SKIN CANCER - MADE EASY

RadOnc Dr REVANTH M KHANDKE

ANATOMY

Epidermis▾
  • The epidermis is thinner in the face than in most portions of the body, measuring approximately 0.04 mm.
  • No consistent change in the thickness of the epidermis occurs with increasing age, and no difference in skin thickness exists between men and women.
  • The layers of the epidermis from superficial to deep are:
    • Stratum corneum
    • Stratum lucidum
    • Stratum granulosum
    • Stratum spinosum
    • Stratum basale
  • It is important to know these layers to understand the origin and behavior of a particular type of skin cancer.
Dermis & Subcutaneous Tissue▾
  • The dermis contains blood and lymphatic vessels, adnexa, hair follicles, sweat glands, and sebaceous glands.
  • Dermis thickness: ~1 to 2 mm; the dermis of the eyelid is thinner, ≤0.6 mm.
  • Beneath the dermis lies subcutaneous tissue containing fat and superficial fascia.
  • No distinct transition occurs from the dermis to the subcutaneous layer.

LYMPHATICS

Overview▾
  • No lymphatics exist in the epidermis.
  • A superficial capillary lymphatic plexus lies in the dermis and is without valves.
  • The deep lymphatic trunks in the dermis and subcutaneous tissues have valves.
  • Density of capillary lymphatics is about the same in all areas except the sole of the foot and palm of the hand where it is denser.
  • Observation suggests SCCs and melanomas on the temple are particularly prone to develop lymphatic metastasis.
  • During healing of wounds (incisions/burns), regeneration of lymphatic capillaries across the scar occurs (similar to blood vessels).
First-echelon nodes for face/scalp carcinomas▾
  • Superficial network of lymph nodes around top of neck:
    • Submental (level IA)
    • Submandibular (level IB)
    • Intraparotid / Preauricular
    • Postauricular (mastoid)
    • Occipital nodes
    • Inconstant facial lymph nodes
  • The first echelon is highly associated with the exact location of the cancer on the face.

PATHOLOGY

Carcinoma Type Features (point-wise)
Basal Cell Carcinoma (BCC)
  • Most common skin cancer (65%)
  • Arises from basal layer of epithelium
  • Variety of gross and microscopic appearance patterns
  • Important subtype because of higher recurrence risk
  • Morpheaform/desmoplastic pattern with infiltrating pattern and high recurrence
  • Microsystic BCC is histologic variant
  • May have mixed BCC and SCC (basosquamous cell carcinoma)
  • Melanin pigment may be seen on gross and microscopic examination
Squamous Cell Carcinoma (SCC)
  • Comprises 30% of skin cancers
  • Verrucous carcinoma is variant, occurs often on foot
  • Most are well differentiated
  • Evans and Smith identified two categories of spindle cell tumors
  • One composed of SCC mixed with spindle cell component
  • Other predominantly spindle cells
  • Spindle cell component similar in both groups
  • Mitoses, giant cells, epithelioid cells may be seen
    		•
    Keratoacanthoma
    • Benign tumor of skin resembling cystic BCC grossly
    • Resembles SCC or squamous papilloma microscopically
    • Occurs most often in exposed head and neck area
    • Unlikely diagnosis for lip vermillion lesion
    • Twice as common in men as women
    • Occurs most often in patients older than 40 years
    • May occur as early as second decade of life
    • Diagnosis with certainty only by biologic behavior (eventual involution)
    Adnexal Carcinoma (sweat/sebaceous/hair follicle origin)
    • Arise from epithelium of sweat glands, sebaceous glands, or hair follicles
    • No reliable histologic criteria to differentiate origin
    • Difficult to distinguish between benign and malignant carcinomas
    • Frequently misdiagnosed at time of first biopsy
    • Malignant trichilemmoma: rare variant first described in 1982
    • Usually presents on upper lip as undilated plaque
    • Tends to be slow growing and locally invasive
    • Microcystic adenexal carcinoma exhibits propensity for local recurrence
    • Associated with perineural invasion (PNI)
    • Lymph node metastases with PNI are rare
    • Role of radiation therapy in treatment undefined
    Merkel Cell Carcinoma (MCC)
    • Small cell neuroendocrine carcinoma arising in skin
    • Associated with polyomavirus infection
    • Produces neuro-specific enolase
    • Contains membrane-bound neurosecretory granules
    • Often misdiagnosed as BCC, lymphoma, adenexal carcinoma
    • Correct diagnosis often not obtained until extensive recurrence noted
    • MCC cells may associate with improved prognosis
    • Occurs primarily in white men between 60-80 years
    • Lesion often painless, raised skin nodule or mass
    Melanoma
    • Arises from melanocytes present in epidermis
    • Found in eye, respiratory, gastrointestinal, and genitourinary tracts
    • More aggressive and prone to metastasize than BCC and SCC
    • Likelihood of regional/distant metastases related to depth of invasion
    • Incidence of positive sentinel lymph node biopsies related to depth
    • Melanoma more aggressive with hematogenous dissemination
    • BCCs rarely produce metastases
    • Usually present as pigmented skin lesion with change in color, shape, or size
    • Some may arise de novo, others from previously benign nevus

    PATTERNS OF SPREAD

    Some lesions remain confined to the epidermis (CIS). Large in situ lesions more often on trunk; small areas of CIS common on head and neck.

