Erythema nodosum is diagnosed clinically. A biopsy can be taken and examined microscopically to confirm an uncertain diagnosis. Microscopic examination usually reveals a neutrophilic infiltrate surrounding capillaries that results in septal thickening, with fibrotic changes in the fat around blood vessels. A characteristic microscopic finding is radial granulomas, well-defined nodular aggregates of histiocytes surrounding a stellate cleft.

Additional evaluation should be performed to determine the underlying cause of erythema nodosum. This may include a full blood count, erythrocyte sedimentation rate (ESR), antistreptolysin-O (ASO) titer and throat culture, urinalysis, intradermal tuberculin test, and a chest x-ray. The ESR is typically high, the C-reactive protein elevated, and the blood showing an increase in white blood cells.

The ESR is initially very high, and falls as the nodules of erythema nodosum. The ASO titer is high in cases associated with a streptococcal throat infection. A chest X-ray should be performed to rule out pulmonary diseases, in particular sarcoidosis and Löfgren syndrome.

Colloid nodules are usually small enough to be undetectable without an ultrasound or other imaging techniques. They usually produce no symptoms, so patients are unlikely to notice them until their size makes them easier to detect. Like other thyroid nodules, they are usually first noticed in a routine physical examination.

Fine Needle Aspiration Cytology (FNAC) is a cheap, simple, and safe method in obtaining cytological specimens for diagnosis by using a needle and a syringe. The "Bethesda System for Reporting Thyroid Cytopathology" is the system used to report whether the thyroid cytological specimen is benign or malignant. It can be divided into six categories:

Repeated FNAC is recommended for Category I, followed by clinical follow-up in Category II, repeat FNAC for Category III, and lobectomy for Category IV, near total-thyroidectomy/lobectomy for Category V, and near total thyroidectomy for Category VI. The risk of malignancy in a malignant FNAC report is 93.7% while for suspicious FNAC report, it is 18.9%.

Blood tests may be done prior to or in lieu of a biopsy. The possibility of a nodule which secretes thyroid hormone (which is less likely to be cancer) or hypothyroidism is investigated by measuring thyroid stimulating hormone (TSH), and the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

Tests for serum thyroid autoantibodies are sometimes done as these may indicate autoimmune thyroid disease (which can mimic nodular disease).

Treatment of rheumatoid nodules is rarely a priority for people with rheumatoid arthritis. However, surgical removal is often successful, even if there is a tendency for nodules to regrow. Of the drug therapies commonly used in rheumatoid arthritis, methotrexate has the disadvantage of tending to make nodules worse. TNF inhibitors do not have a very reliable effect on nodules. B cell depletion with rituximab often leads to disappearance of nodules but this is not guaranteed.

Colloid nodules may be initially identified as an unspecified kind of thyroid nodule. Follow-up examinations typically include an ultrasound if it's unclear whether or not there really is a nodule present. Once the presence of a nodule has been confirmed, the determination of the kind of thyroid nodule is done by fine needle aspiration biopsy.

Colloid nodules are distinguished by an apparently gelatinous mass of colloid both surrounding and contained within follicular cells. Colloid nodules are not surrounded by a fibrous capsule of compressed tissue. However, they are surrounded by flattened epithelial cells. Both the number of cells and the type of colloid may vary considerably.

Microcystic adnexal carcinoma (also known as sclerosing sweat duct carcinoma) is a cutaneous condition characterized by a slow-growing plaque or nodule.

PSN are diagnosed by examining the tissue under a microscope, usually obtained with a dilation and curettage.

Typically, they consist of pink (hyaline) material using the standard stain and contain few cells. Bizarre multinucleated cells may be present; however, there is no mitotic activity. The differential diagnosis includes (cervical) squamous cell carcinoma and exaggerated placental site.

Granuloma annulare, microscopically, consists of dermal epithelioid histiocytes around a central zone of mucin - a so-called palisaded granuloma.

Cutaneous focal mucinosis is a skin condition characterized by a solitary nodule or papule.

Because granuloma annulare is usually asymptomatic and self-limiting with a course of about 2 years, initial treatment is generally topical steroid creams, followed by oral steroids and finally intradermal injections at the site of each ring. Treatment success varies widely, with most patients finding only brief success with the above-mentioned treatments. New research out of India suggests that the combination of rifampin (600 mg), ofloxacin (400 mg), and minocycline hydrochloride (100 mg) once monthly, or ROM therapy, produces promising results. Most lesions of granuloma annulare disappear in pre-pubertal patients with no treatment within two years while older patients (50+) have rings for upwards of 20 years. The appearance of new rings years later is not uncommon.

Solitary cutaneous leiomyoma typically presents as a deeply circumscribed, freely movable, rounded nodule ranging from 2 to 15mm in diameter, with overlying skin that may have a reddish or violaceous tint.

Aspiration pneumonia is typically caused by aspiration of bacteria from the oral cavity into the lungs, and does not result in the formation of granulomas. However, granulomas may form when food particles or other particulate substances like pill fragments are aspirated into the lungs. Patients typically aspirate food because they have esophageal, gastric or neurologic problems. Intake of drugs that depress neurologic function may also lead to aspiration. The resultant granulomas are typically found around the airways (bronchioles) and are often accompanied by foreign-body-type multinucleated giant cells, acute inflammation or organizing pneumonia. The finding of food particles in lung biopsies is diagnostic.

