CUTENEOUS CANCERS OF HEAD AND NECK REGION.pptx

CUTENEOUS CANCERS OF HEAD AND NECK REGION AND MAMANEGEMENT

1. Non Melanoma skin Malignancies H & N Dr. Shyam Popat

2. Introduction The majority of skin cancers of the head and neck are nonmelanoma skin cancers(NMSC). The head and neck are the most common sites of presentation, accounting for >80% of all basal and SCCs. These lesions are typically slow growing and infrequently metastasize. If neglected, they can cause significant local destruction and invade critical structures. Malignant melanoma is an aggressive neoplasm of skin, and the ideal adjuvant therapy has not yet been found, although various options for treatment of skin cancer are available to the patient and physician, allowing high cure rate and excellent functional and cosmetic outcomes

3. NMSC Basal cell carcinoma Squamous cell carcinoma. The ratio of BCC to SCC is ~ 3 to 4:1.

4. BCC Epidemiology BCCs are thought to originate from pluripotent cells in the basal layer of the epidermis. The incidence is significantly higher with increased age and is much greater in Whites than in African Americans. Whites in the United States have a 30% lifetime risk of developing a BCC, and those previously diagnosed with a BCC have a 35% to 50% chance of developing a second tumor over a 5-year period. Geographic location also plays a significant role, with the highest incidence worldwide in Australia

5. Risk factors Risk factors for BCC - Ultraviolet radiation (UVR) exposure, with ultraviolet B (UVB) more implicated than ultraviolet A (UVA). Ultraviolet radiation induces covalent bonds in DNA between adjacent pyrimidines, resulting in mutagenic lesions if not repaired. Exposure to ionizing radiation is also a risk factor for developing BCC. Other risk factors include chemical carcinogen exposure with arsenic or coal tar, and immunosuppression. Smoking and human papillomavirus (HPV) infection are also risk factors for development of BCC

6. Risk factors —> genetic mutations responsible for BCC. Most commonly mutations in tumor suppressor genes. The p53 mutations are the most common genetic aberrations involved in NMSC, although more common in SCC than in BCC. Exposure to ultraviolet radiation can result in the loss of Fas ligand interaction, with resulting accumulation of p53 mutations in the skin Associated with PTCH1 gene mutation in most cases. This pathway is implicated in the increased incidence of BCC seen in genetic syndromes.

7. Genetic syndromes Xeroderma pigmentosa Autosomal-recessive genetic disorder with reduced cell capacity to repair DNA damaged by UVR. It is associated with the development of many skin tumors, particularly SCC, but also BCC and melanoma, at a young age. Nevoid basal cell carcinoma syndrome Autosomal-dominant genetic syndrome Multiple BCCs, cysts of the jaws, rib abnormalities, palmar and plantar pits, and calcification of the falx cerebri. These patients are also at increased risk of medulloblastoma with a 3% to 5% incidence The major treatment is early recognition, then ultraviolet shielding, and lifelong monitoring of the skin for development of malignancies.

8. SONIC HEDGEHOG PATHWAY ( SHH) and BASAL CELL CARCINOMA The Hedge hog pathway plays a significant role in human development and in cutaneous carcinogenesis . The Sonic hedgehog (SHH) pathway is implicated in the etiology of the basal cell carcinoma Mutations in the receptor of SHH, the patched gene (PTCH), have been characterized in sporadic BCCs and Basal cell nevus The mutated genes received the name because when HH protein malfunctions the mutant gene ends up looking like a small prickly ball, similar to a curled up hedgehog

9. Specific inhibitors of the SHH signaling pathway have been developed - such as the steroidal alkaloid cyclopamine , vismodegib and sonidegib - has both teratogenic and antitumor activities. SHH-induced neoplasias appear to lack the aggressiveness of other malignancies - explains the lack of invasive histologic features and metastasis and slow growth rate of BCCs The SHH model may be very useful to understand each step of BCC carcinogenesis - apart from UV light exposure

10. Clinical Features Unlike SCC of the skin, there are no precursor lesions associated with BCC. Patients typically present with a slow-growing, nonhealing papule, most commonly of the head and neck, although multiple clinical variants exist. Locally advanced tumors can show symptoms of disease progression into adjacent structures, including numbness, pain, and weakness

