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.

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.

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.

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.

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):

The mortality rate of basal-cell and squamous-cell carcinoma are around 0.3%, causing 2000 deaths per year in the US. In comparison, the mortality rate of melanoma is 15–20% and it causes 6500 deaths per year. Even though it is much less common, malignant melanoma is responsible for 75% of all skin cancer-related deaths.

The survival rate for people with melanoma depends upon when they start treatment. The cure rate is very high when melanoma is detected in early stages, when it can easily be removed surgically. The prognosis is less favorable if the melanoma has spread to other parts of the body. As of 2003 the overall five year cure rate with Mohs' micrographic surgery was around 95 percent for recurrent basal cell carcinoma.

Australia and New Zealand exhibit one of the highest rates of skin cancer incidence in the world, almost four times the rates registered in the United States, the UK and Canada. Around 434,000 people receive treatment for non-melanoma skin cancers and 10,300 are treated for melanoma. Melanoma is the most common type of cancer in people between 15–44 years in both countries. The incidence of skin cancer has been increasing. The incidence of melanoma among Auckland residents of European descent in 1995 was 77.7 cases per 100,000 people per year, and was predicted to increase in the 21st century because of "the effect of local stratospheric ozone depletion and the time lag from sun exposure to melanoma development."

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.

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.

The first step to diagnosing tonsil carcinoma is to obtain an accurate history from the patient. The physician will also examine the patient for any indicative physical signs. A few tests then, maybe conducted depending on the progress of the disease or if the doctor feels the need for. The tests include:

Fine needle aspiration, blood tests, MRI, x-rays and PET scan.

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.

Keratoacanthoma presents as a fleshy, elevated and nodular lesion with an irregular crater shape and a characteristic central hyperkeratotic core. Usually the patient will notice a rapidly growing dome-shaped tumor on sun-exposed skin.

If the entire lesion is removed, the pathologist will probably be able to differentiate between keratoacanthoma and squamous cell carcinoma. If only part of the lesion is removed, confident diagnosis may be impossible.

In the treatment of Kangri cancer, surgery is, most often, the first-line course of action to remove the primary tumor.

External beam radiotherapy has been used in one person to prevent the relapse and growth of tumor metastases to the head and neck regions. The prophylactic applications of radiation have been noted as “encouraging” in this one case, reducing some tumors and eliminating others.

Another study with a couple of the same authors found that radiotherapy after surgery helped with the reduction and cure of head and neck tumors in additional cases. The researchers suggest that external beam radiotherapy should be part of the treatment course for patients who have or at risk of developing tumors in the head and neck areas.

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.

The basis of deciding the T stage depends on physical examination and imaging of the tumor.

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.

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%.

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.

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.

Physicians usually diagnose actinic keratosis by doing a thorough physical examination, through a combination of visual observation and touch. However a biopsy may be necessary when the keratosis is large in diameter, thick, or bleeding, in order to make sure that the lesion is not a skin cancer. Actinic keratosis and squamous cell carcinoma (SCC) can present similarly on physical exam, and many scientists argue that they are in fact simply different stages of the same condition. In addition to SCCs, AKs can be mistaken for other cutaneous lesions including seborrheic keratoses, basal cell carcinoma, lichenoid keratosis, porokeratosis, viral warts, inflammatory dermatoses, or melanoma.

According to the NIH Consensus Conference , if DCIS is allowed to go untreated, the natural course or natural history varies according to the grade of the DCIS. Unless treated, approximately 60 percent of low-grade DCIS lesions will have become invasive at 40 years follow-up. High-grade DCIS lesions that have been inadequately resected and not given radiotherapy have a 50 percent risk of becoming invasive breast cancer within seven years. Approximately half of low-grade DCIS detected at screening will represent overdiagnosis, but overdiagnosis of high-grade DCIS is rare. The natural history of intermediate-grade DCIS is difficult to predict. Approximately one-third of malignant calcification clusters detected at screening mammography already have an invasive focus.

The prognosis of IDC depends, in part, on its histological subtype. Mucinous, papillary, cribriform, and tubular carcinomas have longer survival, and lower recurrence rates. The prognosis of the most common form of IDC, called "IDC Not Otherwise Specified", is intermediate. Finally, some rare forms of breast cancer (e.g., sarcomatoid carcinoma, inflammatory carcinoma) have a poor prognosis. Regardless of the histological subtype, the prognosis of IDC depends also on tumor size, presence of cancer in the lymph nodes, histological grade, presence of cancer in small vessels (vascular invasion), expression of hormone receptors and of oncogenes like HER2/neu.

These parameters can be entered into models that provide a statistical probability of systemic spread. The probability of systemic spread is a key factor in determining whether radiation and chemotherapy are worthwhile. The individual parameters are important also because they can predict how well a cancer will respond to specific chemotherapy agents.

Overall, the 5-year survival rate of invasive ductal carcinoma was approximately 85% in 2003.

Excision of the entire lesion, with adequate margin, will remove the lesion, allow full tissue diagnosis, and leave a planned surgical wound which can usually be repaired with a good cosmetic result. However, removing the entire lesion (especially on the face) may present difficult problems of plastic reconstruction. (On the nose and face, Mohs surgery may allow for good margin control with minimal tissue removal, but many insurance companies require the definitive diagnosis of a malignancy "before" they are prepared to pay the extra costs of Mohs surgery.) Especially in more cosmetically-sensitive areas, and where the clinical diagnosis is reasonably certain, alternatives to surgery may include no treatment (awaiting spontaneous resolution).

On the trunk, arms, and legs, electrodesiccation and curettage often suffice to control keratoacanthomas until they regress. Other modalities of treatment include cryosurgery and radiotherapy; intralesional injection of methotrexate or of 5-fluorouracil have also been used.

Recurrence after electrodesiccation and curettage can occur; it can usually be identified and treated promptly with either further curettage or surgical excision.