CONCEPTUAL SUMMARY
EPIDEMIOLOGY AND RISK FACTORS
Melanoma: Less common than BCC/SCC but accounts for the majority of skin cancer deaths. Risk factors include UV exposure (intermittent intense exposure more closely linked to melanoma than chronic exposure), fair skin/light hair/light eyes, history of atypical/dysplastic nevi, prior melanoma, blistering sunburns especially during youth, immunosuppression, tanning bed use (especially during young adulthood), and family history/genetic mutations. Melanoma can develop in all ethnicities and in areas with minimal sun exposure.
Basal Cell Carcinoma (BCC): Most common skin cancer (~80% of cases). Risk factors include UV exposure, fair complexion, childhood sunburns, chronic inflammation, and genetic conditions.
Squamous Cell Carcinoma (SCC): Second most common skin cancer. Risk factors include CUMULATIVE prolonged sun exposure (NOT intermittent — that is a melanoma risk factor), actinic keratosis, chronic immunosuppression, organ transplantation, and HPV 16 and 18. Intermittent childhood exposure is a melanoma risk factor, NOT SCC.
Merkel Cell Carcinoma (MCC): Rare but aggressive neuroendocrine tumor. Associated with Merkel cell polyomavirus (MCPyV) and UV exposure.
SCREENING AND PREVENTION: Avoid sun exposure between 10 AM–4 PM. Use sunscreen SPF ≥ 15 and reapply every 2 hours. Avoid tanning beds/sunlamps. Monthly self-examination using ABCDE criteria: Asymmetry, Border irregularity, Color variation, Diameter > 6 mm (≈ ¼ inch = approximately 6 mm), Evolving features (E = Evolution, NOT elevation). Lesion > 6 mm (¼ inch) is a screening criterion suspicious for melanoma. Screening is not limited to those with family history alone.
MELANOMA SUBTYPES: Superficial spreading melanoma: most common (70%), evolves from preexisting nevi. Nodular melanoma: aggressive rapid growth, dark blue-black lesions. Lentigo maligna melanoma: rare, less likely to metastasize, elderly patients with sun-damaged skin. Acral lentiginous melanoma: palms, soles, nailbeds — most common in Blacks, Asians, and Hispanics. Mucosal melanoma: rare (1%), head/neck/GI/genital; screen for KIT, NRAS, and BRAF mutations. Uveal melanoma: most common intraocular malignancy; liver is most common metastasis site.
MELANOMA MOLECULAR MARKERS: BRAF V600E/K: ~50% of cutaneous melanomas — targeted therapy with BRAF + MEK inhibitors. NRAS: ~20%. KIT: relevant in mucosal and acral melanomas. BRAF D594N is a NON-V600 mutation — BRAF/MEK inhibitors are NOT effective; pembrolizumab is preferred. BRAF mutation testing is MANDATORY before initiating systemic therapy.
MELANOMA ADJUVANT THERAPY RULES: Stage IIB–IIID: pembrolizumab (approved for stages IIB–IIID). Stage IIIB–IIID: nivolumab OR pembrolizumab. BRAF V600E/K mutated Stage III: dabrafenib + trametinib is an additional option. Encorafenib + binimetinib: ONLY approved for metastatic (Stage IV) BRAF-mutated melanoma — NOT adjuvant. Ipilimumab: NO longer recommended for adjuvant melanoma therapy (removed from current guidelines). Interferon alfa: NO longer recommended — removed from current guidelines. Historical note: both interferon and ipilimumab improved RFS but NOT OS in Stage III melanoma — this is a high-yield exam distinction.
METASTATIC MELANOMA — FIRST-LINE THERAPY: BRAF wild-type: immunotherapy preferred — ipilimumab + nivolumab (combination, high-risk, patients who can tolerate, no contraindications, strong support), pembrolizumab monotherapy, or nivolumab monotherapy. BRAF V600E/K mutated with SYMPTOMATIC or RAPIDLY GROWING tumors: BRAF + MEK inhibitor combination preferred over immunotherapy (faster response). BRAF + MEK combination options: dabrafenib + trametinib, encorafenib + binimetinib, vemurafenib + cobimetinib. Immunotherapy with autoimmune disease history: T-VEC or BRAF/MEK targeted therapy preferred to avoid immune exacerbation. Nivolumab + ipilimumab combination preferred when: patient is young and healthy with no comorbidities, strong social support, willing to accept high irAE risk, and no autoimmune history.
T-VEC (Talimogene Laherparepvec): approved ONLY for unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery — NOT for visceral/distant metastatic disease.
IMMUNE-RELATED ADVERSE EVENTS (irAEs): Skin rash: earliest irAE — typically appears at 2–3 weeks. GI toxicity/elevated LFTs: typically appears at 6–7 weeks. Endocrine toxicity (hypothyroidism, hypophysitis): typically appears at ≥ 9 weeks (can be prolonged). Flu-like symptoms: NOT characteristic of checkpoint inhibitors (more typical of interferon). Grade 3 diarrhea/colitis: hold immunotherapy + IV methylprednisolone (preferred over oral because GI absorption may be impaired). Grade 1–2 hypothyroidism (TSH < 10 mIU/L, asymptomatic): continue immunotherapy + monitor TSH/T4. Grade 2 hypothyroidism (TSH > 10 mIU/L, symptomatic): continue or hold immunotherapy (clinical judgment) + start levothyroxine — NO steroids needed for isolated hypothyroidism. Grade 3+ immune colitis not responding to steroids after 1 week: infliximab — but MUST perform PPD (TB) testing BEFORE infliximab (risk of TB reactivation). Hypophysitis/secondary adrenal insufficiency (hypotension, tachycardia, low BP, fatigue): perform ACTH stimulation test → hold immunotherapy + start steroids. Pseudoprogression: early tumor growth on imaging with clinical stability = continue immunotherapy (immune-related response criteria/irRC used instead of RECIST).
DABRAFENIB + TRAMETINIB FEVER (PYREXIA): Hold BOTH dabrafenib and trametinib at onset of fever. Restart at full dose once fever resolves. Prednisone is used only for prolonged or severe pyrexia that does not resolve with holding therapy alone.
BRAF/MEK INHIBITOR MONITORING: Baseline and routine: CBC, CMP, CPK (creatinine phosphokinase — binimetinib can increase CK), ECG (QTc prolongation risk), echocardiogram (cardiac dysfunction monitoring), and routine eye exams (retinal detachment, macular edema, visual impairment risk).
ADVANCED BCC TREATMENT: Hedgehog pathway inhibitors are the most active agents: vismodegib (first choice) or sonidegib. Vismodegib key toxicity: dysgeusia (changes in taste) — most common all-grade toxicity (~55% of patients). Other vismodegib toxicities: weight loss (~45%, NOT weight gain), alopecia, muscle spasms. Secondary skin cancers, hypothyroidism, and weight GAIN are NOT side effects of hedgehog inhibitors.
ADVANCED CSCC AND MCC: Advanced CSCC: cemiplimab or pembrolizumab (PD-1 inhibitors preferred). Metastatic MCC: avelumab, pembrolizumab, or nivolumab (immunotherapy preferred). Chemotherapy (cisplatin, carboplatin) for MCC is reserved for patients ineligible for immunotherapy.
MUCOSAL MELANOMA GENETIC SCREENING: Screen for KIT, NRAS, AND BRAF mutations — all three are relevant in mucosal melanoma.
PRACTICE QUESTIONS — MELANOMA AND NON-MELANOMA SKIN CANCERS
AB is a 52-year-old man with newly diagnosed stage IIIB melanoma involving his right upper back. He underwent complete wide resection. NGS confirms BRAF V600E mutation. No satellite or in-transit lesions. AB wishes to pursue adjuvant therapy. Which of the following is the most appropriate adjuvant treatment for AB at this time?
