-fluorouracil therapy should be limited to superficial BCC. PDT, which uses selective activation of a photoactive drug by visible light, has been used in patients with numerous tumors. Intralesional chemotherapy (5-fluorouracil and IFN) for NMSC


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InternalMed_Harrison. BCC. PDT, which uses selective activation of a photoactive drug by visible light, has been used in patients with numerous tumors. Intralesional chemotherapy (5-fluorouracil and IFN) for NMSC has existed since the mid-twentieth century, but is used so infrequently that recent consensus guidelines for the treatment of BCC and SCC do not include it. Like RT, it remains an option for well-selected patients who cannot or will not undergo surgery.


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InternalMed_Harrison. Therapy for cutaneous SCC should be based on the size, location, histologic differentiation, patient age, and functional status. Surgical excision and MMS are standard treatments. Cryosurgery and ED&C have been used for premalignant lesions and small, superficial, in situ primary tumors. Lymph node metastases are treated with surgical resection, RT, or both. Systemic chemotherapy combinations that include cisplatin can palliate patients with advanced disease. SCC and keratoacanthomas that develop in patients receiving BRAF-targeted therapy should be excised, but their development should not deter the continued use of BRAF therapy. Retinoid prophylaxis can also be considered for patients receiving BRAF-targeted therapy, although no prospective studies have been completed thus far.


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InternalMed_Harrison. The general principles for prevention are those described for melanoma earlier. Unique strategies for NMSC include active surveillance for patients on immunosuppressive medications or BRAF-targeted therapy. Chemoprophylaxis using synthetic retinoids and immunosuppression reduction when possible may be useful in controlling new lesions and managing patients with multiple tumors. Neoplasms of cutaneous adnexae and sarcomas of fibrous, mesenchymal, fatty, and vascular tissues make up the remaining 1–2% of NMSCs.


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InternalMed_Harrison. Merkel cell carcinoma (MCC) is a neural crest–derived highly aggressive malignancy with mortality rates approaching 33% at 3 years. An oncogenic Merkel cell polyomavirus is present in 80% of tumors. Many patients have detectable cellular or humoral immune responses to polyoma viral proteins, although this immune response is insufficient to eradicate the malignancy. Survival depends on extent of disease: 90% survive with local disease, 52% with nodal involvement, and only 10% with distant disease at 3 years. MCC incidence tripled over the last 20 years with an estimated 1600 cases per year in the United States. Immunosuppression can increase incidence and diminish prognosis. MCC lesions typically present as an asymptomatic rapidly expanding bluish-red/violaceous tumor on sun-exposed skin of older white patients. Treatment is surgical excision with sentinel lymph node biopsy for accurate staging in patients with localized disease, often followed by adjuvant RT. Patients with extensive


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InternalMed_Harrison. of older white patients. Treatment is surgical excision with sentinel lymph node biopsy for accurate staging in patients with localized disease, often followed by adjuvant RT. Patients with extensive disease can be offered systemic chemotherapy; however, there is no convincing survival benefit. Whenever possible a clinical trial should be considered for this rare but aggressive NMSC, especially in light of the potential for new treatments directed at the oncogenic virus that causes this malignancy.


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InternalMed_Harrison. Extramammary Paget’s disease is an uncommon apocrine malignancy arising from stem cells of the epidermis that are characterized histologically by the presence of Paget cells. These tumors present as moist erythematous patches on anogenital or axillary skin of the elderly. Outcomes are generally good with site-directed surgery, and 5-year disease specific survival is approximately 95% with localized disease. Advanced age and extensive disease at presentation are factors that confer diminished prognosis. RT or topical imiquimod can be considered for more extensive disease. Local management may be challenging because these tumors often extend far beyond clinical margins; surgical excision with MMS has the highest cure rates. Similarly, MMS is the treatment of choice in other rare cutaneous tumors with extensive subclinical extension such as dermatofibromasarcoma protuberans.


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InternalMed_Harrison. Kaposi’s sarcoma (KS) is a soft tissue sarcoma of vascular origin that is induced by the human herpesvirus 8. The incidence of KS increased dramatically during the AIDS epidemic, but has now decreased tenfold with the institution of highly active antiretroviral therapy. Carl V. Washington, MD, and Hari Nadiminti, MD, contributed to this chapter in the 18th edition, and material from that chapter is included here. Claudia Taylor, MD, and Steven Kolker, MD, provided valued feedback and suggested many improvements to this chapter. Everett E. Vokes


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InternalMed_Harrison. Everett E. Vokes Epithelial carcinomas of the head and neck arise from the mucosal surfaces in the head and neck and typically are squamous cell in origin. This category includes tumors of the paranasal sinuses, the oral cavity, and the nasopharynx, oropharynx, hypopharynx, and larynx. Tumors of the salivary glands differ from the more common carcinomas of the head and neck in etiology, histopathology, clinical presentation, and therapy. They are rare and histologically highly heterogeneous. Thyroid malignancies are described in Chap. 405.


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InternalMed_Harrison. Thyroid malignancies are described in Chap. 405. The number of new cases of head and neck cancers (oral cav ity, pharynx, and larynx) in the United States was 53,640 in 2013, accounting for about 3% of adult malignancies; 11,520 people died from the disease. The worldwide incidence exceeds half a million cases annually. In North America and Europe, the tumors usually arise from the oral cavity, oropharynx, or larynx. The incidence of oropharyngeal cancers is increasing in recent years. Nasopharyngeal cancer is more commonly seen in the Mediterranean countries and in the Far East, where it is endemic in some areas. Alcohol and tobacco use are the most significant risk factors for head and neck cancer, and when used together, they act synergistically. Smokeless tobacco is an etiologic agent for oral cancers. Other potential carcinogens include marijuana and occupational exposures such as nickel refining, exposure to textile fibers, and woodworking.


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InternalMed_Harrison. Some head and neck cancers have a viral etiology. Epstein-Barr virus (EBV) infection is frequently associated with nasopharyngeal cancer, especially in endemic areas of the Mediterranean and Far East. EBV antibody titers can be measured to screen high-risk populations. Nasopharyngeal cancer has also been associated with consumption of salted fish and in-door pollution.


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InternalMed_Harrison. In Western countries, the human papilloma virus (HPV) is associated with a rising incidence of tumors arising from the oropharynx, i.e., the tonsillar bed and base of tongue. Over 50% of oropharyngeal tumors are caused by HPV in the United States. HPV 16 is the dominant viral subtype, although HPV 18 and other oncogenic subtypes are seen as well. Alcoholand tobacco-related cancers, on the other hand, have decreased in incidence. HPV-related oropharyngeal cancer occurs in a younger patient population and is associated with increased numbers of sexual partners and oral sexual practices. It is associated with a better prognosis, especially for nonsmokers.


