Following a visual examination and a dermatoscopic exam, or "in vivo" diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining severity. Elliptical excisional biopsies may remove the tumor, followed by histological analysis and Breslow scoring. Incisional biopsies such as punch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling error or local implantation causing misestimation of tumour thickness. However, fears that such biopsies may increase the risk of metastatic disease seem unfounded.

Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up for high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (with any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates metastatic spread of the disease to the liver.

It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, PET and/or PET/CT scans. Although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker.

HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas. It is used in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity. The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal melanocytes but not normal adult melanocytes.

HMB-45 is nonreactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).

Diagnosis is confirmed via biopsy of the tissue(s) suspected to be affected by SCC. For the skin, look under skin biopsy.

The pathological appearance of a squamous cell cancer varies with the depth of the biopsy. For that reason, a biopsy including the subcutaneous tissue and basalar epithelium, to the surface is necessary for correct diagnosis. The performance of a shave biopsy (see skin biopsy) might not acquire enough information for a diagnosis. An inadequate biopsy might be read as actinic keratosis with follicular involvement. A deeper biopsy down to the dermis or subcutaneous tissue might reveal the true cancer. An excision biopsy is ideal, but not practical in most cases. An incisional or punch biopsy is preferred. A shave biopsy is least ideal, especially if only the superficial portion is acquired.

Even though the ideal method of diagnosis of melanoma should be complete excisional biopsy, the location of the melanoma may require alternatives. Dermatoscopy of acral pigmented lesions is very difficult but can be accomplished with diligent attention. Initial confirmation of the suspicion can be done with a small wedge biopsy or small punch biopsy. Thin deep wedge biopsies can heal very well on acral skin, and small punch biopsies can give enough clue to the malignant nature of the lesion. Once this confirmatory biopsy is done, a second complete excisional skin biopsy can be performed with a narrow surgical margin (1 mm). This second biopsy will determine the depth and invasiveness of the melanoma, and will help to define what the final treatment will be. If the melanoma involves the nail fold and the nail bed, complete excision of the nail unit might be required. Final treatment might require wider excision (margins of 0.5 cm or more), digital amputation, lymphangiogram with lymph node dissection, or chemotherapy.

It has been demonstrated that acral lentiginous melanoma has a poorer prognosis compared to that of cutaneous malignant melanoma (CMM).

Definitive diagnosis of Merkel cell carcinoma (MCC) requires examination of biopsy tissue. An ideal biopsy specimen is either a punch biopsy or a full-thickness incisional biopsy of the skin including full-thickness dermis and subcutaneous fat. In addition to standard examination under light microscopy, immunohistochemistry (IHC) is also generally required to differentiate MCC from other morphologically similar tumors such as small cell lung cancer, the small cell variant of melanoma, various cutaneous leukemic/lymphoid neoplasms, and Ewing's sarcoma. Similarly, most experts recommend longitudinal imaging of the chest, typically a CT scan, to rule out that the possibility that the skin lesion is a cutaneous metastasis of an underlying small cell carcinoma of the lung.

Appropriate sun-protective clothing, use of broad-spectrum (UVA/UVB) sunscreen with at least SPF 50, and avoidance of intense sun exposure may prevent skin cancer.

Sunscreen is effective and thus recommended to prevent melanoma and squamous-cell carcinoma. There is little evidence that it is effective in preventing basal-cell carcinoma. Other advice to reduce rates of skin cancer includes avoiding sunburning, wearing protective clothing, sunglasses and hats, and attempting to avoid sun exposure or periods of peak exposure. The U.S. Preventive Services Task Force recommends that people between 9 and 25 years of age be advised to avoid ultraviolet light.

The risk of developing skin cancer can be reduced through a number of measures including decreasing indoor tanning and mid day sun exposure, increasing the use of sunscreen, and avoiding the use of tobacco products.

There is insufficient evidence either for or against screening for skin cancers. Vitamin supplements and antioxidant supplements have not been found to have an effect in prevention. Evidence for a benefit from dietary measures is tentative.

Zinc oxide and titanium oxide are often used in sun screen to provide broad protection from UVA and UVB ranges.

Eating certain foods may decrease the risk of sunburns but this is much less than the protection provided by sunscreen.

Currently, there is no consensus regarding type or frequency of scans following diagnosis and treatment of the primary eye tumor. Of the 50% of patients who develop metastatic disease, more than 90% of patients will develop liver metastases. As such, the majority of surveillance techniques are focused on the liver. These include abdominal magnetic resonance imaging (MRI), abdominal ultrasound and liver function tests. The scientific community is currently working to develop guidelines, but until then, each patient must take into consideration their individual clinical situation and discuss appropriate surveillance with their doctors.

Some ophthalmologists have also found promise with the use of intravitreal avastin injections in patients suffering from radiation-induced retinopathy, a side effect of plaque brachytherapy treatment, as well as imaging surveillance with SD-OCT.