A. Encorafenib and binimetinib
B. Interferon alfa
C. Dabrafenib and trametinib
D. Nivolumab and ipilimumab
Explanation: For stage IIIB melanoma with BRAF V600E mutation, adjuvant options include pembrolizumab, nivolumab, or dabrafenib + trametinib (for BRAF V600E/K mutated patients). Dabrafenib + trametinib is the appropriate BRAF-targeted adjuvant choice for this BRAF V600E-positive patient. Encorafenib + binimetinib (option A) is only approved in the METASTATIC setting — not as adjuvant therapy. Interferon alfa (option B) has been REMOVED from current NCCN guidelines now that safer, more effective options exist. Nivolumab + ipilimumab (option D) is also NOT approved as adjuvant therapy — nivolumab monotherapy (not the combination) is approved adjuvantly, and this combination is used only in the metastatic setting.
[/expand]HB is a 57-year-old man with stage IIIC BRAF wild-type melanoma. He underwent wide excision with negative margins and will start adjuvant pembrolizumab. Which immune-related toxicity is most likely to occur during the first 4 weeks of treatment with pembrolizumab?
A. Skin rash
B. Hypothyroidism
C. Flu-like symptoms
D. Elevated liver enzymes
Explanation: Skin rash is the earliest-onset irAE with checkpoint inhibitors — typically appearing after 2–3 weeks of therapy. GI side effects (diarrhea, colitis) and elevated liver enzymes generally appear later, around 6–7 weeks. Endocrine toxicities including hypothyroidism and hypophysitis are typically seen after several doses — around 9 weeks or later and can persist for a prolonged period. Flu-like symptoms (option C) are NOT characteristic of PD-1 inhibitors like pembrolizumab — they are more typically associated with interferon therapy.
[/expand]AC is a 45-year-old female with metastatic melanoma (liver lesions, BRAF V600E positive). She is started on nivolumab + ipilimumab. After 2 doses, she develops grade 3 diarrhea. What is the most appropriate treatment to manage AC's grade 3 diarrhea?
A. Loperamide (high dose)
B. Octreotide
C. Methylprednisolone
D. Infliximab
Explanation: Corticosteroids are the mainstay of treatment for immune-related toxicities. Because AC has grade 3 diarrhea, GI absorption may be significantly impaired — IV methylprednisolone is preferred over oral prednisone for reliable systemic delivery. Loperamide (option A) and octreotide (option B) address symptoms but do not target the immune-mediated mechanism causing the colitis. Infliximab (option D) is reserved for grade 3–4 immune colitis that does NOT respond to high-dose corticosteroid therapy — it is a second-step escalation, not first-line.
[/expand]Eight months after completing combined immunotherapy, AC has progressive disease with increased tumor burden and worsening symptoms. She has BRAF V600E mutation. Which is the best subsequent treatment option for AC?
A. Talimogene laherparepvec (T-VEC)
B. Pembrolizumab
C. Vemurafenib
D. Dabrafenib and trametinib
Explanation: AC has progressed on combined immunotherapy and has symptomatic BRAF V600E-mutated metastatic melanoma. The combination of a BRAF inhibitor + MEK inhibitor (dabrafenib + trametinib) produces superior outcomes compared to BRAF inhibitor monotherapy and is the appropriate next choice. T-VEC (option A) is approved only for unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery — it is NOT approved for visceral/distant metastatic disease (AC has liver metastases). Pembrolizumab (option B) — retreating with a different PD-1 inhibitor after prior IO progression has limited evidence outside of clinical trials. Vemurafenib alone (option C) — BRAF monotherapy produces inferior outcomes compared to BRAF + MEK combination (higher resistance rates); combination therapy is preferred.
[/expand]AC begins dabrafenib and trametinib. After 3 weeks of therapy, she develops a persistent temperature of 39°C. How should this be managed?
A. Continue therapy and start prednisone 10 mg PO daily
B. Hold dabrafenib and trametinib until fever has resolved, then restart at full dose
C. Hold trametinib only until fever has resolved, then restart at full dose
D. Hold dabrafenib and trametinib and start prednisone 20 mg PO daily
Explanation: Pyrexia (fever) is a well-known toxicity of dabrafenib and trametinib. The standard management for fever is to HOLD BOTH agents simultaneously until the fever resolves, then restart at the FULL DOSE — dose reduction is not the initial step. Prednisone may be used for prolonged or severe pyrexia that does not resolve simply by holding therapy — but it is not the first step. Holding only one agent (option C) is not the guideline-recommended approach — both must be held together.