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InternalMed_Harrison. Dietary factors may contribute. The incidence of head and neck cancer is higher in people with the lowest consumption of fruits and vegetables. Certain vitamins, including carotenoids, may be protective if included in a balanced diet. Supplements of retinoids, such as cisretinoic acid, have not been shown to prevent head and neck cancers (or lung cancer) and may increase the risk in active smokers. No specific risk factors or environmental carcinogens have been identified for salivary gland tumors. HISTOPATHOLOGY, CARCINOGENESIS, AND MOLECULAR BIOLOGY


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InternalMed_Harrison. HISTOPATHOLOGY, CARCINOGENESIS, AND MOLECULAR BIOLOGY Squamous cell head and neck cancers are divided into well-differentiated, moderately well-differentiated, and poorly differentiated categories. Poorly differentiated tumors have a worse prognosis than well-differentiated tumors. For nasopharyngeal cancers, the less common differentiated squamous cell carcinoma is distinguished from nonkeratinizing and undifferentiated carcinoma (lymphoepithelioma) that contains infiltrating lymphocytes and is commonly associated with EBV. Salivary gland tumors can arise from the major (parotid, submandibular, sublingual) or minor salivary glands (located in the submucosa of the upper aerodigestive tract). Most parotid tumors are benign, but half of submandibular and sublingual gland tumors and most minor salivary gland tumors are malignant. Malignant tumors include mucoepidermoid and adenoid cystic carcinomas and adenocarcinomas.


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InternalMed_Harrison. The mucosal surface of the entire pharynx is exposed to alcohol-and tobacco-related carcinogens and is at risk for the development of a premalignant or malignant lesion. Erythroplakia (a red patch) or leukoplakia (a white patch) can be histopathologically classified as hyperplasia, dysplasia, carcinoma in situ, or carcinoma. However, most head and neck cancer patients do not present with a history of premalignant lesions. Multiple synchronous or metachronous cancers can also be observed. In fact, over time, patients with early-stage head and neck cancer are at greater risk of dying from a second malignancy than from a recurrence of the primary disease.


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InternalMed_Harrison. Second head and neck malignancies are usually not therapy-induced; they reflect the exposure of the upper aerodigestive mucosa to the same carcinogens that caused the first cancer. These second primaries develop in the head and neck area, the lung, or the esophagus. Thus, computed tomography (CT) screening for lung cancer in heavy smokers who have already developed a head and neck cancer should be considered. Rarely, patients can develop a radiation therapy–induced sarcoma after having undergone prior radiotherapy for a head and neck cancer.


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InternalMed_Harrison. Much progress has been made in describing the molecular features of head and neck cancer. These features have allowed investigators to describe the genetic and epigenetic alterations and the mutational spectrum of these tumors. Early reports demonstrated frequent overexpression of the epidermal growth factor receptor (EGFR). Overexpression was shown to correlate with poor prognosis. However, it has not proved to be a good predictor of tumor response to EGFR inhibitors, which are successful in only about 10–15% of patients. p53 mutations are also found frequently with other major affected oncogenic driver pathways including the mitotic signaling and Notch pathways and cell cycle regulation. The PI3K pathway is frequently altered, especially in HPV-positive tumors, where it is the only mutated cancer gene identified to date. Overall, these alterations affect mitogenic signaling, genetic stability, cellular proliferation, and differentiation. HPV is known to act through inhibition of the


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InternalMed_Harrison. cancer gene identified to date. Overall, these alterations affect mitogenic signaling, genetic stability, cellular proliferation, and differentiation. HPV is known to act through inhibition of the p53 and RB tumor-suppressor genes, thereby initiating the carcinogenic process, and has a mutational spectrum distinct from alcoholand tobacco-related tumors.


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InternalMed_Harrison. Most tobacco-related head and neck cancers occur in patients older than age 60 years. HPV-related malignancies are frequently diagnosed in younger patients, usually in their forties or fifties, whereas EBV-related nasopharyngeal cancer can occur in all ages, including teenagers. The manifestations vary according to the stage and primary site of the tumor. Patients with nonspecific signs and symptoms in the head and neck area should be evaluated with a thorough otolaryngologic exam, particularly if symptoms persist longer than 2–4 weeks. Males are more frequently affected than women by head and neck cancers, including HPV-positive tumors. Cancer of the nasopharynx typically does not cause early symptoms. However, it may cause unilateral serous otitis media due to obstruction of the eustachian tube, unilateral or bilateral nasal obstruction, or 503 epistaxis. Advanced nasopharyngeal carcinoma causes neuropathies of the cranial nerves due to skull base involvement.


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InternalMed_Harrison. Carcinomas of the oral cavity present as nonhealing ulcers, changes in the fit of dentures, or painful lesions. Tumors of the tongue base or oropharynx can cause decreased tongue mobility and alterations in speech. Cancers of the oropharynx or hypopharynx rarely cause early symptoms, but they may cause sore throat and/or otalgia. HPV-related tumors frequently present with neck lymphadenopathy as the first sign. Hoarseness may be an early symptom of laryngeal cancer, and persistent hoarseness requires referral to a specialist for indirect laryngoscopy and/or radiographic studies. If a head and neck lesion treated initially with antibiotics does not resolve in a short period, further workup is indicated; to simply continue the antibiotic treatment may be to lose the chance of early diagnosis of a malignancy.


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InternalMed_Harrison. Advanced head and neck cancers in any location can cause severe pain, otalgia, airway obstruction, cranial neuropathies, trismus, odynophagia, dysphagia, decreased tongue mobility, fistulas, skin involve ment, and massive cervical lymphadenopathy, which may be unilateral or bilateral. Some patients have enlarged lymph nodes even though no primary lesion can be detected by endoscopy or biopsy; these patients are considered to have carcinoma of unknown primary (Fig. 106-1). If the enlarged nodes are located in the upper neck and the tumor cells are of squamous cell histology, the malignancy probably arose from a mucosal surface in the head or neck. Tumor cells in supraclavicular lymph nodes may also arise from a primary site in the chest or abdomen.


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InternalMed_Harrison. The physical examination should include inspection of all visible mucosal surfaces and palpation of the floor of the mouth and of the tongue and neck. In addition to tumors themselves, leukoplakia (a white mucosal patch) or erythroplakia (a red mucosal patch) may be observed; these “premalignant” lesions can represent hyperplasia, dysplasia, or carcinoma in situ and require biopsy. Further examination should be performed by a specialist. Additional staging procedures include CT of the head and neck to identify the extent of the disease. Patients with lymph node involvement should have CT scan of the chest and upper abdomen to screen for distant metastases. In heavy smokers, the CT scan of the chest can also serve as a screening tool to rule out a second lung primary tumor. A positron emission tomography (PET) scan may also be administered and can help to identify or exclude distant metastases. The definitive staging procedure is an


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InternalMed_Harrison. Physical Examination in Office If lymphoma, sarcoma, or salivary gland tumor Panendoscopy and directed biopsies. Search for occult primary with biopsies of tonsils, nasopharynx, base of tongue, and pyriform sinus. FNA or excision of lymph node Specific workup If squamous cell carcinoma FIGURE 106-1 Evaluation of a patient with cervical adenopathy without a primary mucosal lesion; a diagnostic workup. FNA, fine-needle aspiration.