    Lesion / Category Pattern of Spread (point-wise)
    Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC)
    • Usually well differentiated with indolent growth and distinct margins
    • Small proportion poorly differentiated with poorly defined margins
    • BCC occurs more frequently around central portion of face
    • SCC occurs more frequently on ears, preauricular/temporal areas, scalp, neck
    • Lesions remain superficial and invade adjacent epidermis in circumferential pattern
    • Invasion of dermis usually confined to superficial (papillary) dermis
    • Eventually penetration of reticular dermis, subcutaneous tissues
    • Few skin carcinomas tend to grow beneath skin with surface showing little indication
    • Most early BCCs and SCCs show orderly invasion of superficial dermis
    • Both BCCs and SCCs invade cartilage and bone, develop PNI
    • BCC has low incidence of lymphatic involvement unless recurrent (0.05%)
    • SCC incidence of lymph node spread estimated at least 10-15%
    • Size and age of lesion increase potential for lymphatic spread
    • Basosquamous cell carcinoma acts more aggressively than BCC
    • Metapypical BCC intermediate between BCC and SCC regarding recurrence and metastases
    • Spindle cell tumors of the skin have a gross appearance and growth pattern similar to SCCs
    Carcinoma of Sweat Gland
    • Occurs with equal frequency in males and females
    • Grows 1 to 2 cm in short time
    • May occur even in early adulthood
    • Generally subcutaneous nodular mass (solitary or multiple)
    • Head and neck lesions may be ulcerated
    • Growth rate varies from indolent to rapid
    • May present for several years with little change then suddenly enlarge
    • Frequent regional and distant metastases development
    • Scalp lesions most likely to develop metastases to regional lymph nodes
    • Recurrence after excision is frequent
    • Often multiple recurrences reported
    • Little information on RT response
    • Often insufficiently radiosensitive particularly with excision
    Sebaceous Gland Carcinoma
    • Rare, occurs most often on eyelids
    • Predominantly on upper lid in elderly women
    • Lower lid and canaliculi are sites of origin
    • May occur on head, neck and other body sites
    • Often indolent in growth; may be locally aggressive
    • May develop regional and distant metastases
    • Local recurrence common after excision
    • Lesions often have significant deep and lateral spread
    • Metastasis to regional lymph nodes reported in about 20% of cases
    • Small percentage of patients develop distant metastases
    • Inadequate treatment often occurs due to incorrect histologic diagnosis
    Keratoacanthoma
    • lesion starts as Firm, Round skin nodule
    • Predominantly affects elderly people
    • As the lesion matures, the center becomes separate and can be removed, revealing a small crater
    Basal cell Nevus syndrome
    • The basal cell nevus syndrome(aka Gorlin syndrome) is an autosomal dominant disorder with a high level of penetrance but a variable clinical picture
    • The clinical syndrome may be composed of:
    • Multiple BCCs (differing only in their tendency to develop at an early age and on unexposed skin areas)
    • Jaw cysts
    • Palmar or plantar pits
    • Skeletal abnormalities (short fingers, hypertelorism)
    • Ectopic calcification
    • Eye muscle palsies
    • Hamartomas
    • Epidermal cysts
    • The age at onset is frequently in the second or third decade of life, and a family history is often positive for the disorder
    Lymphatics
    • The overall risk of lymphatic metastases is estimated to be 10% to 15% for cutaneous SCC of the skin
    • The risk increases with the size of the lesion, depth of the penetration, histologic grade, and recurrence.
    • The risk of lymph node metastases from previously untreated BCCs is less than 1% and is not related to size, depth of penetration, or histologic subtype

    CLINICAL PICTURE

    Presenting Symptoms

    • Common history: slowly enlarging growth on or just beneath the skin surface.
    • Often a history of a sore that will not completely heal.
    • Bleeding or pain are unusual until the lesion becomes large; even then symptoms may be relatively mild and infrequent.
    • Patients with PNI may complain of paresthesia, especially the sensation of worms crawling under skin (formication).
    • PNI usually observed with midface lesions and often involves cranial nerves V2 and/or VII.
    • Advanced, neglected lesions may present with bone/cartilage destruction, orbit invasion, and regional metastases; advanced lesions often produce few symptoms leading to delayed presentation.

    Physical Examination

    • Document site, size, and mobility of the primary lesion.
    • Assess evidence of PNI and any findings suggesting involvement of underlying bone or cartilage.
    • Regional lymph nodes must be carefully examined even though they are not often involved.
    • Lymph node metastases may appear within a few months or may take years after primary lesion treatment — long follow-up is necessary.
    • Patients with chronic lymphocytic leukemia and concomitant skin cancer often have enlarged lymph nodes from both processes.

    DIAGNOSTIC IMAGING

    Imaging guidance▾
    • Computed tomography (CT) and magnetic resonance imaging (MRI) are necessary only in a carefully chosen group of patients being treated for skin cancer.
    • CT is the primary modality for showing bone invasion and nodal metastases.
    • MRI is useful in determining muscular or bony invasion in large or neglected lesions and is superior to CT for demonstrating perineural invasion (PNI).
    • Positron emission tomography (PET) is useful to detect regional and distant metastases in patients with MCC and melanoma but should be restricted to patients who are found to be node-positive.

    SELECTION OF TREATMENT MODALITY

    The likelihood of cure is similar after surgery or RT for early-stage BCCs and SCCs. Selection depends on function, cosmesis, age, convenience, cost, availability of RT equipment, and patient wishes. Advanced cancers often best treated with surgery ± adjuvant RT if resectable and acceptable outcome.