[/expand]TC is a 78-year-old male with a history of multiple BCCs. After Mohs surgery and radiation for a sclerosing BCC with extensive positive margins, he develops recurrence with numerous satellite lesions 8 months later. What is the most appropriate systemic therapy for TC's recurrent BCC?
A. Fluorouracil
B. Cisplatin
C. Ipilimumab
D. Vismodegib
Explanation: Hedgehog pathway inhibitors (vismodegib and sonidegib) are the most active systemic agents for advanced or metastatic BCC. Vismodegib is the appropriate systemic therapy for TC's recurrent BCC with satellite lesions. Chemotherapy (fluorouracil, cisplatin — options A and B) has shown very limited response in BCC. Ipilimumab (option C) is not currently recommended for BCC treatment.
[/expand]Which toxicity with vismodegib is most appropriate to discuss with TC prior to starting therapy?
A. Changes in taste
B. Secondary skin cancers
C. Hypothyroidism
D. Weight gain
Explanation: Dysgeusia (changes in taste) is one of the most common all-grade toxicities with vismodegib, occurring in approximately 55% of patients. Weight LOSS (not weight gain — option D) occurs in approximately 45% of patients. Secondary skin cancers (option B) are not associated with hedgehog inhibitors. Hypothyroidism (option C) is not a common side effect of vismodegib.
[/expand]LB is a 42-year-old female with newly diagnosed stage IIC melanoma involving her upper back. NGS confirms BRAF V600E mutation. She wishes to pursue adjuvant therapy. Which of the following is the most appropriate adjuvant treatment for LB at this time?
A. Ipilimumab
B. Nivolumab
C. Encorafenib and binimetinib
D. Pembrolizumab
Explanation: Pembrolizumab is now approved for adjuvant therapy in resected stage IIB to IIID melanoma — making it the appropriate choice for LB who has stage IIC disease. Nivolumab (option B) is approved for adjuvant treatment in stage IIIB to IIID only — NOT stage IIC. Encorafenib + binimetinib (option C) is only approved for BRAF-mutated METASTATIC (Stage IV) melanoma — not adjuvant. Ipilimumab (option A) is NO LONGER recommended for adjuvant melanoma therapy in current NCCN guidelines.
[/expand]KL is a 48-year-old woman with BRAF wild-type metastatic melanoma (lung metastases). She is asymptomatic with no significant PMH and strong family support. She wishes to be as aggressive as possible with treatment. Which of the following treatment options is most appropriate for KL at this time?
A. Pembrolizumab
B. Vemurafenib + cobimetinib + atezolizumab
C. Ipilimumab and nivolumab
D. Pembrolizumab and low-dose ipilimumab
Explanation: KL is young, healthy (no comorbidities, no autoimmune history), has strong family support, and is willing to accept the higher toxicity risk of combination immunotherapy. Ipilimumab + nivolumab is most appropriate here because: no contraindications to immunotherapy, strong support system, can tolerate high irAE risk, and the patient desires aggressive treatment. Combination immunotherapy has superior response rates over monotherapy in eligible patients. Pembrolizumab monotherapy (option A) is appropriate but less aggressive than the combination. Pembrolizumab + low-dose ipilimumab (option D) is a Category 2A recommendation — less preferred. Vemurafenib + cobimetinib + atezolizumab (option B) is not indicated since KL has NO BRAF V600 mutation.
[/expand]KL starts ipilimumab + nivolumab × 4 doses then continues nivolumab monotherapy. At 3 months, she has low-grade fatigue with disease responding to therapy. TSH = 12 mIU/L. What is the most appropriate management strategy at this time?
A. Continue nivolumab and monitor TSH
B. Hold nivolumab until TSH normalizes
C. Continue nivolumab and start levothyroxine
D. Continue nivolumab and start levothyroxine + prednisone 1 mg/kg
Explanation: KL has grade 2 hypothyroidism — symptomatic (low-grade fatigue) with TSH > 10 mIU/L (TSH = 12). Thyroid supplementation with levothyroxine is recommended for symptomatic patients with TSH > 10 mIU/L, with monitoring every 6–8 weeks while the dose is titrated. Nivolumab may be continued — holding is based on clinical judgment based on severity; since she only has low-grade fatigue, continuing is appropriate. Steroids (option D) are NOT used for immune-related isolated hypothyroidism — unlike other irAEs, hypothyroidism is managed with hormone replacement, not immunosuppression.