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InternalMed_Harrison. 504 endoscopic examination under anesthesia, which may include laryngoscopy, esophagoscopy, and bronchoscopy; during this procedure, multiple biopsy samples are obtained to establish a primary diagnosis, define the extent of primary disease, and identify any additional premalignant lesions or second primaries. Head and neck tumors are classified according to the tumornode-metastasis (TNM) system of the American Joint Committee on Cancer (Fig. 106-2). This classification varies according to the specific anatomic subsite. In general, primary tumors are classified as T1 to T3 by increasing size, whereas T4 usually represents invasion of another structure such as bone, muscle, or root of tongue. Lymph nodes are staged by size, number, and location (ipsilateral vs contralateral to the primary). Distant metastases are found in <10% of patients at initial diagnosis and are more common in patients with advanced lymph node stage; microscopic involvement of the lungs, bones, or liver is more


InternalMed_Harrison

InternalMed_Harrison. Distant metastases are found in <10% of patients at initial diagnosis and are more common in patients with advanced lymph node stage; microscopic involvement of the lungs, bones, or liver is more common, particularly in patients with advanced neck lymph node disease. Modern imaging techniques may increase the number of patients with clinically detectable distant metastases in the future.


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InternalMed_Harrison. In patients with lymph node involvement and no visible primary, the diagnosis should be made by lymph node excision (Fig. 106-1). If the results indicate squamous cell carcinoma, a panendoscopy should be performed, with biopsy of all suspicious-appearing areas and directed biopsies of common primary sites, such as the nasopharynx, tonsil, tongue base, and pyriform sinus. HPV-positive tumors especially can have small primary tumors that spread early to locoregional lymph nodes. Patients with head and neck cancer can be grossly categorized into three clinical groups: those with localized disease, those with locally or regionally advanced disease (lymph node positive), and those with recurrent and/or metastatic disease. Comorbidities associated with tobacco and alcohol abuse can affect treatment outcome and define long-term risks for patients who are cured of their disease.


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InternalMed_Harrison. Nearly one-third of patients have localized disease, that is, T1 or T2 (stage I or stage II) lesions without detectable lymph node involvement or distant metastases. These patients are treated with curative intent by either surgery or radiation therapy. The choice of modality differs according to anatomic location and institutional expertise. Radiation therapy is often preferred for laryngeal cancer to preserve voice function, and surgery is preferred for small lesions in the oral cavity to avoid the long-term complications of radiation, such as xerostomia and dental decay. Overall 5-year survival is 60–90%. Most recurrences occur within the first 2 years following diagnosis and are usually local.


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InternalMed_Harrison. Locally or regionally advanced disease—disease with a large primary tumor and/or lymph node metastases—is the stage of presentation for >50% of patients. Such patients can also be treated with curative intent, but not with surgery or radiation therapy alone. Combined-modality therapy including surgery, radiation therapy, and chemotherapy is most successful. It can be administered as induction chemotherapy (chemotherapy before surgery and/or radiotherapy) or as concomitant (simultaneous) chemotherapy and radiation therapy. The latter is currently most commonly used and supported by the best evidence. Five-year survival rates exceed 50% in many trials, but part of this increased survival may be due to an increasing fraction of study populations with HPV-related tumors who carry a better prognosis. HPV testing of newly diagnosed tumors is now performed for most patients at the time of diagnosis, and clinical trials for HPV-related tumors are focused on exploring reductions in treatment


InternalMed_Harrison

InternalMed_Harrison. HPV testing of newly diagnosed tumors is now performed for most patients at the time of diagnosis, and clinical trials for HPV-related tumors are focused on exploring reductions in treatment intensity, especially radiation dose, in order to ameliorate long-term toxicities (fibrosis, swallowing dysfunction).


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InternalMed_Harrison. In patients with intermediate-stage tumors (stage III and early stage IV), concomitant chemoradiotherapy can be administered either as a primary treatment for patients with unresectable disease, to pursue an organ-preserving approach, or in the postoperative setting for intermediate-stage resectable tumors. Induction Chemotherapy In this strategy, patients receive chemotherapy (current standard is a three-drug regimen of docetaxel, cisplatin, and fluorouracil [5-FU]) before surgery and radiation therapy. Most patients who receive three cycles show tumor reduction, and the response is clinically “complete” in up to half of patients. This “sequential” multimodality therapy allows for organ preservation (omission of surgery) in patients with laryngeal and hypopharyngeal cancer, and it has been shown to result in higher cure rates compared with radiotherapy alone.


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InternalMed_Harrison. Concomitant Chemoradiotherapy With the concomitant strategy, chemotherapy and radiation therapy are given simultaneously rather than in sequence. Tumor recurrences from head and neck cancer develop most commonly locoregionally (in the head and neck area of the primary and draining lymph nodes). The concomitant approach is aimed at enhancing tumor cell killing by radiation therapy in the presence of chemotherapy (radiation enhancement) and is a conceptually attractive approach for bulky tumors. Toxicity 505 (especially mucositis, grade 3 or 4 in 70–80%) is increased with concomitant chemoradiotherapy. However, meta-analyses of randomized trials document an improvement in 5-year survival of 8% with concomitant chemotherapy and radiation therapy. Results seem more favorable in recent trials as more active drugs or more intensive radiotherapy schedules are used. In addition, concomitant chemoradiotherapy produces better laryngectomy-free survival (organ preservation) than radiation


InternalMed_Harrison

InternalMed_Harrison. as more active drugs or more intensive radiotherapy schedules are used. In addition, concomitant chemoradiotherapy produces better laryngectomy-free survival (organ preservation) than radiation therapy alone in patients with advanced larynx cancer. The use of radiation therapy together with cisplatin has also produced improved survival in patients with advanced nasopharyngeal cancer. The outcome of HPV-related cancers seems to be especially favorable following cisplatin-based chemoradiotherapy.


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InternalMed_Harrison. The success of concomitant chemoradiotherapy in patients with unresectable disease has led to the testing of a similar approach in patients with resected intermediate-stage disease as a postoperative therapy. Concomitant chemoradiotherapy produces a signifi cant improvement over postoperative radiation therapy alone for patients whose tumors demonstrate higher risk features, such as extracapsular spread beyond involved lymph nodes, involvement of multiple lymph nodes, or positive margins at the primary site following surgery. A monoclonal antibody to EGFR (cetuximab) increases survival rates when administered during radiotherapy. EGFR blockade results in radiation sensitization and has milder systemic side effects than traditional chemotherapy agents, although an acneiform skin rash is commonly observed. Nevertheless, the integration of cetuximab into current standard chemoradiotherapy regimens has failed to show additional improvement in survival and is not recommended.


