Quick Medical Diagnosis & Treatment 2021

Melanoma, Malignant

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For further information, see CMDT Part 6-08: Malignant Melanoma

Key Features

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Essentials of Diagnosis

ABCDE mnemonic = Asymmetry, Border irregularity, Color variegation, Diameter > 6 mm, Evolution
May be flat or raised
Should be suspected in any pigmented skin lesion with recent change in appearance
Examination with good light may show varying colors, including red, white, black, and blue
Borders typically irregular

General Considerations

Leading cause of death due to skin disease and fifth most common cancer
Primary malignant melanomas may be classified into various clinicohistologic types
- Lentigo maligna melanoma (arising on chronically sun-exposed skin of older individuals)
- Superficial spreading malignant melanoma (two-thirds of all melanomas arising on intermittently sun-exposed skin)
- Nodular malignant melanoma
- Acral-lentiginous melanomas (arising on palms, soles, and nail beds)
  - Diagnosis may be difficult or delayed because benign pigmented lesions in these areas occur commonly in more darkly pigmented persons; clinicians may hesitate to biopsy the palms and especially the soles and nail beds
  - Clinicians should give special attention to new or changing lesions in these areas
- Malignant melanomas on mucous membranes

Demographics

One in four cases of melanoma occur before the age of 40
In 2018, approximately 96,480 new melanomas were diagnosed in the United States, approximately 60% cases in men
In 2018, melanoma caused an estimated 7230 deaths (two-thirds in men)

Clinical Findings

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Symptoms and Signs

An irregular notched border where the pigment appears to be leaking into the normal surrounding skin
Topography may be irregular, ie, partly raised and partly flat
Color variegation, and colors such as pink, blue, gray, white, and black are indications for referral
A mole that stands out from the patient's other moles (the "ugly duckling sign")
A patient with a large number of moles is at increased risk for melanoma
The history of a changing mole (evolution including bleeding and ulceration) is the single most important historical reason for close evaluation and possible referral
Acral lentiginous melanomas: dark, sometimes irregularly shaped lesions on the palms and soles and new, often broad and solitary, darkly pigmented longitudinal streaks in the nails

Differential Diagnosis

Acquired nevus (mole), eg, junctional nevus, compound nevus
Seborrheic keratosis
Lentigo, eg, solar lentigo
Dermatofibroma
Basal cell carcinoma (pigmented type)
Congenital nevus
Atypical (dysplastic) nevus
Blue nevus
Halo nevus
Pyogenic granuloma
Kaposi sarcoma
Pregnancy-associated darkening of nevi

Treatment

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Medications

The long-term use of β-blockers may reduce the risk of progression of high-risk melanoma

Surgery

Treatment starts with excision
- After histologic diagnosis, reexcision is recommended with margins dictated by the thickness of the tumor
- Surgical margins of 0.5 cm for melanoma in situ and 1 cm for lesions < 1 mm in thickness are most often recommended
Sentinel lymph node biopsy (selective lymphadenectomy) using preoperative lymphoscintigraphy and intraoperative lymphatic mapping
- Effective for staging melanoma patients with intermediate risk without clinical adenopathy
- Recommended for all patients with lesions over 1 mm in thickness or with high-risk histologic features
- May not confer a survival advantage

Therapeutic Procedures

Identifying the oncogenic mutations in patients with advanced melanoma may dictate targeted therapy, most commonly to specific BRAF mutations
Immunotherapy directed toward immune costimulatory molecules such as PD-1 activates systemic immune-directed destruction of metastatic melanoma (see Table 39–2)

Table 39–2.Treatment choices for cancers responsive to systemic agents.

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Table 39–2. Treatment choices for cancers responsive to systemic agents.