11. Subtypes There are five clinical types of BCC: Nodular BCC - the most common clinical subtype Pigmented BCC - a subtype of nodular BCC that exhibits increased melanization Superficial BCC - most commonly on the trunk Morpheaform (sclerosing/infiltrating) BCC - an aggressive growth variant Basosquamous carcinoma - a form of aggressive growth BCC; can be confused with squamous cell carcinoma (SCC) Fibroepithelioma of Pinkus/Fibroadenoma

12. Nodular BCC The noduloulcerative lesions are the most common type, accounting for 75% of cases of BCC. Histologically, these lesions have islands of tumor cells encased in a mucin-rich stroma. When pigmented, these tumors can often be confused clinically with melanoma. The typical clinical appearance is a well-circumscribed nodule or plaque with pearly border and overlying telangiectasia and may be combined with rodent ulcer. Nodular BCC tends to be slow growing and is rarely associated with aggressive disease

13. Pigmented BCC A subtype of nodular BCC – exhibits increased melanization Pigmented BCC - Presents as a hyperpigmented, translucent papule

14. Superficial BCC Superficial BCC - most commonly on the trunk and extremities Appears as - a well-demarcated erythematous patch which may be confused clinically with eczema or psoriasis An isolated patch of “ eczema ” that does not respond to treatment - raise suspicion for superficial BCC. Unlike nodular subtype, which increases in incidence with advancing age, the superficial subtype tends to peak and then steadily decrease into the late 70s

15. Morpheaform BCC An aggressive growth variant Lesions of morpheaform BCC - have an ivorywhite appearance May resemble a scar or a small lesion of morphea The appearance of scar tissue [ in the absence of trauma/ previous surgical procedure or the appearance of atypical-appearing scar tissue at a previously treated lesion ] - alert for possibility of morpheaform BCC The extent - often larger than the clinical appearance

16. Basosquamous carcinoma A form of aggressive growth BCC Can be confused with squamous cell carcinoma (SCC) Histologically - Shows both basal cell and SCC differentiation in a continuous fashion. Tumors with mixed histologies should be treated as tumors of the more aggressive subtypes

17. BCCs are locally destructive but rarely metastatic The incidence of metastasis in BCC occurs in 0.0028 to 0.1% of patients. Review of the literature shows that morpheaform and basosquamous types of BCC have a relatively high local recurrence rate. The affinity of aggressive BCCs for perineural invasion has also been reported.

18. Squamous cell carcinoma Cutaneous SCC is a malignant tumor of epithelial keratinocytes and represents the second most common form of skin cancer. This neoplasm was first described in the literature in 1775 by Sir Percival Pott, who noted the relationship between scrotal carcinoma and exposure to chimney soot. Although most of the cases are easily treated with a high cure rate, a subset of tumors will behave more aggressively and recur or metastasize, resulting in most NMSC mortalities.

19. Epidemiology The age-specific incidence among persons older than 75 years is increased by a factor of 10.4 . Higher in men than in women. Sun-sensitive individuals with red hair, blue eyes & fair complexion -higher risk than individuals with darker pigmentation Geographic variations in sun exposure also contribute to differences in regional incidence data.

20. Risk factors Ultraviolet radiation (both UVB and UVA) – most important environmental risk factor for the development of SCC with a strong dose-response association. Oral methoxsalen in combination with ultraviolet A radiation (PUVA) for the treatment of psoriasis and other conditions has been definitively associated with an elevated risk of SCC Genetic predisposition - potentiate the risk of environmental factors such as UVR Physical & chemical carcinogens- Arsenic , chronic exposure to ash & polycyclic aromatic hydrocarbons derived from carbon compounds (e.g. coal tar)

21. Immunosuppression including iatrogenic (e. g. solid organ transplantation recipients, with autoimmune or rheumatoid disease), Hematopoietic stem cell transplantation. Viral infection – HPVs, AIDS Chronic inflammation & chronic injury of the skin – chronic ulcers (Marjolin’s), burn scars & radiation dermatitis Chronic inflammatory disorders - discoid lupus erythematodes, mucosal & hypertrophic lichen planus, lichen sclerosus & dystrophic epidermolysis bullosa