The differential for OSSN includes pterygium, pingueculum, papilloma, solar keratosis, lipoma, lymphoma, chronic blepharoconjunctivitis, inflammation, melanoma, ocular pannus, pyogenic granuloma, kaposi sarcoma, keratocanthoma, mucoepidermoid carcinoma, pseudoepitheliomatous hyperplasia, and adenocarcinoma. While confocal microscopy can be used for diagnosis, biopsy is considered the standard, especially before treatment with a cytotoxic medication.

Treatment depends on the thickness of the invasive component of the lentigo maligna. Treatment is essentially identical to other melanomas of the same thickness and stage.

This type of cancer occurs most often in Caucasians between 60 and 80 years of age, and its rate of incidence is about twice as high in males as in females. There are roughly 1,500 new cases of MCC diagnosed each year in the United States, as compared to around 60,000 new cases of melanoma and over 1 million new cases of nonmelanoma skin cancer. MCC is sometimes mistaken for other histological types of cancer, including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, and small cell carcinoma, or as a benign cyst. Researchers believe that exposure to sunlight or ultraviolet light (such as in a tanning bed) may increase the risk of developing this disease. Similar to melanoma, the incidence of MCC in the US is increasing rapidly.

Immunosuppression can profoundly increase the odds of developing Merkel-cell carcinoma. Merkel-cell carcinoma occurs 30 times more often in people with chronic lymphocytic leukemia and 13.4 times more often in people with advanced HIV as compared to the general population; solid organ transplant recipients have a 10-fold increased risk compared to the general population.

Treatment of small melanomas is often not necessary, but large tumors can cause discomfort and are usually surgically removed. Cisplatin and cryotherapy can be used to treat small tumors less than 3 centimeters, but tumors may reoccur. Cimetidine, a histamine stimulator, can cause tumors to regress in some horses, but may take up to 3 months to produce results and multiple treatments may be needed throughout the horse's life. There are few viable treatment options for horses with metastatic melanoma. However, gene therapy injections utilizing interleukin-12 and 18-encoding DNA plasmids have shown promise in slowing the progression of tumors in patients with metastatic melanoma.

Lymphoma is the most common type of blood-related cancer in horses and while it can affect horses of all ages, it typically occurs in horses aged 4–11 years.

Skin cancers result in 80,000 deaths a year as of 2010, 49,000 of which are due to melanoma and 31,000 of which are due to non-melanoma skin cancers. This is up from 51,000 in 1990.

More than 3.5 million cases of skin cancer are diagnosed annually in the United States, which makes it the most common form of cancer in that country. One in five Americans will develop skin cancer at some point of their lives. The most common form of skin cancer is basal-cell carcinoma, followed by squamous cell carcinoma. Unlike for other cancers, there exists no basal and squamous cell skin cancers registry in the United States.

Because there are no lymphatic channels to the uveal tract, metastasis occurs through local extension and/or blood borne dissemination. The most common site of metastasis for uveal melanoma is the liver; the liver is the first site of metastasis for 80%-90% of ocular melanoma patients. Other common sites of metastasis include the lung, bones and just beneath the skin (subcutaneous). Approximately 50 percent of patients will develop metastases within 15 years after treatment of the primary tumor, and the liver will be involved 90% of the time. Metastasis can occur more than 10 years after treatment of the primary tumor, and patients should not be considered cured even after a 10-year interval of monitoring. Molecular features of the tumor including Chromosome 3 status, Chromosome 6p status, and Chromosome 8q status and gene expression profiling (such as the DecisionDx-UM test) can be used to adjust this likelihood of metastasis for an individual patient.

The average survival time after diagnosis of liver metastases depends on the extent of systemic spread. The disease-free interval, the performance status, the liver substitution by metastases and the serum level of lactic dehydrogenase are the most important prognostic factors for metastatic uveal melanoma. There is currently no cure for metastatic uveal melanoma.

First dilemma in diagnosis is recognition. As lentigo malignas often present on severely sun damaged skin, it is frequently found amongst numerous pigmented lesions - thin seborrheic keratoses, lentigo senilis, lentigines. It is difficult to distinguish these lesions with the naked eye alone, and even with some difficulty using dermatoscopy. As the lentigo maligna is often very large, it often merges with, or encompasses other skin tumors - such as lentigines, melanocytic nevi, and seborrheic keratosis.

Second dilemma is the biopsy technique. Even though excisional biopsy (removing the entire lesion) is ideal, and advocated by pathologists, practical reason dictates that this should not be done. These tumors are often large and presenting on the facial area. Excision of such large tumor would be absolutely contraindicated if the lesion's identity is uncertain. The preferred method of diagnosis is by using a shave biopsy because punch biopsies give up to an 80% false negative rate. While one section of the tumor might show benign melanocytic nevus, another section might show features concerning of severe cellular atypia. When cellular atypia is noted, a pathologist might indicate that the entire lesion should be removed. It is at this point that one can comfortably remove the entire lesion, thus confirming the final diagnosis of lentigo maligna. Despite the high false negative rate, punch biopsies are often used and the size of the punch biopsy can vary from 1 mm to 2 mm, but it is preferred to use a punch 1.5 mm or larger. Representative samples of the most atypical part of the nevus should be biopsy, often by the aid of dermatoscopy.