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InternalMed_Harrison. Five to ten percent of patients present with metastatic disease, and 30–50% of patients with locoregionally advanced disease experience recurrence, frequently outside the head and neck region. Patients with recurrent and/or metastatic disease are, with few exceptions, treated with palliative intent. Some patients may require local or regional radiation therapy for pain control, but most are given chemotherapy. Response rates to chemotherapy average only 30–50%; the durations of response are short, and the median survival time is 8–10 months. Therefore, chemotherapy provides transient symptomatic benefit. Drugs with single-agent activity in this setting include methotrexate, 5-FU, cisplatin, paclitaxel, and docetaxel. Combinations of cisplatin with 5-FU, carboplatin with 5-FU, and cisplatin or carboplatin with paclitaxel or docetaxel are frequently used.


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InternalMed_Harrison. EGFR-directed therapies, including monoclonal antibodies (e.g., cetuximab) and tyrosine kinase inhibitors (TKIs) of the EGFR signaling pathway (e.g., erlotinib or gefitinib), have single-agent activity of approximately 10%. Side effects are usually limited to an acneiform rash and diarrhea (for the TKIs). The addition of cetuximab to standard combination chemotherapy with cisplatin or carboplatin and 5-FU was shown to result in a significant increase in median survival. Drugs targeting specific mutations are under investigation, but no such strategy has yet been shown to be feasible in head and neck cancer.


InternalMed_Harrison

InternalMed_Harrison. Complications from treatment of head and neck cancer are usually correlated to the extent of surgery and exposure of normal tissue structures to radiation. Currently, the extent of surgery has been limited or completely replaced by chemotherapy and radiation therapy as the primary approach. Acute complications of radiation include mucositis and dysphagia. Long-term complications include xerostomia, loss of taste, decreased tongue mobility, second malignancies, dysphagia, and neck fibrosis. The complications of chemotherapy vary with the regimen used but usually include myelosuppression, mucositis, nausea and vomiting, and nephrotoxicity (with cisplatin).


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InternalMed_Harrison. 506 The mucosal side effects of therapy can lead to malnutrition and dehydration. Many centers address issues of dentition before starting treatment, and some place feeding tubes to ensure control of hydration and nutrition intake. About 50% of patients develop hypothyroidism from the treatment; thus, thyroid function should be monitored. Most benign salivary gland tumors are treated with surgical excision, and patients with invasive salivary gland tumors are treated with surgery and radiation therapy. These tumors may recur regionally; adenoid cystic carcinoma has a tendency to recur along the nerve tracks. Distant metastases may occur as late as 10–20 years after the initial diagnosis. For metastatic disease, therapy is given with palliative intent, usually chemotherapy with doxorubicin and/or cisplatin. Identification of novel agents with activity in these tumors is a high priority. neoplasms of the Lung Leora Horn, Christine M. Lovly, David H. Johnson


InternalMed_Harrison

InternalMed_Harrison. Lung cancer, which was rare prior to 1900 with fewer than 400 cases described in the medical literature, is considered a disease of modern man. By the mid-twentieth century, lung cancer had become epidemic and firmly established as the leading cause of cancer-related death in North America and Europe, killing over three times as many men as prostate cancer and nearly twice as many women as breast cancer. This fact is particularly troubling because lung cancer is one of the most preventable of all of the major malignancies. Tobacco consumption is the primary cause of lung cancer, a reality firmly established in the mid-twentieth century and codified with the release of the U.S. Surgeon General’s 1964 report on the health effects of tobacco smoking. Following the report, cigarette use started to decline in North America and parts of Europe, and with it, so did the incidence of lung cancer. To date, the decline in lung cancer is seen most clearly in men; only recently has the decline


InternalMed_Harrison

InternalMed_Harrison. to decline in North America and parts of Europe, and with it, so did the incidence of lung cancer. To date, the decline in lung cancer is seen most clearly in men; only recently has the decline become apparent among women in the United States. Unfortunately, in many parts of the world, especially in countries with developing economies, cigarette use continues to increase, and along with it, the incidence of lung cancers is also rising. Although tobacco smoking remains the primary cause of lung cancer worldwide, approximately 60% of new lung cancers in the United States occur in former smokers (smoked ≥100 cigarettes per lifetime, quit ≥1 year), many of whom quit decades ago, or never smokers (smoked <100 cigarettes per lifetime). Moreover, one in five women and one in 12 men diagnosed with lung cancer have never smoked. Given the magnitude of the problem, it is incumbent that every internist has a general knowledge of lung cancer and its management.


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InternalMed_Harrison. Lung cancer is the most common cause of cancer death among American men and women. More than 225,000 individuals will be diagnosed with lung cancer in the United States in 2013, and over 150,000 individuals will die from the disease. The incidence of lung cancer peaked among men in the late 1980s and has plateaued in women. Lung cancer is rare below age 40, with rates increasing until age 80, after which the rate tapers off. The projected lifetime probability of developing lung cancer is estimated to be approximately 8% among males and approximately 6% among females. The incidence of lung cancer varies by racial and ethnic group, with the highest age-adjusted incidence rates among African Americans. The excess in age-adjusted rates among African Americans occurs only among men, but examinations of age-specific rates show that below age 50, mortality from lung cancer is more than 25% higher among African American than Caucasian women. Incidence and mortality rates among Hispanics and


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InternalMed_Harrison. of age-specific rates show that below age 50, mortality from lung cancer is more than 25% higher among African American than Caucasian women. Incidence and mortality rates among Hispanics and Native and Asian Americans are approximately 40–50% those of whites.


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InternalMed_Harrison. Cigarette smokers have a 10-fold or greater increased risk of developing lung cancer compared to those who have never smoked. A deep sequencing study suggested that one genetic mutation is induced for every 15 cigarettes smoked. The risk of lung cancer is lower among persons who quit smoking than among those who continue smoking; former smokers have a ninefold increased risk of developing lung cancer compared to men who have never smoked versus the 20-fold excess in those who continue to smoke. The size of the risk reduction increases with the length of time the person has quit smoking, although generally even long-term former smokers have higher risks of lung cancer than those who never smoked. Cigarette smoking has been shown to increase the risk of all the major lung cancer cell types. Environmental tobacco smoke (ETS) or second-hand smoke is also an established cause of lung cancer. The risk from ETS is less than from active smoking, with about a 20–30% increase in lung cancer


InternalMed_Harrison

InternalMed_Harrison. Environmental tobacco smoke (ETS) or second-hand smoke is also an established cause of lung cancer. The risk from ETS is less than from active smoking, with about a 20–30% increase in lung cancer observed among never smokers married for many years to smokers, in comparison to the 2000% increase among continuing active smokers.