Diagnosis

Initial Treatment

Acute lymphoblastic leukemia (ALL)

Induction combination chemotherapy (Philadelphia chromosome-positive): Cyclophosphamide, vincristine, doxorubicin/daunorubicin, dexamethasone (hyper-CVAD) alternating with cytarabine, methotrexate; add imatinib or dasatinib or nilotinib

Induction combination chemotherapy (Philadelphia chromosome–negative): Daunorubicin, vincristine, prednisone, pegaspargase, cyclophosphamide; or hyper-CVAD) alternating with methotrexate and cytarabine

Maintenance chemotherapy: Methotrexate, 6-mercaptopurine, vincristine, prednisone

Acute myeloid leukemia (AML)

Induction combination chemotherapy:

Cytarabine with daunorubicin or idarubicin,

with gemtuzumab ozogamicin (CD33-positive), or
with midostaurin (FLT3-mutated), or
with cladribine, or
with fludarabine

Alternative chemotherapy for ≥ 60 years old:

Azacitidine, decitabine, or low-dose cytarabine with or without venetoclax; or

Glasdegib plus cytarabine; or

Ivosidenib (IDH1 mutation); or

Enasidenib (IDH2 mutation)

Chronic myeloid leukemia (CML)

Nilotinib or Dasatinib or Imatinib or Bosutinib

Chronic lymphocytic leukemia (CLL)

Combination chemotherapy: Venetoclax, obinutuzumab

Single-agent chemotherapy: Ibrutinib

Hairy cell leukemia

Cladribine or pentostatin

Hodgkin lymphoma

Combination chemotherapy: Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), or

Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP)

Non-Hodgkin lymphoma (intermediate and high grade)

Combination chemotherapy: Cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab (CHOP-R), or

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (dose-adjusted R-EPOCH) (for double-/triple-hit)

Non-Hodgkin lymphoma (low grade)

Combination chemotherapy:

Bendamustine plus obinutuzumab or rituximab, or

Cyclophosphamide, vincristine, doxorubicin, prednisone, rituximab (CHOP-R), or

Cyclophosphamide, vincristine, prednisone, rituximab (CVP-R), or

Lenalidomide, rituximab

Plasma cell myeloma

Combination chemotherapy (transplant candidates):

Bortezomib, dexamethasone, cyclophosphamide, or

Bortezomib, dexamethasone, lenalidomide

Followed by autologous or mini-allogeneic stem cell transplantation

Combination chemotherapy (non-transplant candidates):

Bortezomib, lenalidomide, dexamethasone, or

Daratumumab, lenalidomide, dexamethasone, or

Lenalidomide, dexamethasone, or

Bortezomib, cyclophosphamide, dexamethasone

Waldenström macroglobulinemia

Plasmapheresis alone or followed by combination chemotherapy:

Bortezomib, dexamethasone, rituximab, or

Cyclophosphamide, dexamethasone, rituximab, or

Bendamustine, rituximab

Polycythemia vera

Phlebotomy or hydroxyurea or aspirin

Non–small cell lung cancer

Combination chemotherapy:

Cisplatin, vinorelbine, or

Cisplatin, etoposide, or

Paclitaxel, carboplatin, or

Cisplatin, gemcitabine or docetaxel (squamous histology), or

Cisplatin, pemetrexed (nonsquamous histology), or

Carboplatin, albumin-bound paclitaxel, or

Dabrafenib/trametinib (BRAF V600F mutation), or

Pembrolizumab; carboplatin or cisplatin/pemetrexed/pembrolizumab (nonsquamous); carboplatin/paclitaxel/bevacizumab/atezolizumab (nonsquamous); carboplatin/paclitaxel or albumin-bound paclitaxel/pembrolizumab (squamous) (PD-L1 expression)

Single-agent chemotherapy:

Erlotinib, gefitinib, osimertinib, afatinib or dacomitinib (EGFR mutation positive)

Crizotinib, alectinib, ceritinib, or brigatinib (ALK mutation positive)

Ceritinib, crizotinib, or entrectinib (ROS1 rearrangement)

Larotrectinib or entrectinib (NTRK gene fusion positive)

Small cell lung cancer

Combination chemotherapy:

Cisplatin, etoposide, or

Carboplatin, etoposide, or

Carboplatin, etoposide, atezolizumab

Mesothelioma

Combination chemotherapy:

Cisplatin or carboplatin, pemetrexed, with or without bevacizumab or

Gemcitabine, cisplatin

Single-agent chemotherapy: Pemetrexed or vinorelbine

Head and neck cancer

Combination chemotherapy:

Cisplatin, 5-fluorouracil, or

Paclitaxel, carboplatin, or

Docetaxel, cisplatin, 5-fluorouracil, or

Cisplatin or cetuximab with radiation therapy, or

Cisplatin or carboplatin/5-fluorouracil/cetuximab, or

Pembrolizumab (PD-L1 expression), or

Pembrolizumab/cisplatin or carboplatin/5-fluorouracil

Esophageal and esophagogastric junction cancer

Combination chemotherapy: Cisplatin, 5-fluorouracil or capecitabine, or

Paclitaxel, carboplatin, or

Oxaliplatin, 5-fluorouracil or capecitabine, or

Add trastuzumab for HER2-overexpressing metastatic adenocarcinoma

Uterine cancer

Hormone therapy: Progestins, tamoxifen, aromatase inhibitors, or fulvestrant, or

Combination chemotherapy:

Carboplatin, paclitaxel

Carboplatin, paclitaxel, trastuzumab (HER2 positive)

Ovarian cancer

Combination chemotherapy:

Paclitaxel, carboplatin with or without bevacizumab, or

Carboplatin, liposomal doxorubicin, or

Docetaxel, carboplatin, or

Paclitaxel, cisplatin

Cervical cancer

With radiation: Cisplatin or carboplatin

Combination chemotherapy:

Cisplatin or carboplatin, paclitaxel with or without bevacizumab, or

Cisplatin, topotecan, or

Topotecan, paclitaxel with or without bevacizumab

Breast cancer

Adjuvant hormone therapy: Premenopausal: Tamoxifen

Postmenopausal: Aromatase inhibitors (anastrozole, letrozole, exemestane)

Adjuvant chemotherapy (without trastuzumab):

Doxorubicin, cyclophosphamide, paclitaxel, or

Docetaxel, cyclophosphamide

Adjuvant chemotherapy (HER2 positive):

Doxorubicin, cyclophosphamide, paclitaxel, trastuzumab with or without pertuzumab, or

Docetaxel, carboplatin, trastuzumab with or without pertuzumab or

Paclitaxel plus trastuzumab

Choriocarcinoma (trophoblastic neoplasms)

Single-agent chemotherapy: Methotrexate or dactinomycin for low-risk disease

Combination chemotherapy: Etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine (EMA-CO) for high-risk disease

Testicular cancer

Combination chemotherapy: Cisplatin, etoposide (EP), or

Bleomycin, etoposide, cisplatin (BEP), or

Etoposide, mesna, ifosfamide, cisplatin (VIP)

Kidney (renal cell) cancer

Clear cell histology:

Axitinib plus pembrolizumab, ipilimumab plus nivolumab, pazopanib, sunitinib, or cabozantinib

Non–clear cell histology: Sunitinib

Bladder cancer

Combination chemotherapy: Gemcitabine, cisplatin, or

Methotrexate, vinblastine, doxorubicin, cisplatin (MVAC), or

Atezolizumab, pembrolizumab, or gemcitabine plus carboplatin (cisplatin ineligible)

Prostate cancer

Hormone therapy: Luteinizing hormone–releasing agonist (leuprolide, goserelin, triptorelin, histrelin), or degarelix with or without an antiandrogen (flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide) or abiraterone

Chemotherapy: Docetaxel, prednisone, cabazitaxel

Brain cancer (anaplastic astrocytoma and glioblastoma multiforme)

Single-agent chemotherapy with radiation therapy: Temozolomide

Neuroblastoma

Combination chemotherapy: Cyclophosphamide, doxorubicin, cisplatin, etoposide

Thyroid cancer

Single-agent chemotherapy: Radioiodine (¹³¹I) or sorafenib, lenvatinib, vandetanib (medullary thyroid cancer) or cabozantinib (medullary thyroid cancer)

Combination chemotherapy: Paclitaxel/carboplatin or docetaxel/doxorubicin (anaplastic carcinoma)

Adrenal cancer

Mitotane

Stomach (gastric) cancer

Combination chemotherapy:

5-Fluorouracil, leucovorin, oxaliplatin, docetaxel (perioperative)

5-Fluorouracil or capecitabine oxaliplatin or cisplatin or paclitaxel

Trastuzumab added for HER2-overexpressing adenocarcinomas

Pancreatic cancer

Combination chemotherapy:

Gemcitabine, nab-paclitaxel, or

5-Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or

Gemcitabine, capecitabine, or

Gemcitabine, cisplatin (for BRCA1/2 or PALB2 mutation)

Single-agent chemotherapy: Gemcitabine, capecitabine, or 5-fluorouracil

Colon cancer

Combination chemotherapy:

5-Fluorouracil, leucovorin, oxaliplatin (FOLFOX) with or without bevacizumab, or

Capecitabine, oxaliplatin (CapeOx) with or without bevacizumab, or

5-Fluorouracil, leucovorin, irinotecan (FOLFIRI) with or without bevacizumab

Cetuximab or panitumumab added to FOLFOX or FOLFIRI for KRAS/NRAS/BRAF wild-type and left-sided tumors

Single-agent chemotherapy: Capecitabine or 5-fluorouracil/leucovorin

Rectal cancer

Chemotherapy with radiation: 5-Fluorouracil or capecitabine

For adjuvant treatment, same regimens used with colon cancer

Anal cancer

Combination chemotherapy with radiation: 5-Fluorouracil or capecitabine with mitomycin

Carcinoid

Octreotide LAR with or without telotristat or lanreotide, or everolimus

Osteosarcoma

Combination chemotherapy: Cisplatin, doxorubicin, or

Methotrexate, doxorubicin, cisplatin (MAP)

Soft tissue sarcomas

Combination chemotherapy:

Doxorubicin, dacarbazine (AD), or

Doxorubicin, ifosfamide, mesna (AIM), or

Mesna, doxorubicin, ifosfamide, dacarbazine (MAID), or

Ifosfamide, epirubicin, mesna, or

Gemcitabine and docetaxel, vinorelbine, or dacarbazine

Single-agent chemotherapy: Imatinib or sunitinib or regorafenib (gastrointestinal stromal tumors)

Melanoma

Pembrolizumab, nivolumab or nivolumab/ipilimumab (non-BRAF mutation)

Combination chemotherapy: (BRAF mutation): Dabrafenib/trametinib or vemurafenib/cobimetinib or encorafenib/binimetinib

Single-agent chemotherapy: (BRAF mutation): Vemurafenib or dabrafenib

Hepatocellular cancer

Sorafenib or lenvatinib

Kaposi sarcoma

Liposomal doxorubicin or paclitaxel

Outcome

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Prognosis

Tumor thickness is the single most important prognostic factor
10-year survival rates are related to thickness in millimeters, as follows
- < 1 mm, 95%
- 1–2 mm, 80%
- 2–4 mm, 55%
With lymph node involvement, the 5-year survival rate is 62%
With distant metastases, it is 16%
Increased detection of early melanomas has led to increased survival, but fatalities continue to rise, especially in elderly men

When to Refer

Referral of intermediate-risk and high-risk patients to centers with expertise in melanoma is strongly recommended

References

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Faries MB et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017 Jun 8;376(23):2211–22.
[PubMed: 28591523]

Kim CC et al; Pigmented Lesion Subcommittee, Melanoma Prevention Working Group. Risk of subsequent cutaneous melanoma in moderately dysplastic nevi excisionally biopsied but with positive histologic margins. JAMA Dermatol. 2018 Dec 1;154(12):1401–8.
[PubMed: 30304348]

Luke JJ et al. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017 Aug;14(8):463–82.
[PubMed: 28374786]

Michielin O et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 Dec 1;30(12):1884–1901.
[PubMed: 31566661]

Swetter SM et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019 Jan;80(1):208–50.
[PubMed: 30392755]

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Melanoma, Malignant

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Key Features

Essentials of Diagnosis

General Considerations

Demographics

Clinical Findings

Symptoms and Signs

Differential Diagnosis

Diagnosis

Treatment

Medications

Surgery

Therapeutic Procedures

Outcome

Prognosis

When to Refer

References

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