To diagnose this condition, scans or other imaging tests are used. Enlarged nodes in the vicinity of cancer areas could potentially contain cancer.

Probable patients are observed for few weeks until the cause of lymphadenopathy becomes obvious and they are instructed to return to the doctor if there is increase in node size. Biopsy should be performed in case tests suggest malignancy.

The differential diagnosis of Rosai–Dorfman disease includes both malignant and nonmalignant diseases, such as granulomatosis with polyangiitis, Langerhans cell histiocytosis, Langerhans cell sarcoma, lymphoma, sarcoidosis, and tuberculosis. The disease is diagnosed by biopsy of affected tissues. Microscopic examination of stained specimens will show histiocytes with lymphocytes and possibly other types of cells trapped within them, a phenomenon known as emperipolesis. Upon immunohistochemical staining, the histiocytes will be positive for S100, CD68, and CD163 but negative for CD1a.

Some patients have no symptoms, spontaneous remission, or a relapsing/remitting course, making it difficult to decide whether therapy is needed. In 2002, authors from Sapienza University of Rome stated on the basis of a comprehensive literature review that "clinical observation without treatment is advisable when possible."

Therapeutic options include surgery, radiation therapy, and chemotherapy. Surgery is used to remove single lymph nodes, central nervous system lesions, or localized cutaneous disease. In 2014, Dalia and colleagues wrote that for patients with extensive or systemic Rosai–Dorfman disease, "a standard of care has not been established" concerning radiotherapy and chemotherapy.

lymphadenopathy is a common biopsy finding, and may often be confused with malignant lymphoma. It may be separated into major morphologic patterns, each with its own differential diagnosis with certain types of lymphoma. Most cases of reactive follicular hyperplasia are easy to diagnose, but some cases may be confused with follicular lymphoma. There are seven distinct patterns of benign lymphadenopathy:

- Follicular hyperplasia: This is the most common type of reactive lymphadenopathy.

- Paracortical hyperplasia/Interfollicular hyperplasia: It is seen in viral infections, skin diseases, and nonspecific reactions.

- Sinus histiocytosis: It is seen in lymph nodes draining limbs, inflammatory lesions, and malignancies.

- Nodal extensive necrosis

- Nodal granulomatous inflammation

- Nodal extensive fibrosis (Connective tissue framework)

- Nodal deposition of interstitial substance

These morphological patterns are never pure. Thus, reactive follicular hyperplasia can have a component of paracortical hyperplasia. However, this distinction is important for the differential diagnosis of the cause.

The differential diagnosis of Kikuchi disease includes systemic lupus erythematosus (SLE), disseminated tuberculosis, lymphoma, sarcoidosis, and viral lymphadenitis. Clinical findings sometimes may include positive results for IgM/IgG/IgA antibodies.

For other causes of lymph node enlargement, see lymphadenopathy.

PTGC is treated by excisional biopsy and follow-up. It may occasionally recur and in a small proportion of patients has been reported to subsequently develop Hodgkin lymphoma (usually nodular lymphocyte predominant Hodgkin lymphoma).

Persistent generalized lymphadenopathy (PGL) is enlarged painful lymph nodes occurring in a couple of different areas for more than three to six months for which no other reason can be found. This condition occurs frequently in people in the latency period of HIV/AIDS.

The lymphatic system is part of the immune surveillance system. Blood contains fluid and blood cells. The fluid, which may contain suspended foreign material such as bacteria and viruses, seeps through blood vessel walls into the tissues, where it bathes the body cells and exchanges substances with them. Some of this lymph fluid is then taken up by lymphatic vessels and passed back to the heart, where it is again mixed with the blood. On its way, the fluid passes through the lymph nodes, small nodular organs located throughout the body but concentrated in certain areas such as the armpits or groin. These lymph nodes are also known as "glands" or "lymphoid tissue". If they detect something foreign passing through them, they enlarge. This is called "lymphadenopathy" or "swollen glands". Usually this is localized (for example, an infected spot on the scalp will cause lymph nodes in the neck on that same side to swell). However, when two or more lymph node groups are involved, it is called "generalized lymphadenopathy". Usually this is in response to a significant systemic disease and will subside once the person has recovered. Sometimes it can persist long-term, even when no explanation for the lymphadenopathy can be found.

PGL is often found in cases of autoimmune disease (where the body is attacking itself). These include diseases such as rheumatoid arthritis, lupus and sarcoidosis. Some forms of cancer will also cause PGL. Sometimes, despite exhaustive investigation, no cause for PGL is found. For the patient and the physician, this can continue to be a source of concern, but many adults have had PGL all their lives and suffered no ill effects. In others, the PGL may persist for a decade or more and then mysteriously subside. Children often have generalized lymphadenopathy of the head and neck, or even PGL, without the finding of a sinister cause. At puberty this usually disappears.

The immune system of some people may be sensitized by exposure to a living exogenous irritant such as a bacterial or viral infection, which then results in PGL after the organism has been cleared from the body. In some cases the sensitization is caused by non-living exogenous irritants such as cyclic hydrocarbons (for example, resinous vapours) or pesticides and herbicides.

It is diagnosed by lymph node excision biopsy.

Kikuchi disease is a self-limiting illness which has symptoms which may overlap with Hodgkin's lymphoma leading to misdiagnosis in some patients.

Antinuclear antibodies, antiphospholipid antibodies, anti-dsDNA, and rheumatoid factor are usually negative, and may help in differentiation from systemic lupus erythematosus.

Dermatopathic lymphadenopathy is diagnosed by a lymph node biopsy. It has a characteristic pattern of histomorphology and immunohistochemical staining:

- Paracortical histiocytosis

- Melanin-laden macrophages

- Eosinophils

- Plasma cells (medulla of lymph node)

Lymph nodes or 'glands' or "nodes" or "lymphoid tissue" are nodular bodies located throughout the body but clustering in certain areas such as the armpit, back of the neck and the groin. They are part of the lymphatic system.

The lymphatic system is part of the body's immune surveillance system. Blood contains fluid and blood cells. The fluid, which may contain suspended foreign material such as bacteria and viruses, seeps through blood vessel walls into the tissues, where it bathes the body cells and exchanges substances with them. Some of this fluid is then taken up by lymphatic vessels and passed back to the heart, where it is again mixed with the blood. On its way the fluid passes through the lymph nodes. If nodes detect something foreign passing through them such as a bacterium or a cancer cell they will swell up. This is called "lymphadenopathy" or "swollen glands". Usually this is localised (for example an infected spot on the scalp will cause lymph nodes in the neck on that same side to swell up), but when it is in two or more regions, it is called "generalized lymphadenopathy".

Usually this is in response to a body-wide infectious disease such as influenza and will go away once the person has recovered, but sometimes it can persist long-term, even when there is no obvious cause of disease. This is then called "persistent generalized lymphadenopathy" (PGL).

Lymph node enlargement is recognized as a common sign of infectious, autoimmune, or malignant disease. Examples may include:

- Reactive: acute infection ("e.g.," bacterial, or viral), or chronic infections (tuberculous lymphadenitis, cat-scratch disease).

- The most distinctive sign of bubonic plague is extreme swelling of one or more lymph nodes that bulge out of the skin as "buboes." The buboes often become necrotic and may even rupture.

- Infectious mononucleosis is an acute viral infection caused by Epstein-Barr virus and may be characterized by a marked enlargement of the cervical lymph nodes.

- It is also a sign of cutaneous anthrax and Human African trypanosomiasis

- Toxoplasmosis, a parasitic disease, gives a generalized lymphadenopathy ("Piringer-Kuchinka lymphadenopathy").

- Plasma cell variant of Castleman's disease - associated with HHV-8 infection and HIV infection

- Mesenteric lymphadenitis after viral systemic infection (particularly in the GALT in the appendix) can commonly present like appendicitis.

Less common infectious causes of lymphadenopathy may include bacterial infections such as cat scratch disease, tularemia, brucellosis, or prevotella.

- Tumoral:

- Primary: Hodgkin lymphoma and non-Hodgkin lymphoma give lymphadenopathy in all or a few lymph nodes.

- Secondary: metastasis, Virchow's Node, neuroblastoma, and chronic lymphocytic leukemia.

- Autoimmune: systemic lupus erythematosus and rheumatoid arthritis may have a generalized lymphadenopathy.

- Immunocompromised: AIDS. Generalized lymphadenopathy is an early sign of infection with human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). "Lymphadenopathy syndrome" has been used to describe the first symptomatic stage of HIV progression, preceding a diagnosis of AIDS.

- Bites from certain venomous snakes such as the pit viper

- Unknown: Kikuchi disease, progressive transformation of germinal centers, sarcoidosis, hyaline-vascular variant of Castleman's disease, Rosai-Dorfman disease, Kawasaki disease, Kimura disease

IPMs are diagnosed by examination of the tissue by a pathologist.

They have a rim of peripheral lymphoid tissue (remnant of a lymph node) and consist of spindle cells with nuclear palisading. Red blood cell extravasation is common and blood vessels surrounded by collagen with (fine) peripheral spokes (amianthoid fibers) are usually seen.

Immunostains for smooth muscle actin and cyclin D1 are characteristically positive. The main histologic differential diagnosis is schwannoma.

Axillary lymphadenopathy is lymphadenopathy of the axillary lymph nodes.

The diagnosis usually is made serologically (through complement fixation) and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers. Serologic testing has a sensitivity of 80% after 2 weeks. Serologic testing may not be specific for serotype (has some cross reactivity with other chlamydia species) and can suggest LGV from other forms because of their difference in dilution, 1:64 more likely to be LGV and lower than 1:16 is likely to be other chlamydia forms (emedicine).

For identification of serotypes, culture is often used. Culture is difficult. Requiring a special medium, cycloheximide-treated McCoy or HeLa cells, and yields are still only 30-50%. DFA, or direct fluorescent antibody test, PCR of likely infected areas and pus, are also sometimes used. DFA test for the L-type serovar of C trachomatis is the most sensitive and specific test, but is not readily available.

If polymerase chain reaction (PCR) tests on infected material are positive, subsequent restriction endonuclease pattern analysis of the amplified outer membrane protein A gene can be done to determine the genotype.

Recently a fast realtime PCR (TaqMan analysis) has been developed to diagnose LGV. With this method an accurate diagnosis is feasible within a day. It has been noted that one type of testing may not be thorough enough.

PTGCs is characterized by:

- follicular hyperplasia (many follicles),

- focally large germinal centres, with poorly demarcated germinal centre (GC)/mantle zone interfaces (as GCs infiltrated by mantle zone lymphocytes), and

- an expanded mantle zone.

The diagnosis is usually made by tissue biopsy, however this cannot reliably distinguish between the granulomas of OFG and those of Crohn's disease or sarcoidosis. Other causes of granulomatous inflammation are ruled out, such as sarcoidosis,

Crohn's disease, allergic or foreign body reactions and mycobacterial infections.

Löfgren syndrome is associated with a good prognosis, with > 90% of patients experiencing disease resolution within 2 years. In contrast, patients with the disfiguring skin condition lupus pernio or cardiac or neurologic involvement rarely experience disease remission.

Bilateral hilar lymphadenopathy is a bilateral enlargement of the lymph nodes of pulmonary hila. It is a radiographic term that describes the enlargement of mediastinal lymph nodes and is most commonly identified by a chest x-ray.

NSAIDs (non steroid anti-inflammatory drug) are the usual recommended treatment for Löfgren syndrome.

Inguinal lymphadenopathy causes swollen lymph nodes in the groin area. It can be a symptom of infective or neoplastic processes.

Infective aetiologies include Tuberculosis, HIV, non-specific or reactive lymphadenopathy to recent lower limb infection or groin infections. Another notable infectious cause is Lymphogranuloma venereum, which is a sexually transmitted infection of the lymphatic system. Neoplastic aetiologies include lymphoma, leukaemia and metastatic disease from primary tumours in the lower limb, external genitalia or perianal region and melanoma.

Mediastinal lymphadenopathy or mediastinal adenopathy is an enlargement of the Mediastinal lymph nodes

Prognosis is highly variable. Spontaneous remission is common. Complete cure can be obtained with proper antibiotic treatments to kill the causative bacteria, such as tetracycline, doxycycline, or erythromycin. Prognosis is more favorable with early treatment. Bacterial superinfections may complicate course. Death can occur from bowel obstruction or perforation, and follicular conjunctivitis due to autoinoculation of infectious discharge can occur.

Simple surgical excision is considered curative. Rare recurrences have been reported.

Diagnosis of sarcoidosis is a matter of exclusion, as there is no specific test for the condition. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve a chest radiograph, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with fine-needle aspiration of mediastinal lymph nodes (EBUS FNA). Tissue from biopsy of lymph nodes is subjected to both flow cytometry to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain) to rule out microorganisms and fungi.

Serum markers of sarcoidosis, include: serum amyloid A, soluble interleukin-2 receptor, lysozyme, angiotensin converting enzyme, and the glycoprotein KL-6. Angiotensin-converting enzyme blood levels are used in the monitoring of sarcoidosis. A bronchoalveolar lavage can show an elevated (of at least 3.5) CD4/CD8 T cell ratio, which is indicative (but not proof) of pulmonary sarcoidosis. In at least one study the induced sputum ratio of CD4/CD8 and level of TNF was correlated to those in the lavage fluid. A sarcoidosis-like lung disease called granulomatous–lymphocytic interstitial lung disease can be seen in patients with common variable immunodeficiency (CVID) and therefore serum antibody levels should be measured to exclude CVID.

Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodules, granulomatosis with polyangiitis, varicella infection, tuberculosis, and atypical infections, such as "Mycobacterium avium" complex, cytomegalovirus, and cryptococcus. Sarcoidosis is confused most commonly with neoplastic diseases, such as lymphoma, or with disorders characterized also by a mononuclear cell granulomatous inflammatory process, such as the mycobacterial and fungal disorders.

Chest radiograph changes are divided into four stages:

1. bihilar lymphadenopathy

2. bihilar lymphadenopathy and reticulonodular infiltrates

3. bilateral pulmonary infiltrates

4. fibrocystic sarcoidosis typically with upward hilar retraction, cystic and bullous changes

Although people with stage 1 radiographs tend to have the acute or subacute, reversible form of the disease, those with stages 2 and 3 often have the chronic, progressive disease; these patterns do not represent consecutive "stages" of sarcoidosis. Thus, except for epidemiologic purposes, this categorization is mostly of historic interest.

In sarcoidosis presenting in the Caucasian population, hilar adenopathy and erythema nodosum are the most common initial symptoms. In this population, a biopsy of the gastrocnemius muscle is a useful tool in correctly diagnosing the person. The presence of a noncaseating epithelioid granuloma in a gastrocnemius specimen is definitive evidence of sarcoidosis, as other tuberculoid and fungal diseases extremely rarely present histologically in this muscle.

Blockage of the main parotid duct, or one of its branches, is often a primary cause of acute parotitis, with further inflammation secondary to bacterial superinfection. The blockage may be from a salivary stone, a mucous plug, or, more rarely, by a tumor, usually benign. Salivary stones (also called sialolithiasis, or salivary duct calculus) are mainly made of calcium, but do not indicate any kind of calcium disorder. Stones may be diagnosed via X-ray (with a success rate of about 80%), a computed tomography (CT) scan or Medical ultrasonography. Stones may be removed by manipulation in the doctor's office, or, in the worst cases, by surgery. Lithotripsy, also known as "shock wave" treatment, is best known for its use breaking up kidney stones. Lithotripsy can now be used on salivary stones as well. Ultrasound waves break up the stones, and the fragments flush out of the salivary duct.