22. Clinical Features Variable & depends on the histologic subtype and location Typically, SCCs arise on sun-exposed areas The face, head, and neck region & the forearms & dorsum of the hands The typical clinical finding – includes slowly enlarging, firm, skin-colored to erythematous plaques or nodules Marked hyperkeratosis Ulceration, exophytic or infiltrative growth patterns - seen

23. Review of several studies has shown that SCC may arise from precancerous lesions such as actinic keratosis (AK). These scaly 1- to 3-mm, pink, skin-colored, or brown papules have a characteristic rough texture and are oftentimes more easily palpated than visualised . Histologically, actinic keratoses consist of atypical keratinocytes confined to the basilar layers of the epidermis with overlying parakeratosis. The prevalence of AK in fair-skinned people ranges from 11 to 26%, and it was estimated that the risk of development of SCC from AK ranges between 6% and 10%.

24. Bowen’s disease is another pathologic entity that is thought to represent in situ SCC of the skin; it is commonly misdiagnosed as eczema or psoriasis. It presents as solitary, well-demarcated, pink, brown, or erythematous scaly plaques. Microscopically, Bowen’s disease is characterized by full thickness involvement of the epidermis and the pilosebaceous epithelium by atypical keratinocytes but doesn’t penetrate the basement membrane According to the literature, it becomes invasive SCC in 3 to 5% of patients, of whom 13% will go on to develop metastases.

25. Invasive SCC Invasive SCCs are commonly scaly, pink- or skin-colored papules, or plaques that occur on the head, neck, trunk, and other sun-exposed areas. Patients may complain of pruritus, pain, or bleeding, with mild trauma to affected areas. Biopsy reveals keratinocyte atypia that traverses the basement membrane and involves the dermis and underlying structures. Tumors may be well differentiated, with minimal cytologic atypia, obvious keratinization, or they may be poorly differentiated with significant atypia and mitotic figures seen.

26. Verrucous SCC A slowly growing ulcerated plaque or an exophytic cauliflower-like slowly growing tumor Typical locations Oral cavity (oral florid papillomatosis) Genitoanal region (Giant condyloma acuminatum; Buschke-Löwenstein) Plantar skin (epithelioma cuniculatum) Amputation stumps Less common than other forms of invasive SCC.It is associated with multiple HPV subtypes, including HPV 6, 11, 16, and 18. Unlike other SCCs, irradiation is specifically contraindicated for verrucous carcinoma because it can result in increased tumor aggressiveness.

27. Lesion Assessment Lesions suspicious for cutaneous malignancy should be evaluated. Biopsy Decision If a lesion is suspicious, proceed with a biopsy. Biopsy Methods Shave Biopsy: Use for superficial processes like superficial BCC or SCC in situ. Punch Biopsy: Preferred for deeper tumors suspected. Biopsy Results If consistent with Non-Melanoma Skin Cancer (NMSC): Subtype Identification: Report should specify subtype of BCC or SCC. Note high-risk histologic features. For SCCs: Include degree of differentiation. Include presence of vascular or perineural invasion. Risk Classification Assign tumors to high-risk or low-risk categories based on assessment. Treatment Decision Essential to select appropriate treatment regimen based on risk category.

28. Diagnosis The standard pathology report to indicate: Histologic subtype (acantholytic, spindle cell, verrucous, or desmoplastic type) Grade of differentiation (G1 to G4) Maximum vertical tumor diameter in millimeters Extent of dermal invasion (Clark level) Presence or absence of perineural, vascular, or lymphatic invasion Information about whether the margins are free or not

29. Treatment 2 fold local control is important to limit the extent of immediate tumor destruction and preserve vital functional and cosmetic structures (particularly on the face). Second, complete eradication (either surgical or radiotherapeutic) is crucial for eliminating the risk of metastatic spread

30. Treatment modalities Cryosurgery Electrodessication and curettage, Standard excision, Mohs micrographic surgery, and radiation therapy. In addition, there are several novel therapies, including Laser surgery, Photodynamic therapy, Topical chemotherapy, and the Biological response modifiers