[/expand]MT is a 51-year-old man with metastatic melanoma (scalp, liver, lungs, numerous lymph nodes). BRAF V600E mutation confirmed. He has moderate-to-severe dyspnea requiring oxygen and moderate abdominal pain requiring daily opioids. Which of the following options is most appropriate first-line therapy for MT?
A. Talimogene laherparepvec (T-VEC)
B. Pembrolizumab + low-dose ipilimumab
C. Vemurafenib monotherapy
D. Encorafenib and binimetinib
Explanation: MT has SYMPTOMATIC, rapidly progressive BRAF V600E-mutated metastatic melanoma — BRAF + MEK inhibitor combination is preferred over immunotherapy when patients are symptomatic and/or have rapidly growing tumors, because targeted therapy produces faster responses. Encorafenib + binimetinib is an approved BRAF + MEK combination for metastatic BRAF-mutated melanoma. T-VEC (option A) is only for unresectable cutaneous/subcutaneous/nodal lesions after initial surgery — NOT for visceral metastatic disease. Vemurafenib monotherapy (option C) is inferior to BRAF + MEK combination therapy (higher resistance rates). Pembrolizumab + low-dose ipilimumab (option B) could be appropriate for BRAF-mutated asymptomatic patients, but given MT's symptomatic disease, targeted therapy provides faster clinical benefit.
[/expand]MT is beginning treatment with encorafenib and binimetinib. What baseline labs or other monitoring should be ordered?
A. Magnesium and phosphorus levels
B. CBC, CMP, CPK, ECG, echocardiogram, and routine eye exams
C. PFTs, chest X-ray, CMP
D. INR, PT/PTT
Explanation: BRAF/MEK inhibitor combinations require comprehensive baseline monitoring: CBC (for anemia, thrombocytopenia, leukopenia), CMP including LFTs (potential liver function elevation) and renal function, CPK/creatinine kinase (binimetinib can cause significant CK elevation — myopathy risk), ECG (BRAF/MEK inhibitors have QTc prolongation warnings — baseline and routine monitoring required), echocardiogram (baseline and repeated monitoring for cardiac dysfunction, especially with prior low EF or signs of cardiac toxicity), and routine eye exams (visual impairment, retinal detachment, macular edema are known toxicities). Options A, C, and D do not encompass the comprehensive monitoring required for this regimen.
[/expand]JC is a 53-year-old male with recurrent BRAF wild-type cutaneous melanoma of his right upper arm. His lesion is deemed unresectable. Scans are negative for distant metastases. He has a history of poorly controlled rheumatoid arthritis. Which treatment option is most appropriate for JC?
A. Pembrolizumab
B. Encorafenib and binimetinib
C. Talimogene laherparepvec (T-VEC)
D. Ipilimumab and nivolumab
Answer: C. Talimogene laherparepvec (T-VEC)
Explanation: JC has unresectable cutaneous/nodal recurrent melanoma WITHOUT distant metastases — this fits the approved indication for T-VEC (unresectable cutaneous, subcutaneous, and nodal lesions, melanoma recurrent after initial surgery). His poorly controlled rheumatoid arthritis is a significant consideration: active autoimmune disease is a relative contraindication to checkpoint inhibitors (pembrolizumab — option A, and ipilimumab + nivolumab — option D) because immunotherapy can exacerbate autoimmune conditions. He has no BRAF V600 mutation, so encorafenib + binimetinib (option B) is not indicated.
[/expand]SR is a 45-year-old female on ipilimumab + nivolumab for metastatic melanoma. Two weeks after cycle 3, she calls the triage nurse with persistent watery diarrhea 8–10 times per day with abdominal cramping. What is the most appropriate management strategy at this time?