InternalMed_Harrison

InternalMed_Harrison. Although cigarette smoking is the cause of the majority of lung cancers, several other risk factors have been identified, including occupational exposures to asbestos, arsenic, bischloromethyl ether, hexavalent chromium, mustard gas, nickel (as in certain nickel-refining processes), and polycyclic aromatic hydrocarbons. Occupational observations also have provided insight into possible mechanisms of lung cancer induction. For example, the risk of lung cancer among asbestos-exposed workers is increased primarily among those with underlying asbestosis, raising the possibility that the scarring and inflammation produced by this fibrotic nonmalignant lung disease may in many cases (although likely not in all) be the trigger for asbestos-induced lung cancer. Several other occupational exposures have been associated with increased rates of lung cancer, but the causal nature of the association is not as clear.


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InternalMed_Harrison. The risk of lung cancer appears to be higher among individuals with low fruit and vegetable intake during adulthood. This observation led to hypotheses that specific nutrients, in particular retinoids and carotenoids, might have chemopreventative effects for lung cancer. However, randomized trials failed to validate this hypothesis. In fact, studies found the incidence of lung cancer was increased among smokers with supplementation. Ionizing radiation is also an established lung carcinogen, most convincingly demonstrated from studies showing increased rates of lung cancer among survivors of the atom bombs dropped on Hiroshima and Nagasaki and large excesses among workers exposed to alpha irradiation from radon in underground uranium mining. Prolonged exposure to low-level radon in homes might impart a risk of lung cancer equal or greater than that of ETS. Prior lung diseases such as chronic bronchitis, emphysema, and tuberculosis have been linked to increased risks of lung cancer as


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InternalMed_Harrison. might impart a risk of lung cancer equal or greater than that of ETS. Prior lung diseases such as chronic bronchitis, emphysema, and tuberculosis have been linked to increased risks of lung cancer as well.


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InternalMed_Harrison. Smoking Cessation Given the undeniable link between cigarette smoking and lung cancer (not even addressing other tobacco-related illnesses), physicians must promote tobacco abstinence. Physicians also must help their patients who smoke to stop smoking. Smoking cessation, even well into middle age, can minimize an individual’s subsequent risk of lung cancer. Stopping tobacco use before middle age avoids more than 90% of the lung cancer risk attributable to tobacco. However, there is little health benefit derived from just “cutting back.” Importantly, smoking cessation can even be beneficial in individuals with an established diagnosis of lung cancer, as it is associated with improved survival, fewer side effects from therapy, and an overall improvement in quality of life. Moreover, smoking can alter the metabolism of many chemotherapy drugs, potentially adversely altering the toxicities and therapeutic benefits of the agents. Consequently, it is important to promote smoking cessation


InternalMed_Harrison

InternalMed_Harrison. can alter the metabolism of many chemotherapy drugs, potentially adversely altering the toxicities and therapeutic benefits of the agents. Consequently, it is important to promote smoking cessation even after the diagnosis of lung cancer is established.


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InternalMed_Harrison. Physicians need to understand the essential elements of smoking cessation therapy. The individual must want to stop smoking and must be willing to work hard to achieve the goal of smoking abstinence. Self-help strategies alone only marginally affect quit rates, whereas individual and combined pharmacotherapies in combination with counseling can significantly increase rates of cessation. Therapy with an antidepressant (e.g., bupropion) and nicotine replacement therapy (varenicline, a α4β2 nicotinic acetylcholine receptor partial agonist) are approved by the U.S. Food and Drug Administration (FDA) as first-line treatments for nicotine dependence. However, both drugs have been reported to increase suicidal ideation and must be used with caution. In a randomized trial, varenicline was shown to be more efficacious than bupropion or placebo. Prolonged use of varenicline beyond the initial induction phase proved useful in maintaining smoking abstinence. Clonidine and nortriptyline are


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InternalMed_Harrison. to be more efficacious than bupropion or placebo. Prolonged use of varenicline beyond the initial induction phase proved useful in maintaining smoking abstinence. Clonidine and nortriptyline are recommended as second-line treatments. Of note, reducing cigarettes smoked before quit day and quitting abruptly, with no prior reduction, yield comparable quit rates. Therefore, patients can be given the choice to quit in either of these ways (Chap. 470).


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InternalMed_Harrison. Inherited Predisposition to Lung Cancer Exposure to environmental carcinogens, such as those found in tobacco smoke, induce or facilitate the transformation from bronchoepithelial cells to the malignant phenotype. The contribution of carcinogens on transformation is modulated by polymorphic variations in genes that affect aspects of carcinogen metabolism. Certain genetic polymorphisms of the P450 enzyme system, specifically CYP1A1, and chromosome fragility are associated with the development of lung cancer. These genetic variations occur at relatively high frequency in the population, but their contribution to an individual’s lung cancer risk is generally low. However, because of their population frequency, the overall impact on lung cancer risk could be high. In addition, environmental factors, as modified by inherited modulators, likely affect specific genes by deregulating important pathways to enable the cancer phenotype.


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InternalMed_Harrison. First-degree relatives of lung cancer probands have a twoto threefold excess risk of lung cancer and other cancers, many of which are not smoking-related. These data suggest that specific genes and/or genetic variants may contribute to susceptibility to lung cancer. However, very few such genes have yet been identified. Individuals with inherited mutations in RB (patients with retinoblastoma living to adulthood) and p53 (Li-Fraumeni syndrome) genes may develop lung cancer. Common gene variants involved in lung cancer have been recently identified through large, collaborative, genome-wide association studies. These studies identified three separate loci that are associated with lung cancer (5p15, 6p21, and 15q25) and include genes that regulate acetylcholine nicotinic receptors and telomerase production. A rare germline mutation (T790M) involving the epidermal growth factor receptor (EGFR) maybe be linked to lung cancer susceptibility in never smokers. Likewise, a susceptibility locus


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InternalMed_Harrison. production. A rare germline mutation (T790M) involving the epidermal growth factor receptor (EGFR) maybe be linked to lung cancer susceptibility in never smokers. Likewise, a susceptibility locus on chromosome 6q greatly increases risk lung cancer risk among light and never smokers. Although progress has been made, there is a significant amount of work that remains to be done in identifying heritable risk factors for lung cancer. Currently no molecular criteria are suitable to select patients for more intense screening programs or for specific chemopreventative strategies.