31. Curettage and Electrodesiccation This technique involves using a sharp curette to gently scrape away the tumor tissue, which has less resistance than healthy tissue. Careful pressure ensures tumor removal without disturbing surrounding skin. Following curettage, electrodesiccation is used for hemostasis and to define tumor borders. This cycle is repeated three times. Notably, no pathological specimen is sent for margin evaluation. Unsuitable for hair-bearing skin due to inadequate treatment of follicular extension, this technique is also inappropriate when tumors extend into the subcutaneous layer . Small, non-aggressive primary tumors in low-risk areas have reported high 5-year cure rates (up to 96%)

32. Surgical excision Surgical excision offers benefits like confirming clear tissue margins through histology, faster healing, and potential cosmetic improvements. Small, well-circumscribed NMSCs (<2 cm) can be cleared with a 4 mm margin of normal tissue. High-Risk Features: NMSCs with high-risk features have higher recurrence rates after excision. Tumor size (>2 cm) and poor differentiation contribute to higher recurrence rates. For high-risk lesions, a margin of 6 mm is recommended. For primary NMSCs on the neck, trunk, arms, and legs, a 99% 5-year cure rate is associated with surgical excision. Cure rates for head lesions decrease with increasing tumor size. National Comprehensive Cancer Network (NCCN) guidelines advise 4-6 mm margins for SCC treatment due to concerns about complete tumor removal. For certain situations, like positive margins or lesions >2 cm, larger margins (1 cm) are recommended.

33. Cryosurgery Uses liquid nitrogen in a closed system to rapidly extract heat from tissue. Freezing tissue leads to vascular stasis, disrupted cell membranes, pH changes, loss of balance, ice crystal formation, and thermal shock. Rapid cooling and slow thawing, along with repeated freeze-thaw cycles, are effective for maximum tumor destruction. Extensive tissue necrosis is needed to eradicate malignant lesions. Basal cell carcinoma (BCC) cells absent after 3 days of cryosurgery at -50 to -60°C. Effective for premalignant lesions, in situ malignancies, and certain non-melanoma skin cancers (NMSCs).

34. Suitable NMSC Candidates for Cryosurgery: Nodular and superficial BCC, well-differentiated SCC. Lesions with well-defined borders, small size (<1 cm), and on low-risk areas. High cure rates reported (>97% 5-year) for these selected low-risk tumors.

35. Photodynamic therapy Definition : PDT is a treatment method involving a photosensitizing substance that is localized to a tumor and selectively destroys it when activated by visible light. Activation Principle : Photosensitizing agent is delivered and then activated by specific light wavelengths; light wavelength determines treatment depth. Administration Routes : Photosensitizing agents like ALA and methyl-esterified ALA are administered topically, orally, intralesionally, or intravenously. ALA and similar molecules move to tumor and normal cells; they transform into protoporphyrin IX, a strong photosensitizer. Cellular Effect: Exposure to visible light with oxygen generates reactive oxygen and free radicals, leading to cell death. Maximizing Selectivity: Delayed light delivery enhances PDT's selectivity by accumulating photosensitizers in tumors due to limited lymphatic channels. Advantages of Topical Approach : Topical photosensitizers are easy to apply and cause photosensitivity only at the application site. Limitations: Topical application might be restricted by the depth of tumor perfusion achievable.

36. Mohs micrographic surgery Developed in 1938 by Frederic E. Mohs A microscopically controlled surgery used to treat common types of skin cancer During the surgery, after each removal, the tissue is examined for cancer cells Provides informed decision for additional tissue removal Improves prognosis - After 5 years, MMS-treated BCCs recurred in 1.4% of primary & 4% of recurrent tumors Preferred treatment for any BCC where tissue conservation is desired

37. Advantages of Mohs Surgery Higher Cure Rates: Mohs surgery examines 100% of the surgical margin, leading to superior cure rates. Primary Basal Cell Carcinomas (BCCs) show a 5-year cure rate of 99% with Mohs surgery, compared to 90-93% with standard techniques. Recurrent BCCs achieve a 5-year cure rate of 94.4% with Mohs, as opposed to 80.1% for standard treatments. For Squamous Cell Carcinomas (SCCs), primary tumor cure rate is 96.9% with Mohs versus 89.1% with non-Mohs treatments. Recurrent SCCs experience a 90% cure rate with Mohs, while non-Mohs treatments yield 76.7%. Precise Margin Removal: Mohs surgery uses narrow excisional margins tailored to the tumor, minimizing the removal of healthy tissue required for histologic clearance. Particularly beneficial for high-risk tumors on sensitive areas like the face, preserving critical structures and functions.