    Basal Cell & Squamous Cell Carcinomas▾
    • Small skin cancers on "free skin" (cheek, forehead) may be easily excised with good cosmetic result — surgery is usually treatment of choice for such lesions.
    • Avoid RT in young patients when possible because late effects of irradiation progress gradually with time; long-term follow-up may show suboptimal cosmetic results compared with resection/reconstruction.
    • Resection of early-stage lesions of eyelid, external ear, or nose may result in significant cosmetic deformity — RT may be preferred.
    • Mohs excision with local anesthesia is suitable for small cancers when tissue preservation/cosmesis is important.
    • Patients with locally advanced cancers: combined RT and surgery may improve cure but may worsen cosmetic outcome; postoperative RT is given if surgery reveals high-risk features (positive margins, invasion of nerve/cartilage/bone).
    Melanoma▾
    • The preferred treatment for melanoma is resection of the primary lesion with or without sentinel node biopsy.
    • Patients who have lesions with a depth of invasion exceeding 1 mm and clinically negative nodes should be considered for SLNB.
    • SLNB is also performed for lesions with depth of invasion 0.75 to 1 mm if there are high-risk features including ulceration, regression, invasion into Clark level IV or V, deep margin positive, or young age.
    • Completion lymph node dissection for positive sentinel nodes is controversial but remains standard of care in many practices. Fine needle aspiration should be performed on any grossly positive regional nodes followed by lymph node dissection.
    • Patients with desmoplastic melanoma are usually suitable for surgery alone unless there is extensive PNI associated with a lesion near a named nerve, in which case postoperative RT is considered.
    • Postoperative RT is also employed to treat the primary site when there are in-transit metastases and the margins are equivocal. Adjuvant postoperative RT is often employed for positive regional nodes.
    • Patients at high risk for regional lymph node metastases and unable to undergo SLNB and/or elective node dissection should be considered for elective nodal irradiation of the first-echelon lymphatics.
    • One dose-fractionation schedule (MD Anderson hypofractionation) consists of 3,000 cGy in 5 fractions over 2.5 weeks with reduction off the spinal cord and/or CNS at 2,400 cGy. Alternatively, conventional fractionation (5,000 to 6,000 cGy in 200 cGy fractions) may be employed if late effects and suboptimal cosmesis are a concern.
    • Definitive RT using orthovoltage RT or electrons may be employed for elderly patients with lentigo maligna or lentigo malignant melanoma where excision is not feasible because of cosmesis, function, or medical comorbidities. Dose fractionation schedules are the same as those described for postoperative RT.
    Merkel Cell Carcinoma (MCC)▾
    • The preferred treatment for MCC is resection of the primary tumor with wide surgical margins (2 to 3 cm minimum) and sentinel node biopsy with completion lymph node dissection or primary dissection of any clinically positive regional nodes.
    • Bias is to treat both the primary site and regional lymphatics with postoperative RT. The dose fractionation schedule is the same as that employed for SCC.
    • The role of adjuvant chemotherapy is ill defined. Patients who should be considered for adjuvant chemotherapy are those with positive nodes and/or satellite lesions. Drugs employed are often those used for small cell carcinomas and include etoposide and cisplatin.
    Regional Lymph Nodes▾
    • Patients with SCC and BCC with incidental perineural invasion (PNI) have better outcomes after Mohs surgery and postoperative RT compared with RT following non-Mohs resection.
    • Patients with lesions associated with clinical PNI with gross tumor extending to sites that render complete resection unlikely are treated with RT alone.
    • Subtotal resection does not enhance cure and only increases morbidity.
    • Postoperative RT added after surgery when pathologic exam shows high risk for local recurrence: close/positive margins, invasion of nerve/cartilage/bone.
    • For BCCs of nose, eyelid, ear or lesions with immediate access to major nerve trunks, retreatment when margins positive is usually immediate.
    • Patients with BCC or SCC and focal incidental PNI involving a small nerve trunk <0.1 mm and widely negative margins may be observed; otherwise consider postoperative RT, particularly for SCC.
    • Usual policy for positive margins from SCC is immediate retreatment by re-excision, RT, or both — evidence shows reduced risk of metastasis and death with this approach.