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InternalMed_Harrison. The World Health Organization (WHO) defines lung cancer as tumors arising from the respiratory epithelium (bronchi, bronchioles, and alveoli). The WHO classification system divides epithelial lung cancers into four major cell types: small-cell lung cancer (SCLC), adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma; the latter three types are collectively known as non-small-cell carcinomas (NSCLCs) (Fig. 107-1). Small-cell carcinomas consist of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, absent or inconspicuous nucleoli, and a high mitotic count. SCLC may be distinguished from NSCLC by the presence of neuroendocrine markers including CD56, neural cell adhesion molecule (NCAM), synaptophysin, and chromogranin. In North America, adenocarcinoma is the most common histologic type of lung cancer. Adenocarcinomas possess glandular differentiation or mucin production and may show acinar, papillary, lepidic, or solid features or


InternalMed_Harrison

InternalMed_Harrison. adenocarcinoma is the most common histologic type of lung cancer. Adenocarcinomas possess glandular differentiation or mucin production and may show acinar, papillary, lepidic, or solid features or a mixture of these patterns. Squamous cell carcinomas of the


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InternalMed_Harrison. Small Cell Lung Cancer (SCLC) Non-Small Cell Lung Cancer (NSCLC): FIGURE 107-1 Traditional histologic view of lung cancer. lung are morphologically identical to extrapulmonary squamous cell carcinomas and cannot be distinguished by immunohistochemistry alone. Squamous cell tumors show keratinization and/or intercellular bridges that arise from bronchial epithelium. The tumor tends to consists of sheets of cells rather than the three-dimensional groups of cells characteristic of adenocarcinomas. Large-cell carcinomas comprise less than 10% of lung carcinomas. These tumors lack the cytologic and architectural features of small-cell carcinoma and glandular or squamous differentiation. Together these four histologic types account for approximately 90% of all epithelial lung cancers.


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InternalMed_Harrison. All histologic types of lung cancer can develop in current and former smokers, although squamous and small-cell carcinomas are most commonly associated with heavy tobacco use. Through the first half of the twentieth century, squamous carcinoma was the most common subtype of NSCLC diagnosed in the United States. However, with the decline in cigarette consumption over the past four decades, adenocarcinoma has become the most frequent histologic subtype of lung cancer in the United States as both squamous carcinoma and small-cell carcinoma are on the decline. In lifetime never smokers or former light smokers (<10 pack-year history), women, and younger adults (<60 years), adenocarcinoma tends to be the most common form of lung cancer.


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InternalMed_Harrison. Historically, the major pathologic distinction was simply between SCLC and NSCLC, because these tumors have quite different natural histories and therapeutic approaches (see below). Likewise, until fairly recently, there was no apparent need to distinguish among the various subtypes of NSCLC because there were no clear differences in therapeutic outcome based on histology alone. However, this perspective radically changed in 2004 with the recognition that a small percentage of lung adenocarcinomas harbored mutation in EGFR that rendered those tumors exquisitely sensitive to inhibitors of the EGFR tyrosine kinases (e.g., gefitinib and erlotinib). This observation, coupled with the subsequent identification of other “actionable” molecular alterations (Table 107-1) and the recognition that some active


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InternalMed_Harrison. Neoplasms of the Lung 508 chemotherapy agents performed quite differently in squamous carcinomas versus adenocarcinomas, firmly established the need for modifications in the then-existing 2004 WHO lung cancer classification system. The revised 2011 classification system, developed jointly by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society, provides an integrated approach to the classification of lung adenocarcinomas that includes clinical, molecular, radiographic, and pathologic information. It also recognizes that most lung cancers present in an advanced stage and are often diagnosed based on small biopsies or cytologic specimens, rendering clear histologic distinctions difficult if not impossible. Previously, in the 2004 classification system, tumors failing to show definite glandular or squamous morphology in a small biopsy or cytologic specimen were simply classified as non-small-cell carcinoma, not


InternalMed_Harrison

InternalMed_Harrison. in the 2004 classification system, tumors failing to show definite glandular or squamous morphology in a small biopsy or cytologic specimen were simply classified as non-small-cell carcinoma, not otherwise specified. However, because the distinction between adenocarcinoma and squamous carcinoma is now viewed as critical to optimal therapeutic decision making, the modified classification approach recommends these lesions be further characterized using a limited special stain workup. This distinction can be achieved using a single marker for adenocarcinoma (thyroid transcription factor-1 or napsin-A) plus a squamous marker (p40 or p63) and/or mucin stains. The modified classification system also recommends preservation of sufficient specimen material for appropriate molecular testing necessary to help guide therapeutic decision making (see below). Another significant modification to the WHO classification system is the discontinuation of the terms bronchioloalveolar carcinoma and


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InternalMed_Harrison. necessary to help guide therapeutic decision making (see below). Another significant modification to the WHO classification system is the discontinuation of the terms bronchioloalveolar carcinoma and mixed-subtype adenocarcinoma. The term bronchioloalveolar carcinoma was dropped due to its inconsistent use and because it caused confusion in routine clinical care and research. As formerly used, the term encompassed at least five different entities with diverse clinical and molecular properties. The terms adenocarcinoma in situ and minimally invasive adenocarcinoma are now recommended for small solitary adenocarcinomas (≤3 cm) with either pure lepidic growth (term used to describe single-layered growth of atypical cuboidal cells coating the alveolar walls) or predominant lepidic growth with ≤5 mm invasion. Individuals with these entities experience 100% or near 100% 5-year disease-free survival with complete tumor resection. Invasive adenocarcinomas, representing more than 70–90% of


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InternalMed_Harrison. ≤5 mm invasion. Individuals with these entities experience 100% or near 100% 5-year disease-free survival with complete tumor resection. Invasive adenocarcinomas, representing more than 70–90% of surgically resected lung adenocarcinomas, are now classified by their predominant pattern: lepidic, acinar, papillary, and solid patterns. Lepidic-predominant subtype has a favorable prognosis, acinar and papillary have an intermediate prognosis, and solid-predominant has a poor prognosis. The terms signet ring and clear cell adenocarcinoma have been eliminated from the variants of invasive lung adenocarcinoma, whereas the term micropapillary, a subtype with a particularly poor prognosis, has been added. Although EGFR mutations are encountered most frequently in nonmucinous adenocarcinomas with a lepidicor papillary-predominant pattern, most adenocarcinoma subtypes can harbor EGFR or KRAS mutations. The same is true of ALK, RET, and ROS1 rearrangements. What was previously termed mucinous


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InternalMed_Harrison. a lepidicor papillary-predominant pattern, most adenocarcinoma subtypes can harbor EGFR or KRAS mutations. The same is true of ALK, RET, and ROS1 rearrangements. What was previously termed mucinous bronchioloalveolar carcinoma is now called invasive mucinous adenocarcinoma. These tumors generally lack EGFR mutations and show a strong correlation with KRAS mutations. Overall, the revised WHO reclassification of lung cancer addresses important advances in diagnosis and treatment, most importantly, the critical advances in understanding the specific genes and molecular pathways that initiate and sustain lung tumorigenesis resulting in new “targeted” therapies with improved specificity and better antitumor efficacy.


