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.

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.

The following methods are employed in the treatment of basal-cell carcinoma (BCC):

Basal-cell carcinoma is a common skin cancer and occurs mainly in fair-skinned patients with a family history of this cancer. Sunlight is a factor in about two-thirds of these cancers; therefore, doctors recommend sunscreens with at least SPF 30. One-third occur in non-sun-exposed areas; thus, the pathogenesis is more complex than UV exposure as "the" cause.

The use of a chemotherapeutic agent such as 5-Fluorouracil or imiquimod, can prevent development of skin cancer. It is usually recommended to individuals with extensive sun damage, history of multiple skin cancers, or rudimentary forms of cancer (i.e., solar keratosis). It is often repeated every 2 to 3 years to further decrease the risk of skin cancer.

The long-term outcome of squamous cell carcinomas is dependent upon several factors: the sub-type of the carcinoma, available treatments, location(s) and severity, and various patient health-related variables (accompanying diseases, age, etc.). Generally, the long-term outcome is positive, as less than 4% of Squamous cell carcinoma cases are at risk of metastasis. Some particular forms of squamous cell carcinomas have a higher mortality rate. One study found squamous cell carcinoma of the penis had a much greater rate of mortality than some other forms of squamous cell carcinoma, that is, about 23%, although this relatively high mortality rate may be associated with possibly latent diagnosis of the disease due to patients avoiding genital exams until the symptoms are debilitating, or refusal to submit to a possibly scarring operation upon the genitalia. Squamous cell carcinoma occurring in the organ transplant population is also associated with a higher risk of mortality.

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.

Carcinomas can be definitively diagnosed through biopsy, including fine-needle aspiration (FNA), core biopsy, or subtotal removal of single node. Microscopic examination by a pathologist is then necessary to identify molecular, cellular, or tissue architectural characteristics of epithelial cells.

Staging of carcinoma refers to the process of combining physical/clinical examination, pathological review of cells and tissues, surgical techniques, laboratory tests, and imaging studies in a logical fashion to obtain information about the size of the neoplasm and the extent of its invasion and metastasis.

Carcinomas are usually staged with Roman numerals. In most classifications, Stage I and Stage II carcinomas are confirmed when the tumor has been found to be small and/or to have spread to local structures only. Stage III carcinomas typically have been found to have spread to regional lymph nodes, tissues, and/or organ structures, while Stage IV tumors have already metastasized through the blood to distant sites, tissues, or organs.

In some types of carcinomas, Stage 0 carcinoma has been used to describe carcinoma "in situ", and occult carcinomas detectable only via examination of sputum for malignant cells (in lung carcinomas).

In more recent staging systems, substages (a, b, c) are becoming more commonly used to better define groups of patients with similar prognosis or treatment options.

Carcinoma stage is the variable that has been most consistently and tightly linked to the prognosis of the malignancy.

The criteria for staging can differ dramatically based upon the organ system in which the tumor arises. For example, the colon and bladder cancer staging system relies on depth of invasion, staging of breast carcinoma is more dependent on the size of the tumor, and in renal carcinoma, staging is based on both the size of the tumor and the depth of the tumor invasion into the renal sinus. Carcinoma of the lung has a more complicated staging system, taking into account a number of size and anatomic variables.

The UICC/AJCC TNM systems are most often used. For some common tumors, however, classical staging methods (such as the Dukes classification for colon cancer) are still used.

Photodynamic therapy, cryotherapy (freezing), or local chemotherapy (with 5-fluorouracil) are favored by some clinicians over . Because the cells of Bowen's disease have not invaded the dermis, it has a much better prognosis than invasive squamous cell carcinoma.

Good results have been noted with the use of imiquimod for Bowen's disease, including on the penis (erythroplasia of Queyrat), although imiquimod is not (as of 2013) approved by the U.S. Food and Drug Administration for the treatment of any type of squamous cell carcinoma, and serious side effects can occur with use of imiquimod.

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.

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.

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.

Prognosis can range considerably for patients, depending where on the scale they have been staged. Generally speaking, the earlier the cancer is diagnosed, the better the prognosis. The overall 5-year survival rate for all stages of penile cancer is about 50%.

When associated with the prostate, squamous cell carcinoma is very aggressive in nature. It is difficult to detect as there is no increase in prostate specific antigen levels seen; meaning that the cancer is often diagnosed at an advanced stage.

Human papillomavirus infection (HPV) has been associated with SCC of the oropharynx, lung, fingers and anogenital region.

a) Surgical resection is mainstay of treatment, whenever possible. If tumor is completely removed, post-operative radiation therapy is typically not needed since acinic cell is considered a low-grade histology. Post-operative radiation therapy for acinic cell carcinoma is used if: 1) margins are positive, 2) incomplete resection, 3) tumor invades beyond gland, 4) positive lymph nodes.

b) Neutron beam radiation

c) Conventional radiation

d) Chemotherapy

Treatment is dependent on type of cancer, location of the cancer, age of the person, and whether the cancer is primary or a recurrence. Treatment is also determined by the specific type of cancer. For a small basal-cell cancer in a young person, the treatment with the best cure rate (Mohs surgery or CCPDMA) might be indicated. In the case of an elderly frail man with multiple complicating medical problems, a difficult to excise basal-cell cancer of the nose might warrant radiation therapy (slightly lower cure rate) or no treatment at all. Topical chemotherapy might be indicated for large superficial basal-cell carcinoma for good cosmetic outcome, whereas it might be inadequate for invasive nodular basal-cell carcinoma or invasive squamous-cell carcinoma.. In general, melanoma is poorly responsive to radiation or chemotherapy.