A. Continue therapy and start loperamide
B. Hold therapy and start mycophenolate 1g BID
C. Hold therapy, monitor electrolytes, start prednisone 1 mg/kg/day
D. Skip cycle 4 and start nivolumab maintenance
Explanation: SR has grade 3 immune-related colitis (8–10 diarrheal episodes/day with abdominal cramping). Management: HOLD immunotherapy immediately + initiate corticosteroids (prednisone 1 mg/kg/day) + monitor electrolytes (risk of dehydration and electrolyte abnormalities). Dose escalation to 2 mg/kg/day is warranted if no initial response. Hospitalization may be needed for electrolyte monitoring. Loperamide (option A) addresses symptoms but not the immune-mediated mechanism. Mycophenolate (option B) is used in rare cases of steroid-refractory colitis — not a first-line agent. Skipping one cycle then restarting (option D) does not address the acute grade 3 toxicity requiring treatment.
[/expand]A 60-year-old male with BRAF wild-type metastatic melanoma is on nivolumab. He is clinically well and tolerating therapy. First follow-up CT shows interval growth in two lung nodules (2→3 cm and 1→2 cm) with multiple other nodules stable. What should be the next step in treatment?
A. Continue nivolumab
B. Change from nivolumab to pembrolizumab
C. Add ipilimumab to nivolumab
D. Discontinue nivolumab and start dacarbazine
Explanation: This presentation is consistent with PSEUDOPROGRESSION — a phenomenon unique to immunotherapy where early imaging shows tumor growth but the patient is clinically stable and tolerating therapy. Because of this, immune-related response criteria (irRC) replace RECIST for evaluating immunotherapy response. Since the patient is clinically doing well, nivolumab should be continued. Changing to a different PD-1 inhibitor (option B) has no evidence for benefit. Adding ipilimumab once nivolumab is already started (option C) is not evidence-based. Dacarbazine (option D) is chemotherapy with inferior outcomes compared to checkpoint inhibitors — switching to chemotherapy prematurely would be inappropriate.
[/expand]A 55-year-old male has Stage IIIC, BRAF wild-type melanoma after complete resection and therapeutic inguinal lymph node dissection. He asks what can be done to reduce his high risk of relapse. Which statement is the most accurate regarding adjuvant treatment options in Stage III melanoma?
- Adjuvant use of either interferon or ipilimumab has shown improvement in OS but not RFS in Stage III melanoma
- Adjuvant use of either interferon or ipilimumab has shown improvement in RFS but not OS in Stage III melanoma
- Adjuvant ipilimumab has shown improvement in OS while interferon has not
- Adjuvant interferon has shown improvement in OS while ipilimumab has not
Explanation: This is a critical high-yield distinction. Both interferon alfa (FDA approved in 1995) and ipilimumab (FDA approved in 2015) received approvals for Stage III melanoma adjuvant use based on improved RELAPSE-FREE SURVIVAL (RFS) only — neither agent demonstrated improved OVERALL SURVIVAL (OS). This is why both agents have been superseded by pembrolizumab and nivolumab, which have stronger efficacy and more favorable safety profiles. No adjuvant therapy has yet conclusively demonstrated OS benefit in Stage III melanoma in all comers — though newer checkpoint inhibitor trials have shown promising OS trends.
[/expand]A 60-year-old female on ipilimumab + nivolumab for metastatic melanoma presents to clinic for her fourth dose. She is fatigued, hypotensive (BP 80/45), tachycardic to 120s, and afebrile. BMP, LFTs, TSH, and CBC are all normal. She is started on IV fluids. What should be the next step in management?
A. Initiate broad-spectrum antibiotics
B. Perform echocardiogram
C. Perform ACTH stimulation test
D. Proceed with treatment as planned after IVF administration
Explanation: This patient has a clinical picture consistent with hypophysitis causing secondary adrenal insufficiency — a recognized irAE of combination checkpoint inhibitor therapy, with increased incidence after the third or fourth doses. Symptoms include fatigue, hypotension, and tachycardia with otherwise normal labs (TSH normal because the problem is upstream at the pituitary, not the thyroid). ACTH stimulation test — along with serum cortisol measurement and potentially brain MRI — is needed to evaluate pituitary axis. Broad-spectrum antibiotics (option A) would be appropriate if infectious etiology were suspected — but the immune therapy context strongly suggests immune-mediated cause. Echocardiogram (option B) is for cardiac toxicity — less likely here. Proceeding with immunotherapy (option D) is contraindicated — immunotherapy must be HELD and steroids initiated if hypophysitis is confirmed.