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InternalMed_Harrison. The diagnosis of lung cancer most often rests on the morphologic or cytologic features correlated with clinical and radiographic findings. Immunohistochemistry may be used to verify neuroendocrine differentiation within a tumor, with markers such as neuron-specific enolase (NSE), CD56 or NCAM, synaptophysin, chromogranin, and Leu7. Immunohistochemistry is also helpful in differentiating primary from metastatic adenocarcinomas; thyroid transcription factor-1 (TTF-1), identified in tumors of thyroid and pulmonary origin, is positive in over 70% of pulmonary adenocarcinomas and is a reliable indicator of primary lung cancer, provided a thyroid primary has been excluded. A negative TTF-1, however, does not exclude the possibility of a lung primary. TTF-1 is also positive in neuroendocrine tumors of pulmonary and extrapulmonary origin. Napsin-A (Nap-A) is an aspartic protease that plays an important role in maturation of surfactant B7 and is expressed in cytoplasm of type II pneumocytes.


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InternalMed_Harrison. of pulmonary and extrapulmonary origin. Napsin-A (Nap-A) is an aspartic protease that plays an important role in maturation of surfactant B7 and is expressed in cytoplasm of type II pneumocytes. In several studies, Nap-A has been reported in >90% of primary lung adenocarcinomas. Notably, a combination of Nap-A and TTF-1 is useful in distinguishing primary lung adenocarcinoma (Nap-A positive, TTF-1 positive) from primary lung squamous cell carcinoma (Nap-A negative, TTF-1 negative) and primary SCLC (Nap-A negative, TTF-1 positive). Cytokeratins 7 and 20 used in combination can help narrow the differential diagnosis; nonsquamous NSCLC, SCLC, and mesothelioma may stain positive for CK7 and negative for CK20, whereas squamous cell lung cancer often will be both CK7 and CK20 negative. p63 is a useful marker for the detection of NSCLCs with squamous differentiation when used in cytologic pulmonary samples. Mesothelioma can be easily identified ultrastructurally, but it has historically been


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InternalMed_Harrison. useful marker for the detection of NSCLCs with squamous differentiation when used in cytologic pulmonary samples. Mesothelioma can be easily identified ultrastructurally, but it has historically been difficult to differentiate from adenocarcinoma through morphology and immunohistochemical staining. Several markers in the last few years have proven to be more helpful including CK5/6, calretinin, and Wilms tumor gene-1 (WT-1), all of which show positivity in mesothelioma.


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InternalMed_Harrison. Cancer is a disease involving dynamic changes in the genome. As proposed by Hanahan and Weinberg, virtually all cancer cells acquire six hallmark capabilities: self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. The order in which these hallmark capabilities are acquired appears quite variable and can differ from tumor to tumor. Events leading to acquisition of these hallmarks can vary widely, although broadly, cancers arise as a result from accumulations of gain-of-function mutations in oncogenes and loss-of-function mutations in tumor-suppressor genes. Further complicating the study of lung cancer, the sequence of events that lead to disease is clearly different for the various histopathologic entities.


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InternalMed_Harrison. The exact cell of origin for lung cancers is not clearly defined. Whether one cell of origin leads to all histologic forms of lung cancer is unclear. However, for lung adenocarcinoma, evidence suggests that type II epithelial cells (or alveolar epithelial cells) have the capacity to give rise to tumors. For SCLC, cells of neuroendocrine origin have been implicated as precursors.


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InternalMed_Harrison. For cancers in general, one theory holds that a small subset of the cells within a tumor (i.e., “stem cells”) are responsible for the full malignant behavior of the tumor. As part of this concept, the large bulk of the cells in a cancer are “offspring” of these cancer stem cells. While clonally related to the cancer stem cell subpopulation, most cells by themselves cannot regenerate the full malignant phenotype. The stem cell concept may explain the failure of standard medical therapies to eradicate lung cancers, even when there is a clinical complete response. Disease recurs because therapies do not eliminate the stem cell component, which may be more resistant to chemotherapy. Precise human lung cancer stem cells have yet to be identified.


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InternalMed_Harrison. Lung cancer cells harbor multiple chromosomal abnormalities, including mutations, amplifications, insertions, deletions, and translocations. One of the earliest sets of oncogenes found to be aberrant was the MYC family of transcription factors (MYC, MYCN, and MYCL). MYC is most frequently activated via gene amplification or transcriptional dysregulation in both SCLC and NSCLC. Currently, there are no MYC-specific drugs. Among lung cancer histologies, adenocarcinomas have been the most extensively catalogued for recurrent genomic gains and losses as well as for somatic mutations (Fig. 107-2). While multiple different kinds of aberrations have been found, a major class involves “driver mutations,” which are mutations that occur in genes encoding signaling proteins that when aberrant, drive initiation and maintenance of tumor cells. Importantly, driver mutations can serve as potential Achilles’ heels for tumors, if their gene products can be targeted


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InternalMed_Harrison. FIGURE 107-2 Driver mutations in adenocarcinomas.


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InternalMed_Harrison. appropriately. For example, one set of mutations involves EGFR, which belongs to the ERBB (HER) family of protooncogenes, including EGFR (ERBB1), HER2/neu (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These genes encode cell-surface receptors consisting of an extracellular ligand-binding domain, a transmembrane structure, and an intracellular tyrosine kinase (TK) domain. The binding of ligand to receptor activates receptor dimerization and TK autophosphorylation, initiating a cascade of intracellular events, and leading to increased cell proliferation, angiogenesis, metastasis, and a decrease in apoptosis. Lung adenocarcinomas can arise when tumors express mutant EGFR. These same tumors display high sensitivity to small-molecule EGFR TK inhibitors (TKIs). Additional examples of driver mutations in lung adenocarcinoma include the GTPase KRAS, the serine-threonine kinase BRAF, and the lipid kinase PIK3CA. More recently, more subsets of lung adenocarcinoma have been identifed as defined by


InternalMed_Harrison

InternalMed_Harrison. in lung adenocarcinoma include the GTPase KRAS, the serine-threonine kinase BRAF, and the lipid kinase PIK3CA. More recently, more subsets of lung adenocarcinoma have been identifed as defined by the presence of specific chromsomal rearrangements resulting in the abberant activation of the TKs ALK, ROS1, and RET. Notably, most driver mutations in lung cancer appear to be mutually exclusive, suggesting that acquisition of one of these mutations is sufficient to drive tumorigenesis. Although driver mutations have mostly been found in adenocarinomas, three potential molecular targets recently have been identified in squamous cell lung carcinomas: FGFR1 amplification, DDR2 mutations, and PIK3CA mutations/PTEN loss (Table 107-1). Together, these potentially “actionable” defects occur in up to 50% of squamous carcinomas.