For low-risk disease, radiation therapy (external beam radiotherapy or brachytherapy), topical chemotherapy (imiquimod or 5-fluorouracil) and cryotherapy (freezing the cancer off) can provide adequate control of the disease; all of them, however, may have lower overall cure rates than certain type of surgery. Other modalities of treatment such as photodynamic therapy, topical chemotherapy, electrodesiccation and curettage can be found in the discussions of basal-cell carcinoma and squamous-cell carcinoma.

Mohs' micrographic surgery (Mohs surgery) is a technique used to remove the cancer with the least amount of surrounding tissue and the edges are checked immediately to see if tumor is found. This provides the opportunity to remove the least amount of tissue and provide the best cosmetically favorable results. This is especially important for areas where excess skin is limited, such as the face. Cure rates are equivalent to wide excision. Special training is required to perform this technique. An alternative method is CCPDMA and can be performed by a pathologist not familiar with Mohs surgery.

In the case of disease that has spread (metastasized), further surgical procedures or chemotherapy may be required.

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

This type of carcinoma is commonly managed by local resection, cryotherapy, topical chemotherapy, and radiotherapy. Multimodal therapy has been shown to improve both visual prognosis and survival.

Mohs micrographic surgery has become the treatment of choice for this form of cancer. When used as the primary treatment modality for sebaceous carcinoma of the eyelid, Mohs surgery is associated with significantly lower local and distant recurrence rates.

Prognosis is good for acinic cell carcinoma of the parotid gland, with five-year survival rates approaching is 90%, and 20-year survival exceeding 50%. Patients with acinic cell carcinomas with high grade transformation (sometimes also called dedifferentiation) have significantly worse survival.

The prognosis of an acinic cell carcinoma originating in the lung is much more guarded than cases of this rare histotype occurring in most other organs, but is still considerably better than for other types of lung cancer.

A lesion biopsy is performed if the diagnosis remains uncertain after a clinical physical exam. The most common tissue sampling techniques include shave or punch biopsy. When only a portion of the lesion can be removed due to its size or location, the biopsy should sample tissue from the thickest area of the lesion, as SCCs are most likely to be detected in that area. If a shave biopsy is performed, it should extend through to the level of the dermis in order to provide sufficient tissue for diagnosis; ideally, it would extend to the mid-reticular dermis. Punch biopsy usually extends to the subcutaneous fat when the entire length of the punch blade is utilized.

There are several treatment options for penile cancer, depending on staging. They include surgery, radiation therapy, chemotherapy, and biological therapy. The most common treatment is one of five types of surgery:

- Wide local excision—the tumor and some surrounding healthy tissue are removed

- Microsurgery—surgery performed with a microscope is used to remove the tumor and as little healthy tissue as possible

- Laser surgery—laser light is used to burn or cut away cancerous cells

- Circumcision—cancerous foreskin is removed

- Amputation (penectomy)—a partial or total removal of the penis, and possibly the associated lymph nodes.

Radiation therapy is usually used adjuvantly with surgery to reduce the risk of recurrence. With earlier stages of penile cancer, a combination of topical chemotherapy and less invasive surgery may be used. More advanced stages of penile cancer usually require a combination of surgery, radiation and chemotherapy.

In addition to all the above, treatment of the underlying disease like brucellosis, is important to limit disease recurrence.

Overall, five-year survival rates for vulvar cancer are around 78% but may be affected by individual factors including cancer stage, cancer type, patient age and general medical health. Five-year survival is greater than 90% for patients with stage I lesions but decreases to 20% when pelvic lymph nodes are involved. Lymph node involvement is the most important predictor of prognosis. Thus, early diagnosis is important.

Recurrence is common, although the recurrence rates for block resection followed by bone graft are lower than those of enucleation and curettage. Follicular variants appear to recur more than plexiform variants. Unicystic tumors recur less frequently than "non-unicystic" tumors. Persistent follow-up examination is essential for managing ameloblastoma. Follow up should occur at regular intervals for at least 10 years. Follow up is important, because 50% of all recurrences occur within 5 years postoperatively. Recurrence within a bone graft (following resection of the original tumor) does occur, but is less common. Seeding to the bone graft is suspected as a cause of recurrence. The recurrences in these cases seem to stem from the soft tissues, especially the adjacent periosteum. Recurrence has been reported to occur as many as 36 years after treatment.

To reduce the likelihood of recurrence within grafted bone, meticulous surgery with attention to the adjacent soft tissues is required.

Other cancerous lesions in the differential diagnosis include Paget's disease of the vulva and vulvar intraepithelial neoplasia (VIN). Non-cancerous vulvar diseases include lichen sclerosus, squamous cell hyperplasia, and vulvar vestibulitis. A number of diseases cause infectious lesions including herpes genitalis, human papillomavirus, syphilis, chancroid, granuloma inguinale, and lymphogranuloma venereum.

The prognosis varies dramatically, depending on the type and stage at the time of treatment. However, the most common epitheliomas are very easily treated and rarely result in death.