    GENERAL MANAGEMENT PROTOCOL

    Radiation Therapy Alone▾
    • Small skin cancers located on "free skin", such as the cheek or forehead, may be easily excised and reconstructed with a good cosmetic result and minimal inconvenience; therefore, surgery is usually the treatment of choice for such lesions.
    • It is also desirable to avoid RT in young patients because the late effects of irradiation progress gradually with time and, with very long-term follow-up, may be associated with a suboptimal cosmetic result compared with resection and reconstruction.
    • In contrast, resection of an early-stage skin cancer of the eyelid, external ear, or nose may result in a significant cosmetic deformity and necessitate complex reconstruction that compares unfavorably with RT.
    • This is particularly relevant in older patients who have a limited life expectancy and who are at higher risk for a perioperative complication if the lesion is large and general anesthesia is required.
    • In contrast, small cancers suitable for Mohs excision with local anesthesia are well treated with this technique.
    • Patients with locally advanced skin cancers present a difficult problem because, although the likelihood of cure may be better with combined RT and surgery in some situations, the cosmetic result is sometimes unacceptable.
    • Patients receive postoperative RT if surgery is indicated and feasible. If surgery is not feasible, the patient is managed with RT alone.
    • Although it might seem that the risk of bone and/or cartilage necrosis would be high after RT for a skin cancer invading these structures, the observed risk of complications is relatively low.
    • Exceptions are advanced cancers of the scalp and those overlying the anterior aspect of the tibia where there is little tissue between the skin surface and the bone. Following definitive RT, bone exposure is likely and may progress to an osteoradionecrosis (ORN) requiring surgical intervention.
    Adjuvant Radiation Therapy▾
    • Postoperative RT is added after surgery if pathologic examination of the surgical specimen reveals findings indicative of a high risk for local recurrence, such as close or positive margins and/or invasion of nerve, cartilage, or bone.
    • A significant proportion of patients with positive margins after resection of an early-stage skin cancer may never develop a local recurrence.
    • Postoperative RT may be withheld if the lesion is a BCC, the primary site is located on the free skin, the patient is reliable and will return for close follow-up, and if salvage treatment would have a high likelihood of eradicating recurrent tumor with a good cosmetic result.
    • BCCs of the nose, eyelid, or ear and lesions that would have immediate access to major nerve trunks are usually retreated immediately when resection margins are positive.
    • The risk of recurrence is probably greater than for lesions of the free skin, and the consequences of recurrence may be significant. Observation is particularly attractive for the elderly patient in poor medical condition who may not live to experience a local recurrence.
    • Metatypical BCCs behave more aggressively than BCCs, and those with positive margins after surgery should be re-excised and/or treated with postoperative RT.
    • Patients with focal incidental PNI involving a small nerve trunk (<0.1 mm) and widely negative margins may be safely observed; otherwise, patients with incidental PNI should be considered for postoperative RT, particularly if the lesion is SCC.
    • The usual policy for patients with positive margins from SCC is immediate retreatment by either re-excision, RT, or both, depending on the situation — evidence indicates this leads to reduced risk of metastasis and reduced likelihood of death from cancer.
    Management of Regional Lymph Node Metastases▾
    • Carcinoma of the skin metastatic to the parotid lymph nodes is managed as a high-grade parotid neoplasm, usually with superficial or total parotidectomy followed by postoperative RT.
    • If only one node is involved and there is no extracapsular extension, it may be safe to withhold RT. However, if the tumor recurs in the parotid area after parotidectomy, the likelihood of salvage is remote.
    • It has been practice to use combined treatment in all patients. If the parotid lymph node metastasis is fixed and thought to be incompletely resectable, the patient is treated with high-dose preoperative RT (6,000 to 7,000 cGy) followed by parotidectomy.
    • RT alone is used only in patients who are inoperable because of tumor extent or poor medical condition.
    • Patients who have positive parotid nodes and clinically negative cervical nodes may undergo a parotidectomy withholding the neck dissection followed by postoperative RT to the parotid and the neck with a high likelihood of local–regional control.
    • Cervical lymph node metastases are managed just as they would be for other carcinomas of the head and neck. Neck dissection alone is adequate treatment if only one node is involved and there is no extracapsular extension.
    • If two or more nodes contain tumor or if extracapsular extension is noted, neck dissection is followed by postoperative RT.

    TREATMENT OF MELANOMA

    Treatment Algorithm▾
    Primary site managementcN0 nodal managementClinically occult, pN+, nodal managementClinically detected, cN+, nodal management
    Surgical resection, wide local excision +/− adjuvant RT to primary site (see factors for adjuvant RT to primary site below) TO: Stage IB (T1b): Discuss and consider SLNB, (SLNB not required.)
    Stage IB (T2a) or II: Discuss and offer SLNB
    Stage IIB/IIC: SLNB. Consider adjuvant systemic agent (Luke et al. Lancet 2022)     		Clinically occult/detected nodes by SLNB no longer need CLND per MSLT-2 and DeCOG-SLT. Can consider adjuvant systemic agent Consider neoadjuvant + adjuvant systemic agent versus upfront complete therapeutic lymph node dissection (Patel et al. NEJM 2023). Consider adjuvant radiotherapy to the nodal basin for patients at high risk of regional relapse (see factors for adjuvant RT to nodal site below).
    Radiation Treatment Technique▾
    • SIM: Primary: Radiopaque wire to outline scar and/or treatment field. If using electrons, patient positioning is important to allow for en face beam arrangement. Consider lateral penumbra when shaping field to determine PTV.
    • Dose: Postoperative 30 Gy in 6 Gy/fx, given twice weekly over 2–2.5 weeks (Dmax 30 Gy with goal coverage of D90% [27 Gy]). Alternative TROG regimen: 48 Gy in 2.4 Gy/fx for 20 fractions vs conventional 60 Gy in 30 fx (hypofractionation preferred).
    • Target: Primary: Primary site/scar + 1.5–2 cm margin = CTV
    • Factors for Adjuvant RT to Primary Site
      Only one factor needed
      Pure desmoplastic melanoma (>90% melanoma with desmoplastic features)
      Isolated locally recurrent disease
      Micro- or macro-satellitosis
      Two factors needed
      Breslow thickness ≥4 mm
      Head and neck location
      Ulceration
      PNI in head and neck primary or nonhead and neck primary with PNI of large caliber (≥0.1 mm) or named nerves
    • Factors for Adjuvant RT to Nodal Site: For cN+ Patients
      Location / IndicationLymphedema Risk
      Cervical location (any 1 indication): ECE, ≥2 cm, ≥2 LNs positive10%
      Axillary location (any 1 indication): ECE, ≥3 cm, ≥4 LNs positive15%
      Groin location30%

      BMI <25 kg/m² (any 2 indications): ECE, ≥3 cm, ≥4 LNs positive. BMI ≥25 kg/m²: Increases threshold to treat. Discuss systemic therapy options, RT complications may outweigh regional control benefits in this anatomic location.

    • Nodal: Involved nodal region if high-risk features. Do not electively treat LNs.
    • Head and neck: Involved level plus neighboring levels with additional levels as per risk and degree of nodal evaluation. (High facial/scalp primary include pre/postauricular [superficial] parotid.)
    • Axilla: Ipsilateral levels I–III. Unless bulky or high disease, do not electively include supraclavicular field. Either 3D or VMAT planning (avoid shoulder/AC joint).
    • Groin: Need 2 or more high-risk factors to consider treating groin, with higher threshold at higher BMIs. Do not electively cover pelvic nodes.
    • Technique: Generally VMAT/IMRT. Primary: Bolus needed for primary tumor site treatment. Electrons dosed to Dmax. Normalize to ≥100% to prevent hot spots >30 Gy. Consider skin collimation when appropriate. May use 3D and VMAT treatment as appropriate. For head and neck primaries with need for skin collimation and electrons: draw/wire field and cut out field on mask. If near air gap (ie ear), consider TX-151 bolus (aka "Super Stuff Bolus").
    • IGRT: Daily kV +/- CBCT for hypofractionated schedule. MD verifies IGRT prior to first fraction. If electrons, see set up on table prior to first fraction to verify setup.
    • Planning directive: For 30 Gy in 5 fractions: evaluate the 24 Gy line on all axial slices. 24 Gy line should be off any critical structure (brain, eye, brachial plexus, spinal cord, bowel). Evaluate 27 Gy isodose line for target coverage, as opposed to the 30 Gy line. For 48 Gy in 20 fractions regimen: Max dose to brain and spinal cord <40 Gy.
    Surgery▾
    • Primary: Wide local excision with goal of negative margin. Adequate margin is determined by depth of primary.
      • Primary Tumor DepthMargin Recommended
      In situ0.5–1 cm
      <1.0 mm1 cm
      1.01–2.0 mm1–2 cm
      >2.0 mm2 cm
    • Nodes:
      • cN0: +/- Sentinel lymph node biopsy. SLNB should be done prior to WLE as to not alter the drainage to the sentinel basin.
      • cN+: Involved/regional nodal basin dissection. For certain head and neck primaries, this will involve superficial parotidectomy. If neoadjuvant systemic therapy is planned, surgeon should place clips in pathologically confirmed nodes prior to starting systemic therapy.
    Systemic Therapy▾
    • Stage II: Pembrolizumab for pathologically staged IIB or IIC, with a discussion about benefit versus toxicity.
    • Stage III with occult LNs: Anti–PD1 immunotherapy (per Checkmate-248 and Keynote-54) or BRAF/MEK–directed targeted therapy for patients with BRAF V600–activating mutation (per COMBI-AD). Can consider omission for patients with low-risk disease (single SLN + <1 mm).
    • Stage III with gross nodes: Neoadjuvant + adjuvant therapy with anti-PD1 immunotherapy (vs BRAF/MEK-directed targeted therapy for BRAF-activated melanoma).

    TREATMENT OF NON-MELANOMA SKIN CANCER

    Treatment Algorithm▾

    Definitive RT is recommended for nonsurgical candidates and clinical instances where skin cancer is located in cosmetically sensitive areas or where surgery might result in a functional deficit—guidelines released by ASTRO (Porceddu et al. IJROBP 2020).

    ScenarioRecommended management
    T1/T2 operableSurgical resection (WLE, Mohs, or electrodesiccation for low risk)
    T1/T2 inoperableDefinitive RT
    cN0 but riskElective dissection
    >15% (e.g., G3, PNI)Elective RT
    cN+ or pN+Therapeutic dissection followed by postoperative RT to the nodal bed (unless only 1 LNN, <3 cm without ECE)
    PostoperativeRT for high risk, SCC T3/T4, recurrent disease, or close/positive margins. May be supplemented by chemotherapy in select patients.
    M1Chemotherapy, clinical trial, or best supportive care
    Radiation Treatment Technique▾
    • SIM: CT simulation-based treatment planning is recommended for IMRT, history of adjacent RT, or in anticipation of future retreatment. Clinical setup reasonable for orthovoltage, fixed geometry electronic brachytherapy, and palliation. Wire CTV. Skin collimation for field size <4 cm or for protection of adjacent uninvolved sensitive structures. Bolus to bring dose to surface.
    • Dose — Definitive RT:
      • For most lesions and optimal cosmesis: 66 Gy/33 fx (2 Gy/fx) or 55 Gy/20 fx (2.75 Gy/fx) delivered daily; 44 Gy/10 fx (4.4 Gy/fx) delivered 4 times a week.
      • For <2 cm lesions or palliation of large lesions: 50 Gy/15 fx (3.3 Gy/fx); 40 Gy/10 fx (4 Gy/fx); 35 Gy/5 fx (7 Gy/fx) delivered daily.
      • Skin surface brachytherapy: 40 Gy/8 fx (5 Gy/fx); 44 Gy/10 fx (4.4 Gy/fx) delivered twice or 3 times per week, at least 48 hours apart.
    • Adjuvant RT to primary site:
      • 60 Gy/30 fx (2 Gy/fx) or 50 Gy/20 fx (2.5 Gy/fx) delivered daily.
      • Consider boost to 66 Gy/33 fx if positive margins.
    • Adjuvant RT to regional nodes:
      • 66 Gy (2 Gy/fx) for ECE or gross residual adenopathy.
      • 60 Gy (2 Gy/fx) for no ECE/no residual adenopathy to the involved neck.
      • 50 Gy (2 Gy/fx) to the undissected neck.
    • Target — Definitive RT: CTV = Primary tumor with 0.5– to 2-cm margin. CTV margin varies based on tumor histology, risk factors, location, and mode of therapy.
    • Adjuvant RT to primary site:
      • CTV = Primary tumor bed with 1– to 2-cm margin +/- ipsilateral parotid and neck nodes, +/- trigeminal or facial nerve pathways.
      • CTV boost = Primary tumor bed with 0.5– to 1-cm margin.
    • Technique: Electron beam therapy, orthovoltage, brachytherapy, and IMRT in special circumstances (eg large CTV along scalp convexity, neurotropic spread along CN).
    • Planning directive (for conventional fractionation): Electron beam doses are prescribed to 90% of Dmax. Orthovoltage x-ray doses are specified at Dmax (skin surface). For normal tissue tolerance, refer to Head and Neck planning directives.
    Surgery▾
    • Wide local excision (WLE): Removal of healthy skin; results in a larger wound.
    • Mohs micrographic surgery: Specialized technique allowing precise microscopic control of margins using tangential frozen section histology.
    • Curettage and electrodesiccation (C&E): Commonly performed for low-risk BCC and SCC by scraping off lesion with a curette followed by cauterization. Not recommended for high-risk NMSC.
    Systemic Therapy▾
    • Vismodegib (Erivedge) and sonidegib (Odomzo): Inhibitors of the sonic hedgehog pathway and FDA approved for adult patients with advanced BCC. Common side effects: GI upset, muscle spasms, fatigue, alopecia, and dysgeusia.
    • Topical 5FU (Efudex): Approved for treatment of actinic keratosis (AK) and superficial BCC.
    • Concurrent chemoradiation: Platinum agents can be considered for patients with high-risk features on a case-to-case basis.
    • Neoadjuvant cemiplimab: Can be considered for stage II–IV SCC (Gross, NEJM 2022).

