Chapter 68: Skin Cancer

Chapter 68: Skin Cancer is a topic covered in the Harrison's Manual of Medicine.

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MALIGNANT MELANOMA

Most dangerous cutaneous malignancy, high metastatic potential, poor prognosis with metastatic spread.

Incidence

Melanoma was diagnosed in 91,270 people in the United States in 2018 and caused 9320 deaths.

Predisposing Factors

Fair complexion, sun exposure, family history of melanoma, dysplastic nevus syndrome (autosomal dominant disorder with multiple nevi of distinctive appearance and cutaneous melanoma may be associated with 9p deletion), and presence of a giant congenital nevus (Table 68-1). Blacks have a low incidence.

TABLE 68-1: Factors Associated with Increased Risk of Melanoma
Total body nevi (higher number = higher risk)
Family or personal history
Dysplastic nevi
Light skin/hair/eye color
Poor tanning ability
Freckling
UV exposure/sunburns/tanning booths
CDKN2A mutation
MC1R variants

Prevention

Sun avoidance lowers risk. Sunscreens are not proven effective.

Types

  1. Superficial spreading melanoma: Most common; begins with initial radial growth phase before invasion.
  2. Lentigo maligna melanoma: Very long radial growth phase before invasion, lentigo maligna (Hutchinson’s melanotic freckle) is precursor lesion, most common in elderly and in sun-exposed areas (esp. face).
  3. Acral lentiginous: Most common form in darkly pigmented pts; occurs on palms and soles, mucosal surfaces, in nail beds and mucocutaneous junctions; similar to lentigo maligna melanoma but with more aggressive biologic behavior.
  4. Nodular: Generally poor prognosis because of invasive growth from onset.

Biology

About half of melanomas carry an activating somatic mutation in the BRAF gene, often a valine to glutamate substitution at amino acid 600 (V600E). N-ras is mutated in about 20% and rare pts have activating mutations in c-kit. These mutations have been targeted by therapeutic agents that have antitumor activity.

Clinical Appearance

Generally pigmented (rarely amelanotic); color of lesions varies, but red, white, and/or blue are common, in addition to brown and/or black. Suspicion should be raised by a pigmented skin lesion that is >6 mm in diameter, asymmetric, has an irregular surface or border, or has variation in color.

Prognosis

Best with thin lesions without evidence of metastatic spread; with increasing thickness, ulceration, or evidence of nodal spread, prognosis worsens. Stage I (primary tumor without spread) has 80−92% 15-year survival. Stage II (>1−4 mm) has a 51−62% 15−year survival. Stage III (regional nodes with tumor) has a 60% 15-year survival when 1−3 nodes are microscopically involved and 22–38% when 1−3 nodes are macroscopically involved or 4 or more are involved. Stage IV (disseminated disease) has <10% 15-year survival.

Treatment: Malignant Melanoma

Early recognition and local excision for localized disease is best; 1- to 2-cm margins are as effective as 4- to 5-cm margins and do not usually require skin grafting. Elective lymph node dissection offers no advantage in overall survival compared with deferral of surgery until clinical recurrence. Pts with stage II disease may have risk of recurrence reduced with adjuvant therapy (immune checkpoint inhibitors or interferon-alpha) but this is controversial. More data support nivolumab or pembrolizumab in resected stage III disease, and perhaps targeted therapy in 50% of pts with BRAF mutations. Metastatic disease may be treated with chemotherapy or immunotherapy (Table 68-2). Vemurafenib 960 mg PO bid or dabrafenib 150 mg PO bid induces responses in about 50% of pts with BRAF mutations. Median survival is about 16 months. Some patients develop secondary keratoacanthomas or squamous cell cancers from activation of the MET pathway. Addition of a MET inhibitor (trametinib 2 mg/d) to a BRAF inhibitor improved response rate to 64% and median overall survival to >20 months and prevented secondary skin cancers. The anti-CTLA4 antibody ipilimumab prolongs survival by about 4 months. The combination of ipilimumab and the PD-1 blocker nivolumab induced responses in both BRAF mutant and BRAF wild-type tumors. Response rate 58% with responses lasting about 12 months. Dacarbazine (250 mg/m2 IV daily × 5 q3w) plus tamoxifen (20 mg/m2 PO daily) may induce partial responses in one-quarter of pts. IFN and interleukin 2 (IL-2) at maximum tolerated doses induce partial responses in 15% of pts. Rare long remissions occur with IL-2. Temozolomide is an oral agent that has some activity. It can enter the central nervous system (CNS) and is being evaluated with radiation therapy for CNS metastases. No therapy for metastatic disease is curative. Vaccines and adoptive cellular therapies are being tested.

TABLE 68-2: Treatment Options for Metastatic Melanoma

Surgery: metastasectomy for small number of lesions

Immunotherapy

 Interleukin-2

Immune checkpoint blockade

  • Anti-CTLA-4: ipilimumab
  • Anti-PD-1: nivolumab, pembrolizumab
  • Combined ipilimumab and nivolumab

Experimental

 Anti-PD-L1

Molecular targeted therapy

 BRAF inhibitor: vemurafenib, dabrafenib

 MEK inhibitor: trametinib, cobimetinib

Oncolytic virus: talimogene laherpaepvec

Chemotherapy: dacarbazine, temozolomide, paclitaxel, albumin-bound paclitaxel, carboplatin

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MALIGNANT MELANOMA

Most dangerous cutaneous malignancy, high metastatic potential, poor prognosis with metastatic spread.