38. Radiation therapy Radiation therapy is used for both definitive treatment and in the adjuvant setting. Although the goal of radiation therapy is to maintain or exceed cure rates achieved with other modalities, an emphasis on maintaining form and function is also critical. Primarily, radiation therapy is noninvasive and therefore requires no anesthesia, which is important in this patient population where median age is in the 70s. The major disadvantage to the use of radiation therapy is the inability to histologically determine margins. This allows for the potential of “geographic miss,” where the entire extent of tumor is not adequately included in the treatment field

39. The treatment-related effects of radiation therapy are limited to the area treated. Absolute contraindications include patients with Gorlin syndrome and other genodermatoses because ionizing radiation may result in significant adverse effects, as well as induce more skin cancers. Exception: Xeroderma pigmentosum , where the defect is in nucleotide excision repair, and there does not seem to be an enhanced reaction to ionizing radiation. In addition, patients with active autoimmune disease such as scleroderma and systemic lupus erythromatosus may have increased morbidity from radiation therapy.

40. Melanoma Melanoma (Gr. melas [dark], oma [tumor]) - malignant tumor arising from melanocytic cells Can occur anywhere where melanocytes are found. Most aggressive form of skin cancer 10% melanomas – detected by lymph node metastases [with so-called “unknown primary”]

41. Epidemiology Responsible for 75% of skin cancer deaths. The lifetime risk of being diagnosed with melanoma is 1 in 37 for men and 1 in 55 for women. Mucosal melanoma of the head and neck region has a peak incidence in patients aged 60-80 years. Although melanoma is a highly aggressive cancer, patients can be cured of this disease if they are diagnosed early and managed appropriately. Presentation Melanomas of the head and neck most commonly present on the face The scalp and ears are the next most common sites of presentation .

42. Lymphatics Of utmost importance in the management of head and neck melanoma is a concrete understanding of the surgical anatomy of the lymphatics, as the status of the regional nodes has the most impact on survival. For sentinel lymph node biopsy (SLNB), the identification of lymph nodes in the head and neck may be challenging due to their relationship to the cranial nerves. Lymphatic drainage of regions such as the nasal skin, the lip, and the midface frequently drain to more than one nodal basin and may also drain in bilateral or contralateral directions.

43. Lesions of the scalp that are anterior to a line drawn along the coronal plane through the tragus oftentimes will drain to the parotid, the submental, or the anterior cervical lymph nodes. Alternatively, melanomas that are posterior to this line will most often drain to either the suboccipital, the retroauricular, or the posterior triangle cervical lymphatics.

44. Risk factors History of sunburns from natural UVR and the use of tanning beds (artificial UVR. Positive family history, multiple nevi, dysplastic nevi, freckled or fair skin, blue or green eye color, and red hair color. Unlike skin melanoma, sunlight isn't linked to mucosal melanoma. Airborne irritants and cancer-causing substances like tobacco smoke are suspected, but their exact role is uncertain. A study found that chemicals and physical triggers increased melanocyte production in oral tissue, leading to pigmented mouth lesions.

45. Linked to polymorphisms in the MC1R gene, which encodes the melanocortin-1 receptor. This is related to decreased signaling through the receptor, which ultimately results in decreased melanin production. Germline polymorphisms in other genes involved in melanin synthesis (TYR, TYRP1) have also been linked to an increased melanoma. Approximately 10% of melanomas are familial, and usually has early onset.(CDKN2A gene)

46. Pathology Neural crest —> melanocytes —>migrate most commonly to the epidermis of the skin —>cutaneous. But they can also be found in the Meninges lining the brain —> primary meningeal Uveal tract of the eye —> uveal Ectodermal mucosa —> mucosal.