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InternalMed_Harrison. A large number of tumor-suppressor genes have also been identified that are inactivated during the pathogenesis of lung cancer. These include TP53, RB1, RASSF1A, CDKN2A/B, LKB1 (STK11), and FHIT. Nearly 90% of SCLCs harbor mutations in TP53 and RB1. Several tumor-suppressor genes on chromosome 3p appear to be involved in nearly all lung cancers. Allelic loss for this region occurs very early in lung cancer pathogenesis, including in histologically normal smoking-damaged lung epithelium.


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InternalMed_Harrison. In lung cancer, clinical outcome is related to the stage at diagnosis, and hence, it is generally assumed that early detection of occult tumors will lead to improved survival. Early detection is a process that involves screening tests, surveillance, diagnosis, and early treatment. Screening refers to the use of simple tests across a healthy population in order to identify individuals who harbor asymptomatic disease. For a screening program to be successful, there must be a high burden of disease within the target population; the test must be sensitive, specific, accessible, and cost effective; and there must be effective treatment that can reduce mortality. With any screening procedure, it is important to consider the possible influence of lead-time bias (detecting the cancer earlier without an effect on survival), length-time bias (indolent cancers are detected on screening and may not affect survival, whereas aggressive cancers are likely to cause symptoms earlier in patients and


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InternalMed_Harrison. an effect on survival), length-time bias (indolent cancers are detected on screening and may not affect survival, whereas aggressive cancers are likely to cause symptoms earlier in patients and are less likely to be detected), and overdiagnosis (diagnosing cancers so slow growing that they are unlikely to cause the death of the patient) (Chap. 100).


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InternalMed_Harrison. Because a majority of lung cancer patients present with advanced 509 disease beyond the scope of surgical resection, there is understandable skepticism about the value of screening in this condition. Indeed, randomized controlled trials conducted in the 1960s to 1980s using screening chest x-rays (CXR), with or without sputum cytology, reported no impact on lung cancer–specific mortality in patients characterized as high risk (males age ≥45 years with a smoking history). These studies have been criticized for their design, statistical analyses, and outdated imaging modalities. The results of the more recently conducted Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) are consistent with these earlier reports. Initiated in 1993, participants in the PLCO lung cancer screening trial received annual CXR screening for 4 years, whereas participants in the usual care group received no interventions other than their customary medical care. The diagnostic follow-up of


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InternalMed_Harrison. screening trial received annual CXR screening for 4 years, whereas participants in the usual care group received no interventions other than their customary medical care. The diagnostic follow-up of positive screening results was determined by participants and their physicians. The PLCO trial differed from previous lung cancer screening studies in that women and never smokers were eligible. The study was designed to detect a 10% reduction in lung cancer mortality in the interventional group. A total of 154,901 individuals between 55 and 74 years of age were enrolled (77,445 assigned to annual CXR screenings; 77,456 assigned to usual care). Participant demographics and tumor characteristics were well balanced between the two groups. Through 13 years of follow-up, cumulative lung cancer incidence rates (20.1 vs 19.2 per 10,000 person-years; rate ratio [RR], 1.05; 95% confidence interval [CI], 0.98–1.12) and lung cancer mortality (n = 1213 vs n = 1230) were identical between the two


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InternalMed_Harrison. incidence rates (20.1 vs 19.2 per 10,000 person-years; rate ratio [RR], 1.05; 95% confidence interval [CI], 0.98–1.12) and lung cancer mortality (n = 1213 vs n = 1230) were identical between the two groups. The stage and histology of detected cancers in the two groups also were similar. These data corroborate previous recommendations against CXR screening for lung cancer.


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InternalMed_Harrison. In contrast to CXR, low-dose, noncontrast, thin-slice spiral chest computed tomography (LDCT) has emerged as an effective tool to screen for lung cancer. In nonrandomized studies conducted in the 1990s, LDCT scans were shown to detect more lung nodules and cancers than standard CXR in selected high-risk populations (e.g., age ≥60 years and a smoking history of ≥10 pack-years). Notably, up to 85% of the lung cancers discovered in these trials were classified as stage I disease and therefore considered potentially curable with surgical resection.


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InternalMed_Harrison. These data prompted the National Cancer Institute (NCI) to initiate the National Lung Screening Trial (NLST), a randomized study designed to determine if LDCT screening could reduce mortality from lung cancer in high-risk populations as compared with standard posterior anterior CXR. High-risk patients were defined as individuals between 55 and 74 years of age, with a ≥30 pack-year history of cigarette smoking; former smokers must have quit within the previous 15 years. Excluded from the trial were individuals with a previous lung cancer diagnosis, a history of hemoptysis, an unexplained weight loss of >15 lb in the preceding year, or a chest CT within 18 months of enrollment. A total of 53,454 persons were enrolled and randomized to annual screening yearly for three years (LDCT screening, n = 26,722; CXR screening, n = 26,732). Any noncalcified nodule measuring ≥4 mm in any diameter found on LDCT and CXR images with any noncalcified nodule or mass were classified as “positive.”


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InternalMed_Harrison. n = 26,722; CXR screening, n = 26,732). Any noncalcified nodule measuring ≥4 mm in any diameter found on LDCT and CXR images with any noncalcified nodule or mass were classified as “positive.” Participating radiologists had the option of not calling a final screen positive if a noncalcified nodule had been stable on the three screening exams. Overall, 39.1% of participants in the LDCT group and 16% in the CXR group had at least one positive screening result. Of those who screened positive, the false-positive rate was 96.4% in the LDCT group and 94.5% in the CXR group. This was consistent across all three rounds. In the LDCT group, 1060 cancers were identified compared with 941 cancers in the CXR group (645 vs 572 per 100,000 person-years; RR, 1.13; 95% CI, 1.03 to 1.23). Nearly twice as many early-stage IA cancers were detected in the LDCT group compared with the CXR group (40% vs 21%). The overall rates of lung cancer death were 247 and 309 deaths per 100,000 participants in the LDCT


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InternalMed_Harrison. early-stage IA cancers were detected in the LDCT group compared with the CXR group (40% vs 21%). The overall rates of lung cancer death were 247 and 309 deaths per 100,000 participants in the LDCT and CXR groups, respectively, representing a 20% reduction in lung cancer mortality in the LDCT-screened population (95% CI, 6.8–26.7%; p = .004). Compared with the CXR group, the rate of death in the LDCT group from any cause was reduced by 6.7% (95% CI, 1.2–13.6; p = .02) (Table 107-2). The


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InternalMed_Harrison. Neoplasms of the Lung Rates of Events per 100,000 Relative Risk Event Number Person-Years (95% CI) Source: Modified from PB Bach et al: JAMA 307:2418, 2012. number needed to screen (NNTS) to prevent one lung cancer death was calculated to be 320.