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.

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.

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

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.

This form of cancer is often seen in those who chew tobacco or use snuff orally, so much so that it is sometimes referred to as "Snuff dipper's cancer." Chewing betel nuts is an additional risk factor commonly seen in Taiwan.

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.

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.

Surgical excision or laser therapy are possible treatments. Surgical excision alone was effective for controlling VC, but elective neck dissection was not necessary even in patients in the advanced stages.

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.

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%.

The diagnosis of urachal cancer can be difficult and usually requires a multidisciplinary approach. A calcification in the midline can be detected in some patients in abdominal imaging studies. A cystoscopy is helpful in most cases. For diagnosis evaluation of a tissue biopsy is needed, which is usually obtained by transurethral resection (TURBT). Measurement of serum concentrations of CEA, CA19-9 and CA125 can be helpful in monitoring urachal cancer

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.

The US Preventive Services Task Force (USPSTF) in 2013 stated evidence was insufficient to determine the balance of benefits and harms of screening for oral cancer in adults without symptoms by primary care providers. The American Academy of Family Physicians comes to similar conclusions while the American Cancer Society recommends that adults over 20 years who have periodic health examinations should have the oral cavity examined for cancer. The American Dental Association recommends that providers remain alert for signs of cancer during routine examinations.

There are a variety of screening devices, however, there is no evidence that routine use of these devices in general dental practice is helpful. However, there are compelling reasons to be concerned about the risk of harm this device may cause if routinely used in general practice. Such harms include false positives, unnecessary surgical biopsies and a financial burden on the patient.

Early diagnosis of oral cancer patients would decrease mortality and help to improve treatment. Oral surgeons and dentists can diagnose these patients in the early stages. Health providers, dentists, and oral surgeons shall have high knowledge and awareness that would help them to provide better diagnosis for oral cancer patients. An examination of the mouth by the health care provider, dentist, oral surgeons shows a visible and/or palpable (can be felt) lesion of the lip, tongue, or other mouth area. The lateral/ventral sides of the tongue are the most common sites for intraoral SCC. As the tumor enlarges, it may become an ulcer and bleed. Speech/talking difficulties, chewing problems, or swallowing difficulties may develop. A feeding tube is often necessary to maintain adequate nutrition. This can sometimes become permanent as eating difficulties can include the inability to swallow even a sip of water. The doctor can order some special investigations which may include a chest x-ray, CT or MRI scans, and tissue biopsy.

While a dentist, physician or other health professional may suspect a particular lesion is malignant, there is no way to tell by looking alone - since benign and malignant lesions may look identical to the eye. A non-invasive brush biopsy (BrushTest) can be performed to rule out the presence of dysplasia (pre-cancer) and cancer on areas of the mouth that exhibit an unexplained color variation or lesion. The only definitive method for determining if cancerous or precancerous cells are present is through biopsy and microscopic evaluation of the cells in the removed sample. A tissue biopsy, whether of the tongue or other oral tissues and microscopic examination of the lesion confirm the diagnosis of oral cancer or precancer.

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 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.

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.

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.

It is important to exclude a tumor which is directly extending into the ear canal from the parotid salivary gland, especially when dealing with an adenoid cystic or mucoepidermoid carcinoma. This can be eliminated by clinical or imaging studies. Otherwise, the histologic differential diagnosis includes a ceruminous adenoma (a benign ceruminous gland tumor) or a neuroendocrine adenoma of the middle ear (middle ear adenoma).

PUNLMPs are exophytic lesions that appear friable to the naked eye and when imaged during cystoscopy.

They are definitively diagnosed after removal by microscopic examination by pathologists.

Histologically, they have a papillary architecture with slender fibrovascular cores and rare basal mitoses. The papillae rarely fuse and uncommonly branch. Cytologically, they have uniform nuclear enlargement.

They cannot be reliably differentiated from low grade papillary urothelial carcinomas using cytology, and their diagnosis (vis-a-vis low grade papillary urothelial carcinoma) has a poor inter-rater reliability.

Pathologic grading and staging tumors are:

graded by the degree of cellular atypia (G1->G3), and

staged:

Urachal cancer usually is an adenocarcinoma (about 90%) mostly with mucinous/colloidal histology. The histology can be difficult to distinguish especially from colorectal cancer and primary adenocarcinoma of the urinary bladder. Immunohistochemistry in this situation is of little help with stains for betaCatenin and Cytokeratin 7 can be helpful. Other rare types include urothelial carcinoma, squamous cell carcinoma, neuroendocrine carcinoma and sarcoma.

Diagnostic systems in use are the Sheldon system based on proposals from Wheeler and Hill and Mostofi. Recent diagnostic classification schemes have been proposed by Herr et al and Gopalan et al. For non-adenocarcinoma urachal cancer a diagnostic classification scheme has been proposed by Paner et al.

PUNLMPs are treated like non-invasive low grade papillary urothelial carcinomas, excision and regular follow-up cystoscopies.

There is a rare occurrence of a pelvic recurrence of a low-grade superficial TCC after cystectomy. Delayed presentation with recurrent low-grade urothelial carcinoma is an unusual entity and potential mechanism of traumatic implantation should be considered. Characteristically low-grade tumors are resistant to systemic chemotherapy and curative-intent surgical resection of the tumor should be considered.

Treatment involves biopsy of the lesion to identify extent of dysplasia. Complete excision of the lesion is sometimes advised depending on the histopathology found in the biopsy. Even in these cases, recurrence of the erythroplakia is common and, thus, long-term monitoring is needed.