47. Molecular biology Various melanoma subtypes differ in the prevalence of somatic mutations, some of which serve as prognosis markers and treatment targets. The most common somatic event in melanoma is the alteration of the BRAF gene. Over 90% of detected BRAF alterations in melanoma are missense mutations affecting the valine residue at position 600. Mutation of NRAS is the second most frequent somatic event in melanoma, leading to hyperactive MEK and ERK signaling. Somatic mutation in KIT gene (Usually rare in Cutaneous malignancy) Inactivating mutations and deletions of PTEN, a negative regulator of the PI3K-AKT signaling pathway, have been identified in 10% to 30% of melanomas

48. Clinical features Most head and neck melanoma patients are diagnosed early, usually without initial spread to lymph nodes. Pigmented lesions might exist for years but only raise concern when they significantly change (ABCDE: Asymmetry, Border irregularity, Color changes, Diameter >6 mm, Evolution). Melanomas often develop from existing moles; common signs are bleeding, itching, ulceration, and regression. Satellitosis (spread within the skin) can indicate advanced disease, even without lymph node involvement. Early-stage melanomas can have hidden lymph node spread (20-30% for T2 lesions) that increases with tumor thickness. Melanomas can target nerves (neurotropism); noticing these signs is vital for aggressive subtype evaluation.

49. Clinical features Sinonasal mucosal melanoma present with unilateral nasal obstruction, epistaxis, or a combination of the two. Discharge, epiphora, facial pain, and swelling are more common in advanced cases. The most prevalent clinical presentation of tumors within the oral cavity is a painless mass. Commonly, ulceration and bleeding can be present. Mucosal melanoma can be metastasis of Cutaneous counterpart

50. Clinical Features Cutaneous melanomas, which are by far the most common subtype, have been further subdivided into categories defined by a combination of pathological and clinical features. Superficial spreading melanoma Nodular melanoma Lentigo maligna Lentigo maligna melanoma Acral lentiliginous melanoma Desmoplastic melanoma

51. Superficial spreading melanoma Most common subtype, accounting for approximately 70% Most common on intermittently sunexposed areas The lower extremity of women; the upper back of men Irregular borders and irregular pigmentation May present subtly as a discrete focal area of darkening Varying shades of brown typify most melanocytic lesion.

52. Nodular melanoma Approximately 15%-30% of all melanomas The trunk - the most common site Remarkable for rapid evolution - often arising over several weeks to months Characterised by vertical growth may lack an apparent radial growth phase. Often highly aggressive Typically appears as a uniformly dark blue-black or bluish-red raised lesion 5% are amelanotic

53. Lentigo maligna & Lentigo maligna melanoma Lentigo maligna - melanoma in situ with a prolonged radial growth phase Eventually becomes invasive 🡪 Lentigo maligna melanoma Diagnosed most commonly in the seventh to eighth decades (uncommon before the age 40) Most common location - the chronically sun-exposed face, on the cheeks and nose in particular Clinical appearance - flat, slowly enlarging, brown, freckle-like macule with irregular shape & differing shades of brown and tan

54. Acral lentiginous melanoma Acral lentiginous melanoma ( ∼ 5%) is the least common subtype among Caucasians, but represents 30% to 70% of the melanomas diagnosed in African Americans and Hispanics. Acral lentiginous melanomas occur on the palms or soles, or underneath the nail plate, where exposure to UVR is relatively limited.

55. Pattern of spread Cutaneous melanoma's can spread close by, forming satellite and in-transit lesions, or more commonly, it progresses to nearby lymph nodes. Later, it might spread to distant organs like the skin, lungs, liver, and more. Brain metastasis is common, affecting about 60% of patients with distant spread, and up to 80% show brain involvement in autopsies. Mucosal melanomas follow a similar pattern, spreading to regional lymph nodes before progressing further In contrast to cutaneous and mucosal melanomas, uveal melanomas spread almost uniquely hematogenously, and thus lymph node involvement is quite rare. Almost all uveal melanoma patients with distant disease have liver involvement (95%), but uveal melanomas almost never metastasize to the brain

56. Diagnosis Biopsy is done—either an excisional or incisional. Preferably, a 1-2 mm margin is taken with an excisional biopsy for detailed analysis without disturbing lymphatics if lymph node assessment is needed. However, excisional biopsy alone isn't enough for full treatment; separate surgery is needed to ensure proper margins. Incisional or punch biopsies are used for large or delicate areas like the nose, eyelid, or ear. Shave biopsies, common for skin issues, might not show the full depth of pigmented lesions due to cutting the base, impacting staging

57. Immunohistochemistry - Only 50-70% of lesions in the oral cavity demonstrate melanin; therefore, immunohistochemical analysis is often required to diagnose malignant melanoma. HMB 45, Melan A, MART-1 Magnetic resonance imaging (MRI) - melanin has paramagnetic properties that can affect signal and produce a characteristic intensity pattern on MRI. The appearance is hyperintense on T1-weighted sequences and hypointense on T2-weighted sequences. The appearance of melanoma on computed tomography (CT) scanning is not specific (homogeneously enhancing mass),

58. No universally accepted staging system for mucosal melanoma exists. The following is the system that suffices for staging: Stage I – Localized disease Stage II – Metastases to regional lymphatics Stage III – Distant metastatic disease Most patients (75-83%) present with stage I disease. Among patients with oral cavity lesions, however, a higher prevalence of stage II disease is noted. The Memorial Sloan Kettering Cancer Center proposed a microstaging system for Stage I disease based on the architectural anatomy of the mucosa, as follows level I - In situ mucosal melanoma without invasion or with microinvasion level II - Invasion up to the lamina propria level III - Deep invasion into bone, cartilage, or skeletal muscle

59. Role of SNB This technique has several benefits for melanoma patients: Enhanced sensitivity in detecting regional metastases. Lower morbidity compared to elective nodal dissection. Identification of patients who might benefit from further treatments like neck dissection or systemic therapy. Potential to stop the progression of disease in the regional lymph nodes.

60. SLNB benefits have been shown in retrospective studies and trials. Patients with 1-4 mm melanomas have a 15%-45% risk of hidden spread. SLNB might not help for <1 mm lesions (<5% risk),the following risk factors may benefit from SLNB: mitotic figures > 1/mm 2 , the presence of ulceration, or tumors > 0.7 mm in thickness. Risk grows with thickness: 2-4 mm melanomas have 30%-40% nodal spread, >4 mm have almost 50%. Negative SLNB results link to better survival SLNB status guides adjuvant therapy for melanoma.

61. Management

62. Stage 0-II Surgery Radiation Adjuvant radiation therapy isn't usually needed for stages 0 to II melanomas. Indicated for specific cases, like melanomas with PNS, LVI, Close or positive margins. For extensive melanoma in situ or lentigo maligna, radiation can be a reasonable option. Radiation as the primary treatment is uncommon, reserved for rare situations.

63. Systemic therapy In early-stage melanomas, surgery is the main treatment. If surgery or radiation isn't an option, a topical treatment called imiquimod might be used Interferon alpha 2b (IFN) was approved in 1995 for high-risk melanomas.

64. Stage III Primary Tumor Excision: Wide excision with negative margins is the main approach. Reconstruction depends on defect size and location. Nodal Disease: Clinically visible nodes require complete lymphadenectomy. For face, neck, and anterior scalp, a modified radical neck dissection is performed. Superficial parotidectomy is considered based on tumor location and sentinel lymph node biopsy (SLNB) results. Metastatic Disease: Parotidectomy and neck dissection for first-echelon drainage to parotid gland for the tumors (anterior lateral scalp melanoma, lateral cheek melanoma), even if the parotid gland is not the site of the metastatic disease. Postero-lateral neck dissection for metastasis from posterior scalp or neck melanoma

65. Satellitosis and In-Transit Metastasis: Surgery preferred for satellitosis or in-transit metastasis if feasible. Sentinel node biopsy helps stage regional nodes. If extensive dermal involvement risks severe damage, consider systemic therapy or radiation as primary treatment. High risk of distant metastasis justifies systemic therapy for concurrent distant control.

66. Radiotherapy Extracapsular extension of disease Nodal stage at least N2 ( > 2 lymph nodes) nodes larger than 2 cm, and extensive dermal metastasis or satellitosis. The indications for radiotherapy vis-à-vis the primary tumor remain those as described above for stages I to II patients. Systemic therapy Both HDI and PEG-IFN are FDA-approved options for patients with stage III melanoma, but the relative risks and benefits of these therapies must be considered, and enrollment in clinical trials should be considered as an alternative

67. Stage IV Melanoma Surgery's role in stage IV disease is limited. The potential benefits for surgical extirpation of local or regional disease in the face of distant metastases are primarily palliative and include (a) limiting the morbidity of continued tumor growth into local structures, (b) reducing nodal burden to lessen great vessel and muscular invasion, and (c) potentially decreasing the source of future metastatic foci. Controlling tumor growth in head and neck is important for quality of life. Removing certain metastases (like lung) through surgery can help if disease burden is low or lesions are slow-growing. Brain metastases may require surgery due to lack of effective systemic treatments and risks of mass effects. Surgery for brain metastases is suitable if there are three or fewer lesions.

68. Radiation can provide palliation, not cure, in stage IV. Radiation is important for brain metastases, with stereotactic radiosurgery (SRS) for smaller tumors. Whole brain radiation (WBXRT) and SRS can both be used for multiple brain metastases, but SRS might cause less cognitive decline. Systemic therapies (chemo, immunotherapy, targeted therapy) are the main treatment for stage IV patients, especially melanoma.

69. Chemotherapy First FDA-approved agent for metastatic melanoma: Dacarbazine (DTIC). DTIC's active metabolite methylates guanine nucleotides in DNA, causing replication errors, strand breakage, and cell death. Dacarbazine achieves clinical responses in only 10-15% of patients, and most responses are temporary. Temozolomide (TMZ) is an oral agent that becomes the same active metabolite as DTIC. Clinical trials showed TMZ is comparable but not superior to DTIC. Various single-agent chemotherapies tested, but none better than dacarbazine. Combination regimens like CVD showed promise but didn't significantly improve overall survival (OS) compared to DTIC

70. Immunotherapy Ipilimumab and CTLA-4 Blockade: Ipilimumab is an antibody designed to block CTLA-4. By inhibiting CTLA-4, ipilimumab aims to prevent the inhibitory signaling that dampens T cell activity. This enables a stronger immune response against tumor cells. Toxicities and Side Effects: While ipilimumab's mechanism of action is similar to other immunotherapies like high-dose interleukin-2 (HD IL-2), it differs in terms of toxicities. Unlike HD IL-2, which can have acute hemodynamic effects, ipilimumab's side effects are generally manifestations of autoimmune attack on organs. These include autoimmune colitis, rash, liver dysfunction, fevers, and endocrine insufficiencies.

71. Adoptive cell transfer is a therapeutic approach where immune cells, specifically T cells that have infiltrated the tumor (TIL), are isolated from the patient's resected tumor. These TIL are then grown and expanded in the laboratory to reach sufficient numbers. Treatment Procedure: Patients undergo lymphodepleting treatments, such as high-dose chemotherapy or total-body irradiation, to create space for the infused TIL to proliferate. The expanded TIL are then infused back into the patient's body. High-dose interleukin-2 (HD IL-2) is administered to support the activity and viability of the infused TIL. Clinical Responses and Efficacy: While randomized studies are lacking, single-arm studies have reported encouraging clinical response rates of around 50%. Many of these responses are durable, suggesting the potential for long-term benefits. Toxicity and Limitations: The treatment regimen is associated with significant toxicity. The approach is feasible only for patients from whom TIL can be successfully expanded. Expanding TIL to sufficient numbers takes time, typically 1 to 2 months, making it unsuitable for patients requiring immediate treatment.

72. Target therapy Targeting BRAF: BRAF is frequently mutated in melanoma, particularly the V600E mutation. Initial trials targeting BRAF with sorafenib showed limited efficacy with clinical responses in <3% of patients. Vemurafenib, a V600-mutant-selective BRAF inhibitor, demonstrated potent inhibition of melanoma cell lines with BRAF V600 mutations. Phase I clinical testing showed that vemurafenib achieved clinical responses (83%) in patients with BRAF V600E mutations. The BRIM-3 phase III trial compared vemurafenib to dacarbazine in previously untreated metastatic melanoma patients with a BRAF V600E mutation, demonstrating significant improvements in overall response rate, progression-free survival, and reduced risk of death from melanoma.

73. Targeting KIT: KIT alterations are therapeutic targets, especially in melanoma patients with KIT mutations. KIT inhibitors, approved for gastrointestinal stromal tumors with KIT mutations, have shown promise in melanoma patients with KIT mutations. Trials are now being conducted specifically in melanoma patients with KIT mutations or amplifications. Initial results from trials with KIT inhibitors such as imatinib show clinical response rates of 15% to 25% in patients with KIT mutation