    TREATMENT OF MERKEL CELL CARCINOMA

    Treatment Algorithm▾
    Primary sitecN0 nodal managementcN+ nodal management
    Surgical resection, wide local excision, or Mohs +/− adjuvant RT to primary site* SLNB for staging
    If SLN positive → clinical trial, multidisciplinary discussion. RT to nodal basin (can consider CLND Lee, Ann Surg Oncol 2019; Perez, Ann Surg Oncol 2019).
    Discuss anti–PD1 therapy (Becker, presented at ESMO 2022)     		Surgical resection consisting of WLE with nodal dissection +/− adjuvant RT to primary site/nodal basin. Discuss anti–PD1 therapy (can consider neoadjuvant) (Checkmate 358, Topalian, JCO 2020)

    * Consider observation following WLE if small tumor (<1 cm), without LVSI, and no history of immunosuppression.

    Factors for Adjuvant RT to Primary Site

    Factors
    Positive or close margin
    LVSI
    Consider for tumors >1 cm
    Immunocompromised patient
    Radiation Treatment Technique▾
    • SIM: Depending on anatomic location. Bolus is necessary to ensure that superficial dose is adequate for the skin primary. Wire scar or field. For head and neck location: Aquaplast mask, wire scar or primary site, draw field, and cut out field on mask if using electrons. Consider skin collimation. If near the ear, consider the use of TX-151 bolus.
    • Dose — Primary:
      • Tumor > 2 cm, R0 resection → 50–56 Gy at 2 Gy/fx
      • R1 resection → 56–60 Gy at 2 Gy/fx
      • R2 resection or unresected disease → 60–66 Gy at 2 Gy/fx
    • Nodal Basin:
      • cN0, no nodal evaluation → 46–50 Gy
      • cN0, SLNB negative → no RT (unless potential for false-negative SLNB due to anatomic, operator, or histologic failure)
      • cN0, SLNB positive, no formal dissection → 50 Gy
      • cN+, no dissection → systemic therapy, then consider 50–60 Gy
      • cN+, formal dissection with multiple LNs and/or ECE → 50–56 Gy
    • Target:
      • Primary: Primary site/scar + 4-cm margin for CTV; when planning electrons, consider penumbra and need to expand edges of field another 7–10 mm to cover the target.
      • Lymph nodes: Involved/sentinel nodal basins.
    • Technique: Consider electrons to get adequate dose to the surface for RT to the primary. Consider skin collimation and bolus. Photons may be needed for deep primary tumors and for regional RT.
    • IGRT: Related to modality used and site of the body. Typically weekly kV for 3D plans.
    • Planning directive: Standard dose constraints for 2 Gy/fx for ROIs nearby.
    Surgery▾
    • Primary: Wide local excision with a goal of negative margin when feasible (1- to 2-cm margins). Mohs surgery is an acceptable alternative for smaller lesions. Balance with morbidity of surgery. Avoid complex procedures that would lead to a delay in RT.
    • cN0: Sentinel lymph node biopsy. SLNB must be done prior to WLE so as to not alter the drainage to the sentinel basin. If SLNB is +, consider completion dissection or RT for cN0.
    • cLN+: Nodal basin dissection.
    Systemic Therapy▾
    • No randomized data with survival benefit, impressive response rates have been seen with immunotherapy (Nghiem NEJM 2016; D'Angelo J Immunother Cancer 2021; Kim, Lancet 2022).
    • Immunotherapy considered first line for advanced disease.
    • Platinum + etoposide can be used — induces response but has poor durability (Nghiem Future Oncol 2017).
    AJCC 2018 TNM CLASSIFICATION (Clinical & Pathological) of MERKEL CELL CARCINOMA▾

    Definition of Primary Tumor (T)

    T CategoryT Criteria
    TXPrimary tumor cannot be assessed (e.g., curetted)
    T0No evidence of primary tumor
    TisIn situ primary tumor
    T1Maximum clinical tumor diameter ≤ 2 cm
    T2Maximum clinical tumor diameter > 2 cm but ≤ 5 cm
    T3Maximum clinical tumor diameter > 5 cm
    T4Primary tumor invades fascia, muscle, cartilage, or bone

    Clinical N Category (N)

    N CategoryN Criteria (Clinical)
    NXRegional lymph nodes cannot be clinically assessed (e.g., previously removed)
    N0No regional lymph node metastasis detected on clinical and/or radiologic exam
    N1Metastasis in regional lymph node(s)
    N2In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) without lymph node metastasis
    N3In-transit metastasis (discontinuous from primary tumor; located between primary tumor and draining regional nodal basin, or distal to the primary tumor) with lymph node metastasis

