Clinical presentation and initial evaluation of non-Hodgkin lymphoma

INTRODUCTION — Non-Hodgkin lymphomas (NHL) comprise a diverse group of hematologic malignancies that are variously derived from B cell progenitors, T cell progenitors, mature B cells, mature T cells, or (rarely) natural killer cells. NHL is seen in patients of all ages, races, and socioeconomic status. Diagnosis and classification of NHL requires an adequate biopsy specimen and expert pathologic review because the clinical manifestations, prognosis, and management of lymphomas vary widely according to the type of lymphoma.

This topic will review the clinical presentation and initial evaluation of a patient with suspected NHL.

Classification of NHL and the general pretreatment evaluation, staging, and response assessment in lymphomas are discussed separately. (See "Classification of hematopoietic neoplasms" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

Treatment and prognosis of specific subtypes of NHL are discussed in those particular topics.

CLINICAL PRESENTATION

General — The clinical presentation of NHL varies with the histologic subtype and sites of involvement. Some subtypes of NHL manifest variable lymphadenopathy for years, while others are highly aggressive and can cause death within weeks, if untreated. Even within a specific NHL subtype, the clinical presentation varies widely between individual patients. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)

Following are examples of typical presentations of NHL:

●Aggressive or highly aggressive lymphomas commonly present subacutely or acutely with a rapidly growing mass; constitutional symptoms of fever, night sweats, or weight loss; and/or tumor lysis syndrome. Examples of aggressive or highly aggressive NHL include diffuse large B cell lymphoma, Burkitt lymphoma, precursor B and T lymphoblastic leukemia/lymphoma, adult T cell leukemia-lymphoma, and certain other peripheral T cell lymphomas.

●Indolent lymphomas are often insidious, presenting with slowly growing or waxing and waning lymphadenopathy over months or years, hepatomegaly, splenomegaly, and/or cytopenias. Examples of indolent NHL include follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and splenic marginal zone lymphoma.

A minority of patients initially present with extranodal lymphoma (primary extranodal NHL), but many more patients develop extranodal disease in the course of their disease (secondary extranodal NHL). Examples of extranodal manifestations of NHL include:

●Patients with primary gastrointestinal tract lymphoma may present with anorexia, early satiety, weight loss, vomiting, abdominal fullness, or with visceral obstruction, perforation, or hemorrhage (table 1). (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

●Patients with primary central nervous system lymphoma may present with headache, lethargy, focal neurologic symptoms, seizures, paralysis, spinal cord compression, or lymphomatous meningitis. (See "Approach to the patient with HIV and central nervous system lesions".)

●Patients with cutaneous lymphoma may present with rash that can progress slowly or wax and wane, or with cutaneous plaques, tumors, or ulcers. (See "Classification of primary cutaneous lymphomas".)

Some patients present with atypical findings, such as pruritus, exaggerated (hypersensitivity) reactions to insect stings or bites, generalized fatigue, malaise, fever of unknown origin, ascites, or effusions that may accompany nodal or extranodal NHL or, rarely, may be the sole manifestation of a lymphoma.

Oncologic emergencies — Life-threatening oncologic emergencies and complications may be recognized at the time of presentation of NHL or may develop during the course of the disease or its treatment. Especially for highly aggressive subtypes, such as Burkitt lymphoma, prompt recognition and management are critical, as these complications may be life-threatening or delay treatment of the underlying NHL.

Examples of oncologic complications of NHL and associated clinical manifestations include:

●Spinal cord compression (eg, back pain, weakness, altered sensation, paresthesias, incontinence). (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)

●Lymphomatous meningitis and/or central nervous system mass lesions (eg, headache, visual changes, altered sensorium, lethargy, seizures, cranial neuropathies). (See "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

●Airway obstruction (eg, dyspnea, cough, hemoptysis, wheeze, stridor, tachypnea). (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

●Pericardial tamponade (eg, chest pain, dyspnea, hypotension, peripheral edema, fatigue). (See "Pericardial disease associated with cancer: Clinical presentation and diagnosis".)

●Superior vena cava obstruction (eg, swelling of the face or neck, chest pain, dyspnea, stridor, cough). (See "Malignancy-related superior vena cava syndrome".)

●Gastrointestinal obstruction or liver failure (eg, vomiting, hematemesis, abdominal pain, obstipation, jaundice). (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

●Hydronephrosis or renal failure (eg, flank or groin pain, change in urine output, hematuria, hypertension). (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and "Uric acid kidney diseases" and "Overview of kidney disease in patients with cancer".)

●Tumor lysis syndrome (eg, nausea, vomiting, anorexia, lethargy, hematuria, heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany). (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

●Hypercalcemia (eg, polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, altered sensorium, constipation, fatigue, depression). (See "Treatment of hypercalcemia" and "Clinical manifestations of hypercalcemia".)

●Leukostasis or hyperleukocytosis (eg, visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, coma, dyspnea, hypoxia). (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

●Hyperviscosity syndrome (eg, blurring, diplopia, loss of vision, headache, vertigo, nystagmus, tinnitus, sudden deafness, ataxia, confusion, altered consciousness, stroke). (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)

●Venous thromboembolic disease (eg, deep vein thrombosis, thromboembolism). (See "Overview of the causes of venous thrombosis", section on 'Malignancy'.)

●Autoimmune hemolytic anemia (eg, dyspnea, fatigue, palpitations, jaundice, dark urine, splenomegaly). (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)

●Immune thrombocytopenia (eg, excessive bruising or bleeding). (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Cytopenias'.)

●Cold agglutinin disease (eg, acrocyanosis, Raynaud phenomenon). (See "Cold agglutinin disease".)

●Angioedema (eg, angioedema, with or without urticaria or pruritus). (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)

Abnormal laboratory results — Some patients with NHL present with abnormal laboratory results, such as:

●Hematologic – Anemia, thrombocytopenia, leukopenia, and/or lymphocytosis can have multiple causes, including bone marrow infiltration, hypersplenism from splenic involvement, or immune destruction. (See "Causes of anemia in patients with cancer" and "Anemia of chronic disease/anemia of inflammation" and "Warm autoimmune hemolytic anemia (AIHA) in adults".)

●Hypercalcemia – Hypercalcemia is uncommon at presentation but can occur with human T-lymphotropic virus type 1 (HTLV-1)-associated adult T cell leukemia-lymphoma and occasionally with transformed follicular lymphoma or diffuse large B cell lymphoma. Symptoms include dehydration, lethargy, weakness, nausea, vomiting, and constipation. (See "Hypercalcemia of malignancy: Mechanisms" and "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma", section on 'Hypercalcemia and lytic bone lesions' and "Treatment of relapsed or refractory follicular lymphoma", section on 'Rule out histologic transformation'.)

●Hyperuricemia – Hyperuricemia causing symptoms of gout or nephrolithiasis is unusual at presentation but may be present with tumor lysis syndrome in patients with Burkitt lymphoma and other aggressive or very aggressive NHL. (See "Asymptomatic hyperuricemia" and "Uric acid kidney diseases" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

●Elevated serum lactate dehydrogenase (LDH) – Elevated LDH may be due to high tumor burden, extensive infiltration of the liver, concurrent hemolytic anemia from immune-mediated red blood cell destruction, or rapidly growing forms of NHL, such as Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B cell lymphoma, or transformed follicular lymphoma.

●Abnormal serum protein electrophoresis (SPEP) – A monoclonal immunoglobulin (M-spike) may be detected by SPEP. Relatively large M-spikes (>0.5 g/dL) are most commonly associated with lymphoplasmacytic lymphoma, but other B cell NHLs, particularly small lymphocytic lymphoma/chronic lymphocytic leukemia and extranodal marginal zone lymphoma, may be associated with small M-spikes. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

Paraneoplastic syndromes — NHL may occasionally be associated with a wide variety of localized or systemic paraneoplastic syndromes. Examples of paraneoplastic syndromes include:

●Neurologic findings, such as encephalopathy, gait instability, visual changes, and motor or sensory dysfunction, in the absence of metabolic and nutritional deficits, infections, or coagulopathy. (See "Overview of paraneoplastic syndromes of the nervous system".)

●Sweet syndrome, pruritic or inflammatory seborrheic keratoses, ichthyosis, exfoliative erythroderma, or other cutaneous findings in the absence of direct tumor involvement. (See "Cutaneous manifestations of internal malignancy".)

●Polyarthritis, eosinophilic fasciitis, and other rheumatologic manifestations. (See "Malignancy and rheumatic disorders", section on 'Paraneoplastic rheumatic manifestations'.)

●Membranous nephropathy, minimal change disease, proteinuria, and other forms of renal dysfunction. (See "Overview of kidney disease in patients with cancer".)

HISTORY — The following aspects of the history are particularly important to evaluate:

Lymphadenopathy — Peripheral lymphadenopathy, which is generally firm and painless, is present in more than two-thirds of patients with NHL at presentation. The sites and extent of involvement, rate and pattern of growth, and duration of lymphadenopathy should be documented.

Lymphadenopathy is commonly associated with infections and other causes. The initial evaluation should attempt to exclude infectious and other etiologies, as discussed separately. (See "Evaluation of peripheral lymphadenopathy in adults".)

Systemic "B" symptoms — Unexplained fever, weight loss, or night sweats are referred to as constitutional or "B" symptoms. The duration and pattern of fevers and sweats and extent of weight loss should be documented. The formal definitions of B symptoms follow:

●Fever – Temperature >38°C (>100.4°F)

●Weight loss – Unexplained loss of >10 percent of body weight over the past six months

●Sweats – The presence of drenching night sweats

The presence of constitutional symptoms varies with the subtype of NHL (table 2) [1]. B symptoms are more common in patients with aggressive and highly aggressive subtypes of NHL, especially in those with hepatic and extranodal involvement. In contrast, only a small percentage of patients with indolent lymphomas have B symptoms; when present, they are usually associated with advanced stage disease and/or with bulky tumor masses.

Past medical history — Various diseases, infectious agents, drugs, and toxins have been associated with the development of NHL (table 3) [2-14].

●Personal or family history of lymphoma or other hematologic malignancy, prior radiation or chemotherapy treatment, immunosuppressive agents, organ transplantation, and other underlying diseases should be obtained [15-22]. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

●Infections should be evaluated, including HIV, human T-lymphotropic virus type I (HTLV-I), Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Borrelia burgdorferi (B. afzelii species), and Chlamydia psittaci [23-25]. (See "Overview of the pathobiology of the non-Hodgkin lymphomas" and "Extrahepatic manifestations of hepatitis C virus infection", section on 'Lymphoma' and "Clinical manifestations of Lyme disease in adults".)

●Exposure to agricultural pesticides and dioxin (eg, Agent Orange) may be associated with an increased risk of development of NHL [2].

●Rarely, chronic scarring or local inflammation caused by medical or cosmetic interventions contributes to development of lymphoma. Examples include the development of CD30+ anaplastic large cell lymphoma in scar tissue surrounding textured breast implants, and development of EBV-positive large B cell lymphomas in patients with chronic pyothorax secondary to "artificial" pneumothorax, used as a treatment for lung tuberculosis [26,27]. (See "Breast implant-associated anaplastic large cell lymphoma".)

Associated disorders — Disorders that may be associated with NHL include:

●Autoimmune diseases (eg, lupus erythematosus, rheumatoid arthritis, Sjögren's disease, Hashimoto's thyroiditis) [28-31]. (See "Malignancy and rheumatic disorders" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Hematologic manifestations'.)

●Immunodeficiency disorders, including immunosuppression due to treatment with immunomodulatory drugs. (See "Malignancy in inborn errors of immunity".)

●Mixed cryoglobulinemia. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Lymphoproliferative disorders'.)

●Multicentric Castleman disease. (See "HHV-8/KSHV-associated multicentric Castleman disease", section on 'Complications'.)

●Inflammatory gastrointestinal diseases (eg, gastrointestinal nodular lymphoid hyperplasia, Helicobacter pylori-associated chronic gastritis, and celiac disease). (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Predisposing conditions' and "Management of celiac disease in adults", section on 'Ulcerative jejunitis and intestinal lymphoma'.)

Fever of unknown origin — Fever of unknown origin (FUO) refers to a prolonged febrile illness without an established etiology, despite intensive evaluation and diagnostic testing. Historically, the most common causes of FUO were infection, connective tissue diseases, and malignancy, but the frequency of FUO attributable to malignancy has declined (figure 1), likely due to improved imaging techniques. (See "Fever of unknown origin in adults: Etiologies" and "Fever of unknown origin in adults: Evaluation and management".)

Aggressive or highly aggressive subtypes of NHL are a common cause of FUO due to malignancy. In the absence of an obvious site to biopsy (eg, an enlarged peripheral lymph node), bone marrow aspiration/biopsy may provide critical diagnostic information, as may the use of computed tomography (CT) or positron emission tomography (PET) scanning to detect sites of disease suitable for biopsy.

Intravascular large B cell lymphoma is extremely rare but may present with fever, rash, or prominent and rapidly progressive neurologic signs. Unlike other advanced stage lymphomas, intravascular large B cell lymphoma does not cause cytopenias (even with involvement of marrow sinusoids) or lymph node enlargement, and tumor cells do not appear in the peripheral blood. Biopsy of skin, or sometimes brain, liver, bone marrow, or lung, is required to make a diagnosis and reveals small vessels containing lymphoma cells. (See "Fever of unknown origin in adults: Evaluation and management" and "Intravascular large B cell lymphoma".)

PHYSICAL EXAMINATION

Lymphoid survey — The physical examination should evaluate all potentially involved lymphoid sites (figure 2), including:

●Waldeyer's ring (tonsils, base of the tongue, nasopharynx)

●Clinically accessible lymph node sites (eg, cervical, supraclavicular, axillary, inguinal, femoral, epitrochlear, popliteal)

●Liver and spleen

●Abdominal nodal sites (mesenteric, retroperitoneal)

●Less commonly involved nodal sites (eg, occipital, preauricular, epitrochlear, popliteal)

There are numerous causes of lymphadenopathy, besides NHL. Clinical evaluation of peripheral adenopathy and splenomegaly, and other conditions in the differential diagnosis are discussed separately. (See "Evaluation of peripheral lymphadenopathy in adults" and "Splenomegaly and other splenic disorders in adults".)

Head and neck — Enlargement of preauricular nodes or tonsillar asymmetry may suggest the presence of nodal or extranodal involvement of the head and neck, including Waldeyer's ring (tonsils, base of the tongue, nasopharynx) [32]. Involvement of the orbital structures (eg, eyelid, extraocular muscles, lacrimal apparatus, conjunctivae) is rare [33] but may be seen as a feature of marginal zone lymphoma, mantle cell lymphoma, or primary central nervous system (CNS) lymphoma. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Chest and lungs — The presence of lymphoma in the thoracic cavity may be suggested by superior vena cava syndrome, pleural or pericardial effusions, or associated clinical findings (eg, dyspnea, cough, hemoptysis, wheeze, stridor, tachypnea, hypotension, swelling of the face or neck, peripheral edema). Mediastinal involvement can be seen either as the sole site of disease (eg, primary mediastinal large B cell lymphoma) or as a manifestation of systemic disease. (See "Malignancy-related superior vena cava syndrome" and "Primary mediastinal large B cell lymphoma".)

Abdomen and pelvis — Involvement of retroperitoneal, mesenteric, and pelvic nodes is common in most histologic subtypes of NHL (image 1). Unless it is massive or leads to obstruction, nodal enlargement in these sites usually does not produce symptoms or findings on physical examination.

While diffuse hepatosplenomegaly (image 2) is common in the indolent lymphomas, synthetic liver function is usually intact. In contrast, discrete hepatic and splenic masses are more commonly seen in the aggressive or highly aggressive subtypes (image 3) [34,35].

However, not all focal liver lesions in patients with NHL are due to lymphoma. As an example, in one study of 414 consecutive patients with NHL, only 39 percent of the detected focal liver lesions at disease onset were due to NHL; 58 percent were non-malignant [36]. Conversely, 74 percent of the liver lesions detected during follow-up were due to NHL, while 15 percent were due to a malignancy other than NHL (eg, hepatocellular carcinoma, metastatic lesions from a second malignancy).

Ascites may be present and can be chylous in the setting of lymphatic obstruction if infiltration or compression of lymphatic vessels in the chest (thoracic duct) or abdomen (cisterna chyli or one of its mesenteric tributaries) has occurred. (See "Chylous, bloody, and pancreatic ascites".)

Extranodal sites — Less than one-third of patients have primary extranodal lymphoma at presentation. Symptoms due to extranodal disease are usually associated with aggressive NHL and are uncommon in the indolent lymphomas.

The most common site of primary extranodal disease is the gastrointestinal tract (image 4) followed by skin; other extranodal sites involved by aggressive NHLs include testis, bone, and CNS; rarely, kidney, prostate, bladder, ovary, orbit, heart, breast, salivary glands, thyroid, and adrenal glands may be involved [33,37-47].

●The skin should be carefully examined and all suspicious areas should be biopsied for the presence of lymphoma.

●Testicular NHL, presenting as a mass, constitutes 1 percent of all NHLs and 2 percent of all extranodal lymphomas; it is the most common malignancy involving the testis in men >60 years (image 5) [48]. (See "Anatomy and pathology of testicular tumors", section on 'Testicular lymphoma'.)

●NHL of bone is usually the manifestation of disseminated disease but can present as a solitary lesion, usually with pain, mass, swelling, or pathologic fracture (image 6).

●Epidural spinal cord compression (ESCC) is a medical emergency that can cause irreversible loss of motor, sensory, and/or autonomic function. NHL is thought to first involve the paraspinal soft tissues and to then invade the cord via the vertebral foramen without first causing bony destruction [49,50]. ESCC can occur as an initial manifestation of NHL or later in the course of disease. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)

●NHL can involve the CNS, either as the sole area of disease (primary CNS lymphoma) or as secondary spread of systemic disease. Primary CNS lymphoma constitutes only 1 percent of all NHLs. Direct lymphomatous involvement of peripheral nerves (neurolymphomatosis) is a rare event, often occurring in the presence of widespread systemic disease [51]. (See "Overview of the clinical features and diagnosis of brain tumors in adults" and "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

●Clinical evidence of renal involvement occurs in 2 to 14 percent of patients with NHL, usually of the aggressive or highly aggressive subtypes, but rarely presents with symptoms of renal failure at diagnosis (image 7). Ureteral obstruction due to retroperitoneal disease or tubular obstruction due to acute uric acid nephropathy are more likely causes of renal insufficiency at the time of diagnosis. (See "Overview of kidney disease in patients with cancer" and "Uric acid kidney diseases", section on 'Acute uric acid nephropathy'.)

IMAGING — Imaging can identify sites of lymph node or organ involvement by NHL and aid in the selection of a site and/or guide a diagnostic biopsy.

Ultrasound and computed tomography (CT) are commonly used as a guide for a diagnostic biopsy. Positron emission tomography (PET) alone, or combined with CT, can be useful for identifying suspicious lymph nodes with lymphomas that are fluorodeoxyglucose (FDG)-avid. For these purposes, essentially all types of nodal lymphoma are considered FDG-avid, except chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, mycosis fungoides, and marginal zone lymphoma; however, if transformation of an indolent lymphoma is suspected, PET/CT may be useful for identifying a preferred biopsy site.

The use of CT and PET/CT imaging for staging NHL is discussed separately. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Choice of imaging modality'.)

LYMPH NODE AND TISSUE BIOPSY — A biopsy is required for the diagnosis and classification of NHL. This should be obtained urgently if an aggressive NHL is suspected and, ideally, before treatment with steroids (which may obscure the diagnosis because they are lympholytic). Evaluation by a hematopathologist or a pathologist with expertise in lymphoma improves diagnostic accuracy and may affect clinical management [52].

Type of biopsy — Lymph nodes can be evaluated by excisional or incisional biopsy, core needle biopsy, or fine needle aspiration (FNA). It is preferable to obtain adequate biopsy material so that both the diagnosis and classification of a lymphoma can be established with a single procedure. Submission of fresh tissue (ie, unfixed tissue), with or without formalin-fixed tissue, is preferable when possible. The importance of adequate tissue samples for accurate diagnosis and expert pathologic review cannot be overemphasized [53-56].

In general, an excisional or incisional biopsy of a lymph node or multiple core needle biopsies are required to consistently provide adequate tissue for histologic, immunologic, and molecular biologic assessment. Some clinicians use FNA as an initial evaluation of lymphadenopathy. However, an FNA is neither adequate to exclude a diagnosis of lymphoma (eg, due to limited diagnostic material, sampling issues, loss of fragile cells during processing) nor does it enable definitive classification (because it disrupts the nodal architecture). If an FNA suggests the presence of a lymphoma, it should be followed up with a definitive tissue biopsy [53,57,58]. (See "Evaluation of peripheral lymphadenopathy in adults", section on 'Localized lymphadenopathy'.)

Although a biopsy fixed in formalin may be adequate to establish the diagnosis of a lymphoma, unfixed tissue is needed for flow cytometry and karyotyping, which are often helpful in arriving at a definitive and specific diagnosis.

Lymph node selection — When available, a lymph node is generally the preferred tissue for diagnosis of an NHL.

Selection of a lymph node to biopsy depends on the clinical situation and the location of involved nodes. A lymph node should be considered for biopsy if one or more of the following lymph node characteristics is present:

●Significant enlargement – In general, lymph nodes >2.25 cm² (ie, a node with biperpendicular diameters of 1.5 x 1.5 cm) or 2 cm in a single diameter have the best diagnostic yields, whereas lymph nodes <1 cm diameter are unlikely to provide a specific diagnosis [59,60].

●Persistence for >4 to 6 weeks.

●Progressive increase in size.

Enlarged peripheral lymph nodes are generally preferred because they are easily accessed, have a high diagnostic yield, and are associated with lower procedural risk, when compared with most other sites. If possible, we avoid biopsy of inguinal lymph nodes to avoid infectious complications and because they frequently reveal an inflammatory/reactive pattern that may obscure the diagnosis of lymphoma. When palpably enlarged peripheral lymph nodes are not present, ultrasound, computed tomography (CT), or laparoscopy can be used to obtain diagnostic material in a majority of cases [61,62].

Other tissues — Biopsy of a lymph node is usually the preferred diagnostic test for most patients with NHL. However, some subtypes of NHL do not present with overt lymphadenopathy, and they may require evaluation of another tissue for diagnosis. Pathologic evaluation of these tissues may also be necessary for the staging of patients with signs or symptoms worrisome for involvement of these sites or for patients with subtypes of NHL that have a high incidence of involvement of these tissues.

Bone marrow — Rarely, bone marrow is the only available site to make the diagnosis of NHL. Bone marrow aspirate and biopsy should be evaluated by histologic, immunophenotypic, cytogenetic, and molecular studies by an experienced hematopathologist, as described below. (See 'Analysis of biopsy material' below.)

Use of bone marrow examination for lymphoma staging is discussed separately. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Bone marrow examination'.)

Cerebrospinal fluid — Lumbar puncture with analysis of the cerebrospinal fluid (CSF) is indicated for patients suspected of having leptomeningeal metastases (lymphomatous meningitis) or primary central nervous system (CNS) lymphoma and for patients with subtypes of NHL that have a high incidence of CNS involvement (eg, Burkitt lymphoma).

If there is lymphomatous involvement, the CSF examination usually reveals an elevated protein concentration and a lymphocyte-predominant pleocytosis. Glucose concentration is usually normal but may be low. The presence of malignant lymphoid cells is usually confirmed by flow cytometry, but immunohistochemistry or cytology of cytospin preparations may also demonstrate lymphoma cells [63]. (See "Overview of the clinical features and diagnosis of brain tumors in adults" and "Secondary central nervous system lymphoma: Clinical features and diagnosis".)

Pleural/pericardial fluid — Pleural effusion and/or pericardial fluid should be evaluated for lymphoma involvement. The most common causes are secondary involvement of the body fluid by a systemic lymphoma (ie, secondary effusion), extranodal variants of various subtypes of lymphoma (eg, extranodal large cell lymphoma), and lymphomas that develop primarily within pleural effusions (ie, primary effusion lymphoma, pyothorax-associated lymphoma). (See "Primary effusion lymphoma", section on 'Differential diagnosis'.)

Common findings include an elevated protein concentration, a lymphocyte-predominant pleocytosis, and a normal or low glucose concentration. Reactive T cells may be more prominent than the neoplastic cells. The presence of malignant lymphoid cells can be confirmed by flow cytometry, immunohistochemistry, or cytology performed on cytospin preparations or cell blocks.

Peritoneal fluid — Peritoneal fluid sampling is indicated if ascites is present. Such involvement can develop in the context of a systemic nodal lymphoma or as a primary effusion lymphoma. (See "Primary effusion lymphoma".)

Common findings include an elevated protein concentration, a lymphocyte-predominant pleocytosis, and a normal or low glucose concentration. Reactive T cells may be more prominent than the neoplastic cells, and the presence of malignant lymphoid cells may be confirmed by flow cytometry, immunohistochemistry, cytology, or molecular analysis.

Spleen — In some centers, splenic biopsy can be used for diagnosis of a lymphoma [64]. The most common subtypes of lymphoma that are confined to the spleen include splenic marginal zone lymphoma, splenic red pulp lymphoma, and hepatosplenic T cell lymphoma. Pathologic findings in such cases vary depending upon the histologic subtype. (See "Splenic marginal zone lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)

ANALYSIS OF BIOPSY MATERIAL — The diagnosis of lymphoma is based on a comprehensive evaluation of histologic, immunophenotypic, cytogenetic, and molecular studies that are interpreted in the context of the clinical scenario. When possible, biopsy specimens should include both fresh tissue and formalin-fixed material and should be evaluated by an experienced hematopathologist [65].

Histology — The histologic evaluation of a lymphoma includes assessment of the morphology of the individual tumor cells and the pattern of lymph node involvement, which is best appreciated through examination of an intact lymph node.

The evaluation of biopsy material should determine if there is effacement or preservation of the normal lymph node architecture. Determining the aspects of a lymph node that are infiltrated by malignant cells (eg, follicular, perifollicular, interfollicular areas) are important for defining the subtype of NHL. Patterns of lymph node involvement may include:

●Nodular/follicular pattern (picture 1)

●Diffuse pattern (picture 2)

●Change from a nodular to a diffuse pattern in adjacent nodes (picture 3)

●Change from a lower to a higher grade of involvement within a single node (picture 4)

Immunophenotype — The immunophenotype of lymphoma cells can be determined by flow cytometry performed on fresh, unfixed single cell suspensions or by immunohistochemistry on tissue sections. Improvements in antigen retrieval have greatly enhanced immunohistochemical detection of markers in formalin-fixed, paraffin-embedded (FFPE) tissue, obviating the need for fresh frozen tissue for immunophenotyping by immunohistochemistry.

Immunophenotyping is crucial for the diagnosis and subclassification of most forms of NHL, which are generally divided according to whether they are of B, T, or natural killer (NK) cell derivation. Expression of cell surface lymphoid differentiation antigens is used to distinguish between B and T cells at various developmental stages (table 4). (See "Normal B and T lymphocyte development".)

Flow cytometry is complementary to immunohistochemistry, as it enables simultaneous detection of multiple markers (antigens), has a rapid turnaround time (hours), provides reproducible quantitation (ie, high versus lower levels of antigen expression), and more reliably detects certain markers (eg, surface immunoglobulin light chains) than immunohistochemistry. Flow cytometry is especially useful for diagnostic testing of fine needle aspiration (FNA) specimens.

Nearly all diagnostically relevant lymphoid markers can be effectively evaluated in FFPE tissue sections. Immunoglobulin light chains can be detected with substantially higher sensitivity in fresh frozen tissue sections but, in practice, assessment of clonality is usually evaluated by flow cytometry or molecular techniques. (See 'Molecular analysis' below.)

Cytogenetic studies — Cytogenetic studies are important adjuncts for the diagnosis of NHL, as certain chromosomal abnormalities are characteristic for particular types of lymphoma.

Cytogenetic abnormalities can be detected by conventional karyotype or by fluorescence in situ hybridization (FISH). The preferred technique depends on the clinical situation, available tissue, and suspected diagnosis. Fresh tissue is generally used to perform a conventional karyotype and evaluate chromosomal translocations, while fresh or fixed tissue can be used for FISH. Technical aspects of these techniques are discussed separately. (See "General aspects of cytogenetic analysis in hematologic malignancies" and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Detecting cytogenetic abnormalities'.)

Molecular analysis — Molecular analysis of a biopsy specimen may involve testing for mutations, gene rearrangements, gain or loss of certain genes, and/or epigenetic alterations. Various techniques may be used, including polymerase chain reaction (PCR), DNA sequencing, gene expression studies, and genomic analysis. Discussion of these techniques is presented separately. (See "Polymerase chain reaction (PCR)" and "Tools for genetics and genomics: Cytogenetics and molecular genetics".)f

Examples of use of molecular studies to aid the evaluation of lymphomas include:

●Immunoglobulin (Ig) gene rearrangement studies using PCR can determine clonality of B-lymphocytes, since every normal B-lymphocyte carries one or two rearranged Ig heavy chain genes (IgH) with a unique DNA sequence [66]. PCR with consensus IgH primers followed by sizing of products by capillary electrophoresis detects clonal rearrangements in about 85 percent of B cell lymphomas [67]. PCR testing is rapid, does not require radioactivity, and can be performed reliably on DNA retrieved from FFPE tissues; for these reasons, it has supplanted Southern blot analysis. (See "Immunoglobulin genetics".)

●Similarly, T cell receptor (TCR) gene rearrangement studies using PCR can determine if T-lymphocytes are clonal or nonclonal [66]. The TCR is composed of several subunits, including heterodimers composed of the alpha/beta and gamma/delta chains in association with the CD3 complex. PCR is conducted with consensus primers designed to amplify rearranged TCR gamma genes. When coupled to precise sizing of products by capillary electrophoresis, this test detects clonal rearrangements in about 90 percent of T cell lymphomas [67]. As with Ig rearrangements, PCR has replaced Southern blot analysis. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)

●Gene expression profiling (GEP) can be used to stratify diffuse large B cell lymphoma into different risk groups. While potentially helpful, to date, GEP has mainly been restricted to the clinical research arena because of the requirement for fresh tissue and technical complexity. Newer technologies can reliably generate GEPs using RNA retrieved from FFPE tissues [68], but they have yet to become a standard part of lymphoma characterization and classification. (See "Prognosis of diffuse large B cell lymphoma", section on 'Gene expression profiling'.)

●DNA sequencing is being evaluated for diagnosis and stratification of NHL but has not yet been validated for clinical practice. Many centers use DNA sequencing to identify somatic mutations that are characteristic of certain lymphomas (eg, MYD88 mutations in lymphoplasmacytic lymphoma), and routine use of DNA sequencing as part of the work-up of NHL is likely to continue to increase. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma", section on 'MYD88 mutations'.)

These and other studies can be important adjunct tests, particularly when samples are obtained by FNA, where limited diagnostic material is available for conventional histologic evaluation [69].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lymphoma (The Basics)")

SUMMARY

●Non-Hodgkin lymphomas (NHLs) – NHLs are malignancies of B-cell, T-cell, or T/NK (natural killer) cell lineages. NHLs range from indolent disorders to highly aggressive malignancies and they can involve lymph nodes, other lymphoid tissues, extranodal sites, and/or blood or bone marrow. NHLs differ from Hodgkin lymphomas based on pathophysiology, histology, natural history, and treatment.

●Clinical presentation – The clinical presentation varies with the type of NHL. Lymphadenopathy and/or hepatosplenomegaly are the most common presentations and some patients have constitutional symptoms (ie, fever, weight loss, night sweats). Less common presentations are symptoms related to extranodal disease, an oncologic emergency, paraneoplastic syndrome, or isolated laboratory abnormalities. (See 'Clinical presentation' above.)

●Emergencies – Tumor lysis syndrome, spinal cord compression, compression of a major airway, or involvement of the central nervous system (CNS) is seen with some NHLs and may require immediate management, even while the diagnosis of NHL is being established. (See 'Oncologic emergencies' above.)

●Initial evaluation

•Clinical – History and physical examination should assess lymphadenopathy (which is generally firm and painless) (figure 2), organomegaly, constitutional symptoms, extranodal involvement, and medical conditions that may affect management. (See 'History' above and 'Physical examination' above.)

•Laboratory – Initial laboratory studies should include:

-Hematology – Complete blood count (CBC) with differential count, coagulation studies

-Serum chemistries – Electrolytes, renal function tests, liver function tests, lactate dehydrogenase (LDH), and uric acid

●Diagnostic evaluation – For patients suspected to have an NHL based on clinical or laboratory findings, analysis of an involved lymph node or other involved tissue is required. Whenever possible, the biopsy specimen should be obtained before administration of a glucocorticoid, because steroids are lymphocytolytic and may interfere with analysis. (See 'Lymph node and tissue biopsy' above.)

•Preferred biopsy specimen – An excisional lymph node biopsy is preferred; if this is not possible, an incisional biopsy or multiple core biopsies are acceptable. Importantly, fine needle aspiration is generally not an acceptable substitute, because it provides only limited tissue and does not enable evaluation of the lymph node architecture, which is needed to classify the lymphoma. (See 'Lymph node and tissue biopsy' above.)

•Alternative tissue specimens – If no lymph node is accessible, biopsy of a site of extranodal involvement, liver, or bone marrow is acceptable. (See 'Other tissues' above.)

•Analysis – Diagnosis and classification of a lymphoma requires (see 'Analysis of biopsy material' above):

-Histology – Microscopic appearance of the malignant cells and the pattern of involvement of the lymph node (picture 1) or extranodal site (See 'Histology' above.)

-Immunophenotype – Immunophenotype of the malignant cells by flow cytometry or immunohistochemistry (See 'Immunophenotype' above.)

-Cytogenetics – Conventional karyotype or fluorescence in situ hybridization (FISH); the preferred technique depends on the clinical situation, available tissue, and suspected diagnosis (See 'Cytogenetic studies' above.)

-Molecular analysis – Analysis for mutations, gene rearrangements, and gain or loss of certain genes, by polymerase chain reaction (PCR), DNA sequencing, or other techniques (See 'Molecular analysis' above.)