Incidence

Melanoma was diagnosed in 91,270 people in the United States in 2018 and caused 9320 deaths.

Predisposing Factors

Fair complexion, sun exposure, family history of melanoma, dysplastic nevus syndrome (autosomal dominant disorder with multiple nevi of distinctive appearance and cutaneous melanoma may be associated with 9p deletion), and presence of a giant congenital nevus (Table 68-1). Blacks have a low incidence.

TABLE 68-1: Factors Associated with Increased Risk of Melanoma
Total body nevi (higher number = higher risk)
Family or personal history
Dysplastic nevi
Light skin/hair/eye color
Poor tanning ability
Freckling
UV exposure/sunburns/tanning booths
CDKN2A mutation
MC1R variants

Prevention

Sun avoidance lowers risk. Sunscreens are not proven effective.

Types

  1. Superficial spreading melanoma: Most common; begins with initial radial growth phase before invasion.
  2. Lentigo maligna melanoma: Very long radial growth phase before invasion, lentigo maligna (Hutchinson’s melanotic freckle) is precursor lesion, most common in elderly and in sun-exposed areas (esp. face).
  3. Acral lentiginous: Most common form in darkly pigmented pts; occurs on palms and soles, mucosal surfaces, in nail beds and mucocutaneous junctions; similar to lentigo maligna melanoma but with more aggressive biologic behavior.
  4. Nodular: Generally poor prognosis because of invasive growth from onset.

Biology

About half of melanomas carry an activating somatic mutation in the BRAF gene, often a valine to glutamate substitution at amino acid 600 (V600E). N-ras is mutated in about 20% and rare pts have activating mutations in c-kit. These mutations have been targeted by therapeutic agents that have antitumor activity.

Clinical Appearance

Generally pigmented (rarely amelanotic); color of lesions varies, but red, white, and/or blue are common, in addition to brown and/or black. Suspicion should be raised by a pigmented skin lesion that is >6 mm in diameter, asymmetric, has an irregular surface or border, or has variation in color.

Prognosis

Best with thin lesions without evidence of metastatic spread; with increasing thickness, ulceration, or evidence of nodal spread, prognosis worsens. Stage I (primary tumor without spread) has 80−92% 15-year survival. Stage II (>1−4 mm) has a 51−62% 15−year survival. Stage III (regional nodes with tumor) has a 60% 15-year survival when 1−3 nodes are microscopically involved and 22–38% when 1−3 nodes are macroscopically involved or 4 or more are involved. Stage IV (disseminated disease) has <10% 15-year survival.

Treatment: Malignant Melanoma

Early recognition and local excision for localized disease is best; 1- to 2-cm margins are as effective as 4- to 5-cm margins and do not usually require skin grafting. Elective lymph node dissection offers no advantage in overall survival compared with deferral of surgery until clinical recurrence. Pts with stage II disease may have risk of recurrence reduced with adjuvant therapy (immune checkpoint inhibitors or interferon-alpha) but this is controversial. More data support nivolumab or pembrolizumab in resected stage III disease, and perhaps targeted therapy in 50% of pts with BRAF mutations. Metastatic disease may be treated with chemotherapy or immunotherapy (Table 68-2). Vemurafenib 960 mg PO bid or dabrafenib 150 mg PO bid induces responses in about 50% of pts with BRAF mutations. Median survival is about 16 months. Some patients develop secondary keratoacanthomas or squamous cell cancers from activation of the MET pathway. Addition of a MET inhibitor (trametinib 2 mg/d) to a BRAF inhibitor improved response rate to 64% and median overall survival to >20 months and prevented secondary skin cancers. The anti-CTLA4 antibody ipilimumab prolongs survival by about 4 months. The combination of ipilimumab and the PD-1 blocker nivolumab induced responses in both BRAF mutant and BRAF wild-type tumors. Response rate 58% with responses lasting about 12 months. Dacarbazine (250 mg/m2 IV daily × 5 q3w) plus tamoxifen (20 mg/m2 PO daily) may induce partial responses in one-quarter of pts. IFN and interleukin 2 (IL-2) at maximum tolerated doses induce partial responses in 15% of pts. Rare long remissions occur with IL-2. Temozolomide is an oral agent that has some activity. It can enter the central nervous system (CNS) and is being evaluated with radiation therapy for CNS metastases. No therapy for metastatic disease is curative. Vaccines and adoptive cellular therapies are being tested.

TABLE 68-2: Treatment Options for Metastatic Melanoma

Surgery: metastasectomy for small number of lesions

Immunotherapy

 Interleukin-2

Immune checkpoint blockade

  • Anti-CTLA-4: ipilimumab
  • Anti-PD-1: nivolumab, pembrolizumab
  • Combined ipilimumab and nivolumab

Experimental

 Anti-PD-L1

Molecular targeted therapy

 BRAF inhibitor: vemurafenib, dabrafenib

 MEK inhibitor: trametinib, cobimetinib

Oncolytic virus: talimogene laherpaepvec

Chemotherapy: dacarbazine, temozolomide, paclitaxel, albumin-bound paclitaxel, carboplatin

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