    Pathological N (pN)

    pN CategorypN Criteria (Pathological)
    pNXRegional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic evaluation)
    pN0No regional lymph node metastasis detected on pathologic evaluation
    pN1Metastasis in regional lymph node(s)
    pN1a(sn)Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy
    pN1aClinically occult regional lymph node metastasis following lymph node dissection
    pN1bClinically and/or radiologically detected regional lymph node metastasis, microscopically confirmed
    pN2In-transit metastasis (discontinuous) located between primary tumor and draining regional nodal basin, or distal to primary tumor, without lymph node metastasis
    pN3In-transit metastasis (discontinuous) located between primary tumor and draining regional nodal basin, or distal to primary tumor, with lymph node metastasis

    Clinical M (Distant Metastasis)

    M CategoryM Criteria (Clinical)
    M0No distant metastasis detected on clinical and/or radiologic examination
    M1Distant metastasis detected on clinical and/or radiologic examination
    M1aMetastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s)
    M1bMetastasis to lung
    M1cMetastasis to all other visceral sites

    Pathological M

    pM CategorypM Criteria
    M0No distant metastasis detected on clinical and/or radiologic examination
    pM1Distant metastasis microscopically confirmed
    pM1aMetastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s), microscopically confirmed
    pM1bMetastasis to lung, microscopically confirmed
    pM1cMetastasis to all other distant sites, microscopically confirmed

    AJCC Prognostic Stage Groups — Clinical (cTNM)

    When T is…And N is…And M is…Then the stage group is…
    TisN0M00
    T1N0M0I
    T2–3N0M0IIA
    T4N0M0IIB
    T0–4N1–3M0III
    T0–4Any NM1IV

    AJCC Prognostic Stage Groups - Pathological (pTNM)

    When T is…And N is…And M is…Then the stage group is…
    TisN0M00
    T1N0M0I
    T2–3N0M0IIA
    T4N0M0IIB
    T0N1a(sn) or N1aM0IIIA
    T1–4N1b–3M0IIIB
    T0–4Any NM1IV
    AJCC 2018 — MELANOMA TNM & STAGING▾

    Definition of Primary Tumor (T) — Melanoma

    T ThicknessUlceration status
    TXNot applicableNot applicable
    T0Not applicableNot applicable
    Tis(melanoma in situ)Not applicable
    T1≤1.0 mmUnknown or unspecified / Without ulceration / With ulceration (subdivided T1a/T1b below)
    T1a≤0.8 mmWithout ulceration
    T1b≤0.8 mm with ulceration OR 0.8–1.0 mm with/without ulcerationWith ulceration or other high-risk
    T2>1.0–2.0 mmUnknown or unspecified / subdivided T2a (without ulceration) and T2b (with ulceration)
    T2a>1.0–2.0 mmWithout ulceration
    T2b>1.0–2.0 mmWith ulceration
    T3>2.0–4.0 mmUnknown or unspecified / T3a without ulceration; T3b with ulceration
    T3a>2.0–4.0 mmWithout ulceration
    T3b>2.0–4.0 mmWith ulceration
    T4>4.0 mmUnknown or unspecified / T4a without ulceration; T4b with ulceration
    T4a>4.0 mmWithout ulceration
    T4b>4.0 mmWith ulceration

    Definition of Regional Lymph Node (N) — Melanoma

    N categories depend on number of tumor-involved nodes, presence of in-transit/satellite/microsatellite metastases, and whether nodes are clinically or pathologically detected.

    NSummary criteria
    NXRegional nodes not assessed (e.g., SLN biopsy not performed; nodes previously removed)
    N0No regional metastases detected
    N1One tumor-involved node or in-transit/satellite/microsatellite metastasis with no tumor-involved nodes
    N1aOne clinically occult node (detected by SLN biopsy)
    N1bOne clinically detected node
    N1cNo regional lymph node disease but in-transit/satellite/microsatellite metastasis present
    N2Two or three tumor-involved nodes or in-transit/satellite/microsatellite metastases with one tumor-involved node
    N2aTwo or three clinically occult nodes (detected by SLN biopsy)
    N2bTwo or three nodes, at least one clinically detected
    N2cOne clinically occult or clinically detected node AND in-transit/satellite/microsatellite metastasis
    N3Four or more tumor-involved nodes or in-transit/satellite/microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes
    N3aFour or more clinically occult nodes (detected by SLN biopsy)
    N3bFour or more nodes, at least one clinically detected, or any matted nodes
    N3cTwo or more clinically occult or clinically detected nodes AND presence of any number of matted nodes or in-transit/satellite disease

    Definition of Distant Metastasis (M) — Melanoma

    MAnatomic siteLDH level
    M0No evidence of distant metastasisNot applicable
    M1Evidence of distant metastasis
    M1aMetastasis to skin, soft tissue including muscle, and/or nonregional lymph nodeNot recorded or unspecified / Not elevated
    M1bDistant metastasis to lung with or without M1a sitesNot recorded or unspecified / Not elevated or Elevated
    M1cDistant metastasis to non-CNS visceral sites with or without M1a or M1b sitesNot recorded/unspecified or Elevated
    M1dDistant metastasis to CNS with or without M1a, M1b, or M1c sitesNormal or Elevated

    AJCC Clinical Stage Groups — Melanoma (cTNM)

    When T is…And N is…And M is…Then the clinical stage group is…
    TisN0M00
    T1a/T1bN0M0IA / IB
    T2a/T2bN0M0IB / IIA
    T3a/T3bN0M0IIA / IIB
    T4a/T4bN0M0IIC / IIC
    T0–4N1–3M0III (subgroups based on T & N below)
    Any TAny NM1IV