[/expand]A 50-year-old male on ipilimumab + nivolumab for metastatic melanoma develops grade 3 immune colitis confirmed on CT. After 1 week of high-dose steroids, his diarrhea has not significantly decreased. C. difficile is negative. What diagnostic test should be performed in anticipation of the next therapeutic step?
A. Repeat CT abdomen/pelvis
B. Colonoscopy
C. Hepatitis B testing
D. PPD testing for tuberculosis
Explanation: For immune-mediated colitis that does NOT respond to corticosteroids, the next therapeutic step is infliximab (anti-TNF-α monoclonal antibody). However, infliximab carries a risk of tuberculosis reactivation — therefore, PPD (tuberculin skin test) or IGRA testing for TB must be performed BEFORE administering infliximab. Repeat CT (option A) and colonoscopy (option B) would be for further diagnostic workup but are not the required pre-step for the next therapeutic escalation. Hepatitis B testing (option C) is important before some biologic therapies but is not the priority pre-infliximab test in this scenario — TB testing is the critical safety step.
[/expand]A 35-year-old female with multiple sclerosis is diagnosed with BRAF V600E-mutated melanoma metastatic to the lungs. She is clinically well-appearing. What would be the most appropriate first-line therapy?
A. Dabrafenib + trametinib
B. Trametinib monotherapy
C. Ipilimumab + nivolumab
D. Nivolumab monotherapy
E. Dacarbazine
Explanation: This patient has multiple sclerosis — an active autoimmune disease — making checkpoint inhibitors (options C and D) high-risk due to potential exacerbation of MS through immune activation. Molecularly targeted therapy (dabrafenib + trametinib) has a safer toxicity profile for patients with pre-existing autoimmune conditions. Since she has a BRAF V600E mutation, dabrafenib + trametinib (BRAF + MEK combination) is the preferred approach — superior to trametinib monotherapy alone (option B). Dacarbazine (option E) has very low efficacy and is not first-line in the modern era.
[/expand]A 75-year-old male is diagnosed with melanoma of the rectal mucosa following workup for hematochezia. Which of the following genetic mutations should you screen for?
A. KIT
B. NRAS
C. CDKN2A
D. BRAF
E. A, B, and D
Explanation: Mucosal melanomas (such as rectal melanoma) are molecularly distinct from cutaneous melanomas and frequently harbor mutations in KIT, NRAS, AND BRAF. Screening for all three is important to identify targeted therapy options. KIT mutations specifically are more common in mucosal and acral melanomas than in cutaneous disease. CDKN2A (option C) is associated with familial cutaneous melanoma predisposition — it is less relevant in mucosal melanoma and not a target for directed therapy.
[/expand]Which of the following is NOT a risk factor for squamous cell carcinoma (SCC) of the skin?
A. HPV 16 and 18
B. Intermittent exposure during childhood and youth more than prolonged exposure
C. Immunosuppressive diseases
D. Organ transplantation
Explanation: Intermittent, intense sun exposure during childhood and youth is a risk factor for MELANOMA — NOT squamous cell carcinoma. SCC of the skin is associated with CUMULATIVE, PROLONGED sun exposure over years (chronic UV exposure), actinic keratosis, chronic immunosuppression, organ transplantation (highest risk), and HPV 16 and 18 infection. This is a classic melanoma vs. SCC distinction frequently tested: intermittent exposure → melanoma; chronic cumulative exposure → SCC.
[/expand]Which of the following is correct about melanoma screening?