Imaging studies such as X-rays, computed tomography scans, or MRI may be required to diagnose clear-cell sarcoma together with a physical exam. Normally a biopsy is also necessary. Furthermore, a chest CT, a bone scan and positron emission tomography (PET) may be part of the tests in order to evaluate areas where metastases occur.

First dilemma in diagnosis is recognition. As lentigo malignas often present on severely sun-damaged skin, it is frequently found amongst numerous pigmented lesions – thin seborrheic keratoses, lentigo senilis, lentigines. It is difficult to distinguish these lesions with the naked eye alone, and even with some difficulty using dermatoscopy. As the lentigo maligna is often very large, it often merges with, or encompasses other skin tumors – such as lentigines, melanocytic nevi, and seborrheic keratosis.

Second dilemma is the biopsy technique. Even though excisional biopsy (removing the entire lesion) is ideal, and advocated by pathologists; practical reason dictates that this should not be done. These tumors are often large and presenting on the facial area. Excision of such large tumor would be absolutely contraindicated if the lesion's identity is uncertain. The preferred method of diagnosis is by using a punch biopsy, allowing the physician to sample multiple full thickness pieces of the tumor at multiple sites. While one section of the tumor might show benign melanocytic nevus, another section might show features concerning for severe cellular atypia. When cellular atypia is noted, a pathologist might indicate that the entire lesion should be removed. It is at this point that one can comfortablly remove the entire lesion, and thus confirm the final diagnosis of lentigo maligna. The size of the punch biopsy can vary from 1 mm to 2 mm, but it is preferable to use a punch 1.5 mm or larger. Representative samples of the most atypical parts of the nevus should be biopsied, often guided by dermatoscopy.

Most conjunctival squamous cell carcinomas are removed with surgery. A few selected cases are treated with topical medication. Surgical excision with a free margin of healthy tissue is a frequent treatment modality. Radiotherapy, given as external beam radiotherapy or as brachytherapy (internal radiotherapy), can also be used to treat squamous cell carcinomas.

Therapies for metastatic melanoma include the biologic immunotherapy agents ipilimumab, pembrolizumab, and nivolumab; BRAF inhibitors, such as vemurafenib and dabrafenib; and a MEK inhibitor trametinib.

Since 80% of grey horses will develop a melanoma tumor at some point in their lives, it is important to know what kind of treatments are available. There are several treatment options when a horse is found to have a melanoma tumor including surgical or injections:

The U.S. Preventive Services Task Force (USPSTF) issues recommendations for various cancers:

- Strongly recommends cervical cancer screening in women who are sexually active and have a cervix at least until the age of 65.

- Recommend that Americans be screened for colorectal cancer via fecal occult blood testing, sigmoidoscopy, or colonoscopy starting at age 50 until age 75.

- Evidence is insufficient to recommend for or against screening for skin cancer, oral cancer, lung cancer, or prostate cancer in men under 75.

- Routine screening is not recommended for bladder cancer, testicular cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

- Recommends mammography for breast cancer screening every two years from ages 50–74, but does not recommend either breast self-examination or clinical breast examination. A 2013 Cochrane review concluded that breast cancer screening by mammography had no effect in reducing mortality because of overdiagnosis and overtreatment.

Screens for gastric cancer using photofluorography due to the high incidence there.

The best treatment of lentigo maligna is not clear as it has not been well studied.

Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is high (up to 50%). This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The use of dermatoscopy can significantly improve the surgeon's ability to identify the surgical margin. The narrow surgical margin used (smaller than the standard of care of 5 mm), combined with the limitation of the standard bread loafing technique of fixed tissue histology - result in a high "false negative" error rate, and frequent recurrences. Margin controlled (peripheral margins) is necessary to eliminate the false negative errors. If breadloafing is utilized, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.

Where the lesion is on the face and either large or 5mm margins are possible, a skin flap or skin graft may be indicated/required. Grafts have their own risks of failure and poor cosmetic outcomes. Flaps can require extensive incision resulting in long scars and may be better done by plastic surgeons (and possibly better again by those with extensive LM or "suspicious of early malignant melanoma" experience.

Mohs surgery has been done with cure rate reported to be 77%. The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.

Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. In view of the very poor cure rate with standard excision, some surgeons combine the two methods: surgical excision of the lesion, then three months treatment of the area with imiquimod cream.

Studies seem to conflict about the level of certainty associated with using imiquimod.

Another treatment to be considered where standard margins cannot be achieved or cosmetics are a major consideration is ultra-soft x-ray/grenz-ray radiation.

In the very elderly or those with otherwise limited life expectancy, the impact of major day surgery for excision with 5mm margins and large skin flap could be worse than doing nothing or the possibility of failed treatments with imiquimod or Grenz ray.