The formation of gummata is rare in developed countries, but common in areas that lack adequate medical treatment.

Syphilitic gummas are found in most but not all cases of tertiary syphilis, and can occur either singly or in groups. Gummatous lesions are usually associated with long-term syphilitic infection; however, such lesions can also be a symptom of benign late syphilis.

The clinical management of a cyst of Montgomery depends upon the symptoms of the patient.

If there are no signs of infection, a cyst of Montgomery can be observed, because more than 80% resolve spontaneously, over only a few months. However, in some cases, spontaneous resolution may take up two years. In such cases, a repeat ultrasonography may become necessary. If, however, the patient has signs of an infection, for example reddening (erythema), warmth, pain and tenderness, a treatment for mastitis can be initiated, which may include antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs). With treatment, inflammatory changes usually disappear quickly. In rare cases, drainage may become necessary. A surgical treatment of a cyst of Montgomery, i.e. a resection, may become necessary only if a cyst of Montgomery persists, or the diagnosis is questioned clinically.

The prognosis seems to be excellent. In one series, all adolescent patients with a cyst of Montgomery had a favourable outcome.

The granulomas of tuberculosis tend to contain necrosis ("caseating tubercules"), but non-necrotizing granulomas may also be present. Multinucleated giant cells with nuclei arranged like a horseshoe (Langhans giant cell) and foreign body giant cells are often present, but are not specific for tuberculosis. A definitive diagnosis of tuberculosis requires identification of the causative organism by microbiologic cultures.

Angiolymphoid hyperplasia with eosinophilia (also known as: "Epithelioid hemangioma," "Histiocytoid hemangioma," "Inflammatory angiomatous nodule," "Intravenous atypical vascular proliferation," "Papular angioplasia," "Inflammatory arteriovenous hemangioma," and "Pseudopyogenic granuloma") usually presents with pink to red-brown, dome-shaped, dermal papules or nodules of the head or neck, especially about the ears and on the scalp.

It, or a similar lesion, has been suggested as a feature of IgG4-related skin disease, which is the name used for skin manifestations of IgG4-related disease.

PSN are benign. Once removed, they do not require any treatment and do not recur.

Treatment usually involves surgical removal of the lesion down to the bone. If there are any adjacent teeth, they are cleaned thoroughly to remove any possible source of irritation. Recurrence is around 16%.

Spiradenoma, also spiroma or eccrine spiradenoma, is a cutaneous condition that is typically characterized, clinically, as a solitary, deep-seated dermal nodule of approximately one centimeter, occurring on the ventral surface of the body. Spiradenoma lesions are benign sudoriferous tumors, and have also been described as cystic epitheliomas of the sweat glands.

The histological origin is controversial.

Eccrine carcinoma (also known as a syringoid carcinoma) is a rare cutaneous condition characterized by a plaque or nodule on the scalp, trunk, or extremities.

Papillary eccrine adenoma (also known as "tubular apocrine adenoma") is a cutaneous condition characterized by an uncommon benign sweat gland neoplasm that presents as a dermal nodule located primarily on the extremities of black patients.

A cyst of Montgomery may be asymptomatic. Yet, a cyst of Montgomery usually is diagnosed when a female patient, 10–20 years of age, complains to a healthcare professional of breast pain (mastalgia), inflammation or a palpable nodule in the breast. The diagnosis is made clinically, when a palpable nodule is felt in the retroareolar area.

The diagnosis can be confirmed with ultrasonography, frequently showing a simple cyst in the retroareolar area. In some patients, multiple cysts or bilateral cysts may exist. Cysts of Montgomery may have liquid content with an echogenic or calcific sediment.

Fibroma of tendon sheath is a benign tumor that presents as a small subcutaneous nodule that slowly increases in size. The tumors often have a multinodular growth pattern, with individual nodules being composed of bland, slender, spindle-shaped cells (myofibroblasts) in a dense, fibrous matrix.” A common microscopic finding is the presence of elongated, slit-like blood vessels. The lesions nearly always arise in the distal portions of the extremities. They often occur on the fingers, hands, toes, or feet. Although they are benign, they may recur in up to 40% of cases.

Although they may be regarded as a tumor of the skin, the lesions arise from tendons and aponeuroses in superficial sites, and are therefore properly classified as in the category "soft tissue tumor."

The biological nature of Fibroma of tendon sheath is not known, but the category appears to comprise a number of different pathologic processes. It is considered that about one-third of the lesions in this category may be acral variants of the entity, nodular fasciitis.

A limbal nodule is any nodular lesion at the limbus (junction of the cornea and sclera) of the eye.

The differential diagnosis for a limbal nodule can include:

- Pinguecula

- Early Pterygium

- Foreign body / foreign body granuloma

- Phlycten, an inflamed nodule of lymphoid tissue

- Episcleritis

- Scleritis

- Granuloma

- Limbal dermoid, a kind of choristoma (NB: in other organs "dermoid" can refer to a teratoma)

- malignant melanoma