A. It depends only on shape and size of lesion
B. It should be done only for those with a family history of skin cancers
C. E in the ABCDE clinical features means elevation
D. One of the screening criteria: lesion larger than ¼ inch is suspected to be melanoma
Explanation: Diameter > 6 mm (approximately ¼ inch) is the D criterion in the ABCDE rule for melanoma screening — lesions exceeding this size are suspicious for melanoma. Option A is incorrect — screening involves multiple factors (ABCDE criteria), not just shape and size. Option B is incorrect — screening is recommended for all individuals with UV exposure risks, not solely those with family history. Option C is incorrect — E in ABCDE stands for EVOLUTION (changes over time in size, shape, color, new bleeding/crusting), NOT elevation. Elevation is not part of the ABCDE criteria.
[/expand]HC is a 56-year-old man with newly diagnosed stage IIIB melanoma after complete wide excision. NGS confirms BRAF D594N mutation (a non-V600 mutation). He wishes to pursue adjuvant therapy. Which of the following is the most appropriate adjuvant treatment for HC?
A. Ipilimumab
B. Interferon alfa
C. Dabrafenib and trametinib
D. Pembrolizumab
Explanation: HC has a BRAF D594N mutation — this is a NON-V600 mutation. BRAF/MEK inhibitors (dabrafenib + trametinib, option C) are NOT effective for non-V600 BRAF mutations — they are specifically approved and effective only for BRAF V600E/K mutations. Therefore, pembrolizumab (anti-PD-1 immunotherapy) is the appropriate adjuvant choice. Ipilimumab (option A) is NO LONGER recommended in current NCCN adjuvant melanoma guidelines. Interferon alfa (option B) has also been REMOVED from current guidelines in favor of safer, more effective options.
[/expand]BF is a 63-year-old female with stage IIIB BRAF-negative superficial spreading melanoma (3.8 mm, T3b, 2 positive local lymph nodes — N2a). She underwent wide local excision and sentinel lymph node biopsy. What is the most appropriate adjuvant therapy for BF?
A. Nivolumab
B. Ipilimumab
C. Interferon alfa
D. Dabrafenib and trametinib
Explanation: BF has stage IIIB BRAF-negative melanoma — adjuvant options include nivolumab or pembrolizumab. Nivolumab is approved for adjuvant treatment in stage IIIB–IIID melanoma. Dabrafenib + trametinib (option D) requires BRAF V600 activating mutation — BF is BRAF-negative. Interferon alfa (option C) has been REMOVED from current NCCN guidelines. Ipilimumab (option B) is also NO LONGER included in current adjuvant melanoma guidelines.
[/expand]Three months into ipilimumab + nivolumab therapy, AC is tolerating therapy well with minimal side effects and responding to treatment. TSH level is 8 mIU/L. He is asymptomatic. What is the most appropriate management strategy at this time?
A. Continue therapy with nivolumab and monitor TSH and T4
B. Hold nivolumab until TSH normalizes
C. Hold nivolumab and start thyroid replacement
D. Continue nivolumab and start thyroid replacement + prednisone 1 mg/kg
Explanation: AC has grade 1 hypothyroidism — asymptomatic with TSH < 10 mIU/L (TSH = 8). For grade 1, the appropriate management is to CONTINUE nivolumab and MONITOR TSH and T4 closely. Thyroid supplementation is not yet indicated — it is recommended only when the patient is symptomatic AND TSH is persistently > 10 mIU/L. Holding nivolumab (options B and C) is not warranted for grade 1 hypothyroidism without symptoms. Steroids (option D) are NEVER used for isolated immune-related hypothyroidism — they are not part of management of this specific irAE.
[/expand]80. Which tyrosine kinase inhibitor is targeted towards BRAF mutations in melanoma patients?
- Erlotinib (Tarceva) (20%)
- Sorafenib (Nexavar) (15%)
- Vandetanib (Caprelsa) (9%)
- Vemurafenib (Zelboraf) (57%)
- Vemurafenib is a tyrosine kinase inhibitor for the BRAF target.
- It is indicated for the treatment of metastatic or unresectable BRAF V600E mutation melanoma.
- Both its generic (vemurafenib) and brand name (Zelboraf®) have the RAF designation, which indicates it has activity against BRAF.
- Sorafenib also has RAF in its name as active against BRAF; however, it is not active in melanoma patients.