These lymphomas are difficult to differentiate from gastric adenocarcinoma. The lesions are usually ulcers with a ragged, thickened mucosal pattern on contrast radiographs.

The diagnosis is typically made by biopsy at the time of endoscopy. Several endoscopic findings have been reported, including solitary ulcers, thickened gastric folds, mass lesions and nodules. As there may be infiltration of the submucosa, larger biopsy forceps, endoscopic ultrasound guided biopsy, endoscopic submucosal resection, or laparotomy may be required to obtain tissue.

Imaging investigations including CT scans or endoscopic ultrasound are useful to stage disease. Hematological parameters are usually checked to assist with staging and to exclude concomitant leukemia. An elevated LDH level may be suggestive of lymphoma.

The majority of gastric lymphomas are non-Hodgkin's lymphoma of B-cell origin. These tumors may range from well-differentiated, superficial involvements (MALT) to high-grade, large-cell lymphomas. Sometimes, it's hard to differentiate poorly differentiated high grade B-cell gastric lymphoma from gastric adenocarcinoma clinically or radiologically, yet histopathology with immunohistochemistry is recommended to stain specific markers on the malignant cell that favor the diagnosis of lymphoma. Immunohistochemistry stains specific clusters of differentiation that are present on B-cells like CD20. Cytokeratin is also a surface marker that is presented on epithelial cells, is stained histochemically and favors the diagnosis of epithelial tumors like adenocarcinoma.

Differentiating poor gastric lymphoma from adenocarcinoma is essential because the prognosis and modalities of treatment differ significantly.

Other lymphomas involving the stomach include mantle cell lymphoma and T-cell lymphomas which may be associated with enteropathy; the latter usually occur in the small bowel but have been reported in the stomach.

Prognoses and treatments are different for HL and between all the different forms of NHL, and also depend on the grade of tumour, referring to how quickly a cancer replicates. Paradoxically, high-grade lymphomas are more readily treated and have better prognoses: Burkitt lymphoma, for example, is a high-grade tumour known to double within days, and is highly responsive to treatment. Lymphomas may be curable if detected in early stages with modern treatment.

After a diagnosis and before treatment, a cancer is staged. This refers to determining if the cancer has spread, and if so, whether locally or to distant sites. Staging is reported as a grade between I (confined) and IV (spread). Staging is carried out because the stage of a cancer impacts its prognosis and treatment.

The Ann Arbor staging system is routinely used for staging of both HL and NHL. In this staging system, I represents a localized disease contained within a lymph node, II represents the presence of lymphoma in two or more lymph nodes, III represents spread of the lymphoma to both sides of the diaphragm, and IV indicates tissue outside a lymph node.

CT scan or PET scan imaging modalities are used to stage a cancer.

Age and poor performance status are established poor prognostic factors, as well.

Gastric MALT lymphoma is frequently associated (72–98%) with chronic inflammation as a result of the presence of "Helicobacter pylori", potentially involving chronic inflammation, or the action of "H. pylori" virulence factors such as CagA.

The initial diagnosis is made by biopsy of suspicious lesions on esophagogastroduodenoscopy (EGD, upper endoscopy). Simultaneous tests for "H. pylori" are also done to detect the presence of this microbe.

In other sites, chronic immune stimulation is also suspected in the pathogenesis (e.g. association between chronic autoimmune diseases such as Sjögren's syndrome and Hashimoto's thyroiditis, and MALT lymphoma of the salivary gland and the thyroid).

In order to diagnose MALT, a biopsy is needed from the affected tissue. If the abnormal tissue is suspected to be in the stomach or bowel, an endoscopy is done in order to get the biopsy. This requires either a gastroscopy or colonoscopy. If the lymphoma is thought to have spread to other areas in this region, an ultrasound scan is often done at the same time. If the abnormal tissue is thought to be in the lungs, a bronchoscopy is ordered.

In order to determine the correct type of lymphoma and stage it accurately, the physician will also need to do a physical exam, blood tests to determine blood cell counts, a CT scan, an MRI and/or a PET scan. A PET scan is the most important in planning a course of treatment.

A bone marrow biopsy may be ordered to test for lymph node involvement. If the lymphoma is in the stomach, the physician will test for H.pylori infection through a stool sample. This infection would be necessary to treat in conjunction to treating the cancer.

Due to the causal relationship between "H. pylori" infection and MALT lymphoma, identification of the infection is mandatory. Histological examination of GI biopsies yields a sensitivity of 95% with five biopsies, but these should be from sites uninvolved by lymphoma and the identification of the organism may be compromised by areas of extensive intestinal metaplasia. As proton-pump inhibition can suppress infection, any treatment with this class of drug should be ceased 2 weeks prior to biopsy retrieval. Serology should be performed if histology is negative, to detect suppressed or recently treated infections. Following the recognition of the association of gastric MALT lymphoma with "H. pylori" infection, it was established that early-stage gastric disease could be cured by "H. pylori" eradication, which is now the mainstay of therapy. Fifty to 95% of cases achieve complete response (CR) with "H. pylori" treatment.

A t(11;18)(q21;q21) chromosomal translocation, giving rise to an "API2-MLT" fusion gene, is predictive of poor response to eradication therapy.

Splenic MZL is difficult to diagnose and can look similar to other types of lymphoma. Tests include a physical examination, blood tests to determine overall health and detect infections (ex. hepatitis C), a bone marrow biopsy, CT scan, and a PET scan. Sometimes a splenectomy is necessary during the diagnosis process in order to determine the exact type of lymphoma. If the spleen is removed, you will be at a larger risk of infection.

Diagnosis usually occurs at an early stage of disease progression.

Treatment with dose-adjusted EPOCH with rituximab has shown promising initial results in a small series of patients (n=17), with a 100% response rate, and 100% overall survival and progression-free survival at 28 months (median follow-up).

Biopsy of affected lymph nodes or organs confirms the diagnosis, although a needle aspiration of an affected lymph node can increase suspicion of the disease. X-rays, ultrasound and bone marrow biopsy reveal other locations of the cancer. There are now a range of blood tests that can be utilised to aid in the diagnosis of lymphoma. Flow cytometry detects antibodies linked to tumour cell surface antigens in fluid samples or cell suspensions. Polymerase chain reaction (PCR) for antigen receptor rearrangements (PARR) identifies circulating tumour cells based on unique genetic sequences. The canine Lymphoma Blood Test (cLBT) measures multiple circulating biomarkers and utilises a complex algorithm to diagnose lymphoma. This test utilises the acute phase proteins (C-Reactive Protein and Haptoglobin). In combination with basic clinical symptoms, it gives in differential diagnosis the sensitivity 83.5% and specificity 77%. The TK canine cancer panel is an indicator of general neoplastic disease. The stage of the disease is important to treatment and prognosis. Certain blood tests have also been shown to be prognostic.

The stage of the disease is important to treatment and prognosis.

- Stage I - only one lymph node or lymphoid tissue in one organ involved.

- Stage II - lymph nodes in only one area of the body involved.

- Stage III - generalized lymph node involvement.

- Stage IV - any of the above with liver or spleen involvement.

- Stage V - any of the above with blood or bone marrow involvement.

Each stage is divided into either "substage a", those without systemic symptoms; or "substage b", those with systemic symptoms such as fever, loss of appetite, weight loss, and fatigue.

Tumors generally located in the peripheral lymph nodes which can be detected via PET scan and CT scan.

Hodgkin's lymphoma must be distinguished from non-cancerous causes of lymph node swelling (such as various infections) and from other types of cancer. Definitive diagnosis is by lymph node biopsy (usually excisional biopsy with microscopic examination). Blood tests are also performed to assess function of major organs and to assess safety for chemotherapy. Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. PET scans are also useful in functional imaging (by using a radiolabeled glucose to image tissues of high metabolism). In some cases a Gallium scan may be used instead of a PET scan.

Treatment of Hodgkin's disease has been improving over the past few decades. Recent trials that have made use of new types of chemotherapy have indicated higher survival rates than have previously been seen. In one recent European trial, the 5-year survival rate for those patients with a favorable prognosis (FFP) was 98%, while that for patients with worse outlooks was at least 85%.

In 1998, an international effort identified seven prognostic factors that accurately predict the success rate of conventional treatment in patients with locally extensive or advanced stage Hodgkin's lymphoma. Freedom from progression (FFP) at 5 years was directly related to the number of factors present in a patient. The 5-year FFP for patients with zero factors is 84%. Each additional factor lowers the 5-year FFP rate by 7%, such that the 5-year FFP for a patient with 5 or more factors is 42%.

The adverse prognostic factors identified in the international study are:

- Age ≥ 45 years

- Stage IV disease

- Hemoglobin < 10.5 g/dl

- Lymphocyte count < 600/µl or < 8%

- Male

- Albumin < 4.0 g/dl

- White blood count ≥ 15,000/µl

Other studies have reported the following to be the most important adverse prognostic factors: mixed-cellularity or lymphocyte-depleted histologies, male sex, large number of involved nodal sites, advanced stage, age of 40 years or more, the presence of B symptoms, high erythrocyte sedimentation rate, and bulky disease (widening of the mediastinum by more than one third, or the presence of a nodal mass measuring more than 10 cm in any dimension.)

More recently, use of positron emission tomography (PET) early after commencing chemotherapy has demonstrated to have powerful prognostic ability. This enables assessment of an individual's response to chemotherapy as the PET activity switches off rapidly in patients who are responding. In this study, after two cycles of ABVD chemotherapy, 83% of patients were free of disease at 3 years if they had a negative PET versus only 28% in those with positive PET scans. This prognostic power exceeds conventional factors discussed above. Several trials are underway to see if PET-based risk adapted response can be used to improve patient outcomes by changing chemotherapy early in patients who are not responding.

The most typical symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes.

The factors of poor prognosis for patients with thyroid lymphoma are advanced stage of the tumor, large size (>10 cm) as well as spreading to mediastinum. The overall survival for primary thyroid lymphoma is 50% to 70%, ranging from 80% in stage IE to less than 36% in stage IIE and IVE in 5 years.

Of all cancers involving the same class of blood cell (lymphoproliferative disorders), 22% of cases are follicular lymphomas.

Median survival is around 10 years, but the range is wide, from less than one year, to more than 20 years. Some patients may never need treatment. The overall survival rate at five years is 72–77%. Recent advances and addition of Rituximab, improved median survival. Recent reports for the period 1986 and 2012 estimates median survival of over 20 years.

Normal B cells of a germinal center possess rearranged immunoglobulin heavy and light chain genes, and each isolated B cell possesses a unique IgH gene rearrangement. Since Burkitt lymphoma and other B-cell lymphomas are a clonal proliferative process, all tumor cells from one patient are supposed to possess identical IgH genes. When the DNA of tumor cells is analyzed using electrophoresis, a clonal band can be demonstrated, since identical IgH genes will move to the same position. On the contrary, when a normal or reactive lymph node is analyzed using the same technique, a smear rather than a distinct band will be seen. This technique is useful since sometimes benign reactive processes (e.g. infectious mononucleosis) and malignant lymphoma can be difficult to distinguish.

The most common chemotherapy used for non-Hodgkin lymphoma is R-CHOP.

With the apparent success of gene expression profiling in separating biologically distinct cases of DLBCL, NOS, some researchers examined whether a similar distinction could be made using immunohistochemical staining (IHC), a widely used method for characterizing tissue samples. This technique uses highly specific antibody-based stains to detect proteins on a microscope slide, and since microarrays are not widely available for routine clinical use, IHC is a desirable alternative. Many of these studies focused on stains against the products of prognostically significant genes which had been implicated in DLBCL gene expression studies. Examples of such genes include BCL2, BCL6, MUM1, LMO2, MYC, and p21. Several algorithms for separating DLBCL cases by IHC arose out of this research, categorizing tissue samples into groups most commonly known as GCB and non-GCB. The correlation between these GCB/non-GCB immunohistochemical groupings and the GCB/ABC groupings used in gene expression profiling studies is uncertain, as is their prognostic value. This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.

Chemotherapy with CHOP, infusional EPOCH, hyperCVAD, and CODOX-M/IVAC is often used. The prognosis is generally poor, for example 6 to 7 months and 14 months.

Nevertheless, the Working Formulation and the NHL category continue to be used by many. To this day, lymphoma statistics are compiled as Hodgkin's versus non-Hodgkin lymphomas by major cancer agencies, including the US National Cancer Institute in its SEER program, the Canadian Cancer Society and the IARC.

Treatment with conventional immunochemotherapy is usually indicated; in younger patients, allogeneic bone marrow transplantation may be curative.

Thyroid lymphoma shows a diagnostic and therapeutic challenge in many cases, because some manifestation patterns are similar to anaplastic thyroid cancer (ATC). Performance of fine-needle aspiration (FNA) has helped to distinguish these between two entities preoperatively.