    AJCC Pathological Stage Groups — Melanoma (pTNM)

    When T is…And N is…And M is…Then the pathological stage group is…
    TisN0M00
    T1a–T2aN1b or N1cM0IIIB
    T2b/T3aN1a–N2bM0IIIB
    T1a–T3aN2c or N3a/b/cM0IIIC
    T3b/T4aAny N ≥ N1M0IIIC
    T4bN3a/b/cM0IIID
    Any T, TisAny NM1IV

    TRIALS

    Melanoma▾
    Name / Inclusion Arms Outcomes Notes
    Guadagnolo et al.
    Cancer 2014
    Retrospective Review (RR) of 130 patients with desmoplastic melanoma    		 Surgery alone (45%)
    Surgery + postoperative RT (55%)    		 24% of surgery alone patients developed LR at 6 years, dropped to 7% with postoperative RT Postoperative RT beneficial for desmoplastic melanoma
    Strom et al. Cancer 2014
    RR of 277 patients with desmoplastic melanoma    		 Surgery alone (59%)
    Surgery + postoperative RT (41%)    		 LR 54% in surgery alone with positive margins vs 14% with postoperative RT Postoperative RT beneficial for desmoplastic melanoma in most cases
    Consider omitting postoperative RT if negative margins, depth less than or equal to 4mm, no PNI, non H&N location
    TROG 02.01,
    Burmeister et al. Lancet Oncol 2012 and Henderson et al. Lancet Oncol 2015
    250 patients with cN+ s/p LND. Randomized    		 Lymph node dissection alone
    Lymph node dissection + adj RT (depending on location/risk factors, see above table)    		 RT decreased LN recurrence by ~50%
    No impact on RFS or OS
    Gr 3-4 toxicities after RT in H&N, axilla, and groin were 8%, 21%, and 29%    		 Postoperative RT for high-risk LN involvement decreases local recurrence, no impact on OS
    Trial conducted prior to modern systemic therapy/immunotherapy
    Guadagnolo et al. Lancet Oncol 2009
    Review    		 Review of melanoma patients who received RT Improved LC with PORT
    Risk of complications differ with anatomic location    		 Prior to modern systemic therapy
    Additional details about fields and planning
    MSLT-II,
    Faries et al. NEJM 2017
    1934 patients with +SLNB. Randomized    		 Completion LND vs Observation Improved regional control with CLND (3 y 92% vs 77%)
    No change in melanoma-specific survival (3-y 86% vs 86%)    		 CLND improves local control but not melanoma-specific survival after positive SLNB
    DeCOG-SLT
    Leiter et al. Lancet Oncol 2016
    483 patients with +SLNB for micrometastases. Randomized    		 Completion LND vs Observation DSS 75% with CLND and 77% with observation at 3 years CLND does not improve DSS for melanoma in patients with micrometastases found on SLNB
    Non-Melanoma▾
    Name / InclusionArmsOutcomesNotes
    Veness et al. Laryngoscope, 2005
    Retrospective Review (RR) of 167 patients with SCC with nodal involvement    		 Surgery only (13%)
    Surgery with adjuvant RT (87%)    		 Decreased locoregional recurrence w/ PORT (20% vs 43%)
    Improved 5-y DSS with PORT (73% vs 54%)    		 Improved LRR and DSS with adjuvant RT for locally advanced SCC
    Herman et al. Eur Arch Otorhinolaryngol 2016
    RR of 107 patients with SCC metastatic to parotid LNs, cN0 cervical nodes    		 Elective neck dissection + RT (42 patients)
    RT alone (65 patients)    		 Local regional control the same between the two arms (1 recurrence in each arm) PORT (50-60 Gy) to a cN0 neck is a suitable alternative to a neck dissection
    TROG 05.01,
    Porceddu et al. JCO 2018
    310 patients with high-risk SCC. Randomized    		 PORT (60–66 Gy) alone
    PORT (60–66 Gy) + concurrent carboplatin    		 LRC was similar for both at 5 years (83% for chemoRT, 87% for RT alone)
    No difference in OS or DFS    		 No benefit of adding carboplatin to PORT for high-risk SCC
    Van Hezewijk et al. Radiother Oncol 2010 Electron beam hypofractionation is safe and effective for NMSC (RR of 434 nonmelanomatous skin cancers)
    Merkel Cell▾
    Name / InclusionArmsOutcomesNotes
    Strom et al. Ann Surg Oncol 2016
    RR of 171 patients with merkel cell    		 All patients treated for merkel cell carcinoma with definitive local therapy who had a surgical lymph node assessment Improved 3-y LC (91% vs 77%), DFS (57% vs 30%), and OS (73% vs 66%) with PORT
    DSS improved in node-positive patients (76% vs 48%) but not node negative (90% vs 81%)    		 Improved disease control and OS with the addition of RT
    Bishop et al. Head Neck 2015
    RR of 106 patients with merkel cell    		 Most patients were postoperative, 92% with cN0 disease received regional nodal RT to 46 Gy 5-y LRC, DSS, OS were 96%, 76%, and 58%, respectively
    5% with long-term grade 3 toxicity    		 Postoperative RT to primary and nodal basins well-tolerated
    Lee et al. Ann Surg Oncol 2018 RR of 163 patients with merkel cell + SLND CLND (n = 137) VS RT (n=26) No significant difference in DSS (71% CLND vs 64% RT), NRFS (76% vs 91%) or DFS (52% vs 61%) at 5 years RT to the nodal basin has similar outcomes to CLND for those with +SLNB
    RR of 163 patients with merkel cell with +SLNB; RT (n = 26) in DSS (71% CLND vs 64% RT), NRFS (76% vs 91%) or DFS (52% vs 61%) at 5 years