approach to the patient with lymphadenopathy and splenomegaly

APPROACH TO THE PATIENT

WITH LYMPHADENOPATHY AND

SPLENOMEGALY

NHLNHL اهداف اهداف

اختصاصي :اختصاصي :

كلي- 11 كلي- مشخصات مشخصات

22 - -DDDD

برخورد- برخورد- 33

و- 44 و- تعريف تعريفاتيولوژي اتيولوژي

بندي- 55 بندي- طبقه طبقه

66--STAGINGSTAGING

تظاهرات- تظاهرات- 77

پيشآگهي- پيشآگهي- 88

درمان- درمان- 99

HDHD

تعريف- تعريف- 11

اپيدميولوژي- اپيدميولوژي- 22

پاتولوژي- پاتولوژي- 33

تشخيص- تشخيص- 44

تظاهر-تظاهر-55

پيشآگهي- پيشآگهي- 66

درمان- درمان- 77

APPROACH TO THE PATIENT WITH LYMPHADENOPATHY AND SPLENOMEGALY

PHYSIOLOGY AND ANATOMYLymph nodes are populated predominantly by

macrophages, dendritic cells, B lymphocytes, and T lymphocytes.

B lymphocytes are located primarily in the follicles and perifollicular areas,

T lymphocytes are found primarily in the interfollicular or paracortical areas of the lymph node.


PHYSIOLOGY AND ANATOMYIn young childrenpalpable lymphadenopathy is the rule.

who are continuously undergoing exposure to new antigens,

In fact, the absence of palpable lymphadenopathy would be considered abnormal

In adults, lymph nodes larger than 1 to 2 cm in diameter are generally considered abnormal.

However, lymph nodes 1 to 2 cm in diameter in the groin are sufficiently frequent to often be considered "normal.“


Generalized immune proliferation and lymphadenopathy can occur with a

systemic disorder of the immune system,

disseminated infection, or

disseminated neoplasia.

Malignancies of the immune system might be manifested as:

localized or

disseminated lymphadenopathy.


more than two-thirds of patients with LAP have :

nonspecific causes or upper respiratory illnesses (viral or bacterial),

fewer than 1% have a malignancy

in another study :16% had a malignancy

(lymphoma or metastatic adenocarcinoma)

Thus, the vast majority of patients with lymphadenopathy will have a nonspecific etiology requiring few diagnostic tests.


Differential diagnosis of lymphadenopathy

TABLE 178–1. CAUSES OF LYMPHADENOPATHY

Infection

Bacterial (e.g., all pyogenic bacteria, cat-scratch disease, syphilis,

tularemia)

Mycobacterial (e.g., tuberculosis, leprosy)

Fungal (e.g., histoplasmosis, coccidioidomycosis)

Chlamydial (e.g., lymphogranuloma venereum)

Parasitic (e.g., toxoplasmosis, trypanosomiasis, filariasis)

Viral (e.g., Epstein-Barr virus, cytomegalovirus, rubella, hepatitis, HIV)

Benign disorders of the immune system (e.g., rheumatoid arthritis, systemic


TABLE 178–1. CAUSES OF LYMPHADENOPATHY

lupus erythematosus, serum sickness,

drug reactions such as to phenytoin,Castleman's disease, sinus histiocytosis with massive lymphadenopathy, Langerhans'cell histiocytosis,Kawasaki syndrome, Kimura's disease)Malignant disorders of the immune system (e.g., chronic and acute myeloid andlymphoid leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, angioimmunoblastic-likeT-cell lymphoma, Waldenström's macroglobulinemia, multiple myeloma with amyloidosis, malignant histiocytosis)Other malignancies (e.g., breast carcinoma, lung carcinoma, melanoma, head andneck cancer, gastrointestinal malignancies, germ cell tumors, Kaposi's sarcoma)Storage diseases (e.g., Gaucher's disease, Niemann-Pick disease)Endocrinopathies (e.g., hyperthyroidism, adrenal insufficiency, thyroiditis)Miscellaneous (e.g., sarcoidosis, amyloidosis, dermatopathic lymphadenitis)


TABLE 178–2. MOST FREQUENT CAUSES OF LYMPHADENOPATHY IN ADULTS IN AMERICA

Unexplained

Infection

In drainage area of infection (e.g., cervical adenopathy with pharyngitis)

Disseminated (e.g., mononucleosis, HIV infection)

Immune disorders (e.g., rheumatoid arthritis)

Neoplasms

Immune system malignancies (e.g., leukemia and lymphomas)

Metastatic carcinoma or sarcoma


FACTORS TO CONSIDER IN THE DIAGNOSIS OF LYMPHADENOPATHY

Associated systemic symptoms

Patient age

History of infection, trauma, medications, travel experience, previousmalignancy, etc.

Location: cervical, supraclavicular, epitrochlear, axillary, intrathoracic(hilar versus mediastinal), intra-abdominal (retroperitoneal versus mesentericversus other), iliac, inguinal, femoral

Localized versus disseminated

Tenderness/inflammationSizeConsistency


LYMPH NODE EVALUATION.a careful history a thorough physical examination laboratory tests imaging studies to determine the extent and character of the lymphadenopathy age of the patientThe occurrence of fever, sweats, or weight lossof a site of infection, a particular medication, a travel history, or a previous malignancy.


physical examination

localized or generalized

size of nodes

Texture

presence or absence of nodal tenderness

signs of inflammation over the node

skin lesions

splenomegaly.


Generalized adenopathy has been defined as

involvement of three or more noncontiguous lymph node areas.

generalized lymphadenopathy is frequently associated with nonmalignant disorders


physical examination

(localized or generalized), size of nodes, texture, presence or absence of nodal tenderness, signs of inflammation over the node, skin lesions, and splenomegaly.

Generalized adenopathy has been defined as involvement of three or more noncontiguous lymph node areas.

generalized lymphadenopathy is frequently associated with nonmalignant disorders

The site of localized or regional adenopathy

Nodes <1.0 cm2 in area (1.0 ´ 1.0 cm or less) are almost always secondary to benign, nonspecific reactive causes.

Patients with node(s) <1.0 cm2 should be observed after excluding infectious mononucleosis and/or toxoplasmosis unless there are symptoms and signs of an underlying systemic illness.


METHODS OF LYMPH NODE EVALUATION

Physical examination

Imaging

Chest radiography

Lymphangiography

Ultrasonography

Computed tomography

Magnetic resonance imaging

Gallium scanning

Positron emission tomography

Sampling

Needle aspiration

Cutting needle biopsy

Excisional biopsy


lymph nodes that are tendertender are more likely to be due to an infectious process,

whereas painlesspainless adenopathy raises the concern of malignancy.

Lymph node consistencyconsistency

lymph nodes containing metastatic carcinoma are rock hard,

lymph nodes containing lymphoma are firm and rubbery,

lymph nodes enlarged in response to an infectious process are soft.

The largerlarger the lymph node, the more likely a serious underlying cause exists, and lymph nodes greater than 3 to 4 cm in diameter in an adult are very concerning


Chest radiographsChest radiographs provide the most economical and easiest method to assess mediastinal and hilar lymphadenopathy but are not as accurate as CT of the chest.

lymphangiographylymphangiography provides an extremely accurate assessment of the lower abdominal lymph nodes and, because of retained contrast material, allows repeat examinