Immune System

There are studies that have found chances of melanoma in immune-suppressed patients are almost 6 times than the general population. This weakening of the immune-system increases the chances of developing melanoma.

Skin

Patients with melanoma are presented with several numbers of nevi on their skin. These are differentiated between typical and atypical lesions. There is a ABCDEs method for differentiating early melanomas from benign nevi, which is dealt with in the “Patient Information” segment of the present article. Some of the other presentation includes:

• Appearance of a new mole after puberty or a long-standing mole, which is changing shape, color and size.
• Mole which is itching and bleeding.
• New pigmented line in a nail, where there is damage to the nails.

• Inguinal Lymphadenopathy

  A 57-year-old woman presented with an inguinal lymphadenopathy. Sixteen years before, cutaneous malignant melanoma of the lower limb had been excised. [ncbi.nlm.nih.gov]

  lymphadenopathy, examination of the genital and urinary tracts and anorectum is especially relevant.[16] All patients should be staged with CT scans of the head, chest, abdomen and pelvis.[16] Dabrafenib, vemurafenib is recommended by the National Institute [patient.info]

• Nausea

  Most common causes of discontinuation of therapy were fatigue, fever, depression, and nausea. [ncbi.nlm.nih.gov]

  Cell Inhibitory drugs have side effects, such as nausea and vomiting. Therefore, it is often a good idea to take medicine for nausea before receiving chemotherapy to reduce or prevent the side effect. [firstderm.com]

• Blister

  'Blood blisters' especially under toenails, that are not the result of a blow. The appearance of a new irregular mole (it is quite normal for people to develop new moles from time to time until they reach their 40s. [netdoctor.co.uk]

  A history of prolonged or excessive sun exposure, including blistering sunburns. A history of tanning bed use. Many moles, especially “atypical” moles. A weakened immune system. [my.clevelandclinic.org]

  Other risk factors include UV exposure (sunlight or tanning booths), history of blistering sunburns, dysplastic nevi, large numbers of ordinary moles, red or blonde hair, blue or green eyes, very fair skin, personal or family history of melanoma and weakened [dermspecpa.com]

• Keratosis

  Dull or lackluster surface, and with keratin cysts seen histologically.[2]:769 Stucco keratosis (deratosis alba,[13] digitate seborrheic keratosis, hyperkeratotic seborrheic keratosis, serrated seborrheic keratosis, verrucous seborrheic keratosis) Common [en.wikipedia.org]

  Actinic Keratosis What is an actinic keratosis? An actinic keratosis (AK) is a precancerous skin growth, also known as a sun spot, that may progress to a skin cancer. [apexskin.com]

  Hemangioma – cherry, thrombosed Dermatofibroma – firm, tan or brown papule with positive dimple sign Halo nevus – tan or brown papule with surrounding depigmented patch Metastatic carcinoma Paget disease Tinea nigra Subungual hematoma Pigmented actinic keratosis [visualdx.com]

  Lesions of actinic keratosis may be macular or papular. FIGURE 1. Actinic keratoses. Note the scaly appearance of the multiple lesions. Lesions of actinic keratosis may be macular or papular. [aafp.org]

  Actinic keratosis Psoriasis Psoriasis video library Seborrheic dermatitis Skin cancer Find skin cancer information and treatment options and learn how you can prevent and detect the disease. [skincarephysicians.com]

• Pruritus

  With only grade 1 pruritus, the patient continues to be on nivolumab treatment at 15 months after the induction therapy, with no progression observed after the second episode of pseudoprogression in the liver and peritoneal nodule. [ncbi.nlm.nih.gov]

  High-grade adverse events during the maintenance phase were infrequent; among the grade 3 or 4 adverse events noted were colitis and diarrhea (in 1 patient) and rash or pruritus (in 3 patients). [doi.org]

  Because pruritus remains a prevalent early symptom in almost one half of patients with a melanoma, the onset of itching in a new or longstanding mole should not be ignored. [aafp.org]

  A: Asymmetry in the shape B: Border irregularity C: Color variegation D: Diameter greater than 6 mm (not absolute) E: Evolving morphologically or symptomatically (such as growth faster than other lesions, pruritus, pain, bleeding and crusting). [bccancer.bc.ca]

  Patients are predominantly elderly White women; they frequently present with vulvar bleeding, pruritus or dysuria. Treatment of tumours with a thickness of 14 Trimble EL (1996) Melanomas of the vulva and vagina. [codes.iarc.fr]

• Fair Complexion

  Race More common in whites More common in whites Skin type/ethnicity Increased incidence in those with fair complexions; those who burn easily, tan poorly and freckle; those who have red, blonde or light brown hair; and those of Celtic ancestry Increased [aafp.org]

  Risk factors that can increase a person's chances of melanoma include: a fair complexion (light skin that freckles or burns easily) blue or green eyes blond or red hair having many moles (usually, more than 25) UV exposure (from the sun or a tanning bed [kidshealth.org]

  Melanoma is more common in men than women and among individuals of fair complexion and those who have been exposed to natural or artificial sunlight (such as tanning beds) over long periods of time. [web.archive.org]

• Alopecia

  Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. [ncbi.nlm.nih.gov]

  Alopecia areata Dandruff: How to treat Hair loss Scalp psoriasis Itchy skin Are you suffering from itchy skin? Find out the possible causes that are making you want to scratch. [skincarephysicians.com]

  Common toxicities observed with vemurafenib include arthralgia, photosensitivity, rash, pruritus, alopecia, nausea, diarrhea and fatigue [ 24 ]. [doi.org]

• Headache

  Here, we describe a case of a 37-year-old male who visited our hospital due to worsening headaches. [ncbi.nlm.nih.gov]

  Common Yervoy side effects may include: fever, cough; nausea, diarrhea, loss of appetite, weight loss ; rash or itching; headache, tiredness; or pain in your muscles, joints, or bones. [drugs.com]

  […] increased bowel movements, black or bloody stools, stomach tenderness; pain in your upper stomach, dark urine, jaundice (yellowing of the skin or eyes), easy bruising or bleeding; unusual muscle weakness, numbness or tingling in your hands or feet; unusual headaches [web.archive.org]

Pathology

The thickness of the tumor is defined by the Breslow’s Depth of Invasion. Greater the thickness of the tumor, the poorer is the prognosis of metastatis. Measuring the vertical depth of the tumor in (mm) with an ocular micrometer is the method to determine Breslow thickness. Tumor of thickness <1 mm has a 5-year survival rate of 95-100%, while that for >4 mm, the 5-year survival rate reduces to 37-50% [8].

Mitotic Rate

This rate can be determined by counting the number of cells that shows cell-division (mitosis). Greater the mitosis rate, lower is the survival rate.

Diagnosis of Melanoma

Diagnosis of melanoma is not easy. Since the symptoms of the disease are not obvious, careful attention for the diagnosis of the disease is sought. Family history of the patients is equally important. In case of suspicious lesions, skin biopsy is recommended.

Biopsy: Though there are several types of biopsies, the most common is one that involves the removal of the tissue from the skin and examining the same under microscope. Important types of skin biopsies include: Fine needle Aspirate (FNA), Shave biopsy, punch biopsy, excisional biopsy and incisional biopsy.

Lymph Node Status: Lymph nodes of the patients are examined to check if the cells have travelled beyond the primary site. To confirm this, a lymph node biopsy is performed. In case, the melanoma cells are found in the sentinel node, a second surgery to examine and remove the additional lymph nodes must be performed [5]. If there are no melanoma cells found, then no further surgical intervention needs to be done. Stage of the melanoma is ascertained by the extent of lymph node involvement and some other factors. Determination of the stage of melanoma helps to determine the treatment option(s) and the prognosis. Early detection of melanoma can help save the life of the patient.

Medical Therapy

Recent drugs approved by FDA for managing Melanoma include dabrafenib, vemurafenib and Trametinib. While trametinib is a MEK inhibitor useful in melanoma with BRAF V600E or V600K mutations, Dabrafenib works as a BRAF protein-kinase inhibitor. In advanced stages of melanoma, medical therapy serves as an adjunct [9].

Surgical Therapy

The basis of surgical management of melanoma is the predicted risk of local recurrences and metastatic disease as well as the potential morbidity of the operation. If the lesion has not spread away from the primary site and lesions are thin, they are considered potentially curable [6].

Stage 0: For the management of the melanoma at Stage 0, one must excise the tumor properly. No further therapy is needed, though observation is necessary for recurrent disease.

Stage 1: For treating tumor in stage 1, 1-cm excision is sufficient, though lesions > 1mm require 2-cm margins. Lesions that are >1 mm, sentinel lymph node biopsy is recommended. It must be noted that no improvement in recurrence and survival rates with larger margins of resection was seen.

Stage II: To manage this stage of melanoma, a 2-cm surgical resection is to be done. There should be complete therapeutic lymphadenectomy in patients with suspected node metastases. Sentinel lymph node biopsy is to be considered in case of no clinically positive nodes. Analysis of the sentinel node must be performed by a pathologist. Adjuvant chemotherapy must also be initiated.

Stage III: Local excision of the primary tumor with 2-cm margin is the first line of therapy. In this stage, rate of Treatment failure is higher with wider local excision.

Stage IV: This stage of melanoma is usually refractory to standard therapy. Though some of the treatments have yielded objective responses, they are short-lived. Response rate of 20% observed with dacarbazine, carmustine, lomustine. With interferon-alfa and interleukin 2, the response rates were 8-22% with and 10-20%, respectively. Surgical resection of isolated metastases can be performed for palliation, with very less chances of survival [7].

Recurrent Melanoma: Surgical excision has shown good efficacy in cases where they can be accomplished.

Follow-up care

Follow-up must be done to monitor the new primary lesions, recurrences of the lesion and/or metastates. Physical examination and history of the patients are also crucial factors that must be noted. Though most of the patients observe their patients every 3-6 months, they eventually decrease the frequency of the visit. Patients with thicker tumors are advised to frequent the doctors more than the ones with thinner lesions.

Follow-up with dermatologists is equally important. Education and awareness about the disease and the symptoms can help to self-examine the tumor and aid in early detection of the disease.

• Wound infection is the potential complication of melanoma.
• In about 27% of the patients population, seromas and lymphoceles is observed at the time of dissection of axillary node.
• 22% of the patient population has shown nerve dysfunction and pain.
• Hematoma is seen in 1% of the population [4].
• At the preoperative stage, intra-operative attention to details can help to minimize the risk associated with the complications.

Poor prognostic factors include the following:

• Thickness of the tumor: Thicker the lesion, the worse is the prognosis.
• Location of the tumor: Presence of tumor in the lymph nodes-Stage III disease. 
• Presence of distant metastasis: Stage IV disease
• Greater number of the lymph nodes.
• Ulcers present.
• Male gender.

Family history: There is a higher risk of having melanoma in people with a positive family history of the disease in as high as 10% of cases.

Personal profile of the patients with melanoma that increases their risk of having melanoma, are as follows:

• Blue eyes
• Red hair
• Pale complexion
• Sensitivity to sun
• Immunosuppressive states (transplantation patients, hematologic malignancies)

Sun exposure over the lifetime: High levels of UVB and UVA exposure to radiation can increase the chances of developing melanoma.

Socioeconomic status: The detection of the disease is delayed in patients who form the economically lower strata of the population. In one study, it was found that the newly-diagnosed patients in this group of population. This stratum of the population has decreased perception of the melanoma risk.

According to WHO, there are currently 2 and 3 million non-melanoma skin cancer patients across the globe, while about 132,000 melanoma skin cancers is reported each year. About 33% of all the cancers reported is a skin cancer [1].

The annual increase in the incidence of melanoma has is approximately 3-7% among Caucasians. This can be attributes to better diagnosis, enhanced public awareness, and rise in the exposure of skin to natural or artificial ultraviolet radiation [3]. In females, thin lesions melanoma was more than males. Men were more susceptible to thick lesions melanoma.

With the exposure of the UV light, the patients with higher genetic susceptibility to this environmental exposure (patients with CDKN2A, CDK4, MC1R, BRAF, p16/ARF genes) can cause the genetic mutations in the melanocytes activating the oncogenes, inactivation of the tumor suppressor genes and impairment of DNA repair process [2].

Due to these changes, there is melanocyte proliferation, tumor invasion, evasion of the immune system and finally metastatis.

To prevent melanoma in patients, avoiding the direct rays of the sun is a good idea. Exposing the skin to the harsh UV-rays of the sun trigger the oncogenes, hence wearing sunscreen throughout the year is important. Familiarity with the skin and awareness about melanoma can help early detection of the disease. Since family history also plays significant role in the pathogenesis of melanoma, knowing about the same can help in identifying the disease.

Malignant melanoma is a neoplasia of the melanocytes. Melanocytes are the pigment cells present in the skin. Though the common region where the melanoma is seen is the skin, gastrointestinal tract and brain (as both these regions are derived from the neural crest) can also be affected by this menace.

Melanoma, if detected earlier, can be completely treated. The 5-year relative survival rate of patients detected with stage 0 melanoma is 97% compared to just 10% if the same is diagnosed with stage IV of this disease. It is, however, more serious form of skin cancer as it spreads to the other parts of the body, causing serious illness and even death. As melanomas generally occur in the skin, the patient is themselves the first to detect the condition.

Melanoma generally affects the adults with peak incidence in the fourth decade of one’s life. Both the genders are equally affected. The incidence of melanoma is increasing by around 6% each year. Awareness of the symptoms can therefore help to fight this disease on the global scale. The incidence of melanoma varies significantly. While the white population, living in the sunny areas across the globe is more prone to develop melanomas, Asian populations have reported the lowest rates of this type of cancer.

Characteristics of the disease in the patients with melanoma follow the acronym called “ABCDE” of lesion. While “A” stands for Asymmetry, “B”, “C”,”D” and “E” stands for Irregular border, Color variations (ranging from red, white, and blue tones in a brown or black lesion), Diameter (>6mm) and Elevated surface respectively. Melanomas also itch, bleed and build satellites.

Clinical presentation of the different stages of the melanoma is described below:

• For Stage I and II, the thickness of tumor is most important. Hence, the full-thickness biopsy specimen must be obtained for adequate pathologic interpretation.
• Biopsy results help to determine the margins of resection.
• In patients where the primary sites of melanoma are other than the skin, the signs and symptoms are related to the affected organ systems.

1. Rigel DS, Friedman RJ, Kopf AW. The incidence of malignant melanoma in the United States: issues as we approach the 21st century. J Am Acad Dermatol. May 1996;34(5 Pt 1):839-47.
2. Heasley DD, Toda S, Mihm MC Jr. Pathology of malignant melanoma. Surg Clin North Am. Dec 1996;76(6):1223-55.
3. Autier P, Dore JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma. Curr Opin Oncol. Dec 29 2010
4. Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol. Jun 1998;5(4):322-8.
5. Norman J, Cruse CW, Espinosa C, et al. Redefinition of cutaneous lymphatic drainage with the use of lymphoscintigraphy for malignant melanoma. Am J Surg. Nov 1991;162(5):432-7
6. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. Sep 1993;218(3):262-7; discussion 267-9.
7. Bakotic B, Ackerman AB. Staging of melanoma: a critique in historical perspective: part I. Am J Dermatopathol. Apr 2005;27(2):160-4.
8. Messina JL. Pathologic examination of sentinel lymph nodes. Techniques 2000. 1996.
9. Legha SS. Current therapy for malignant melanoma. Semin Oncol. Feb 1989;16(1 Suppl 1):34-44.
10. National Institutes of Health. NIH Consensus conference. Diagnosis and treatment of early melanoma.JAMA. Sep 9 1992;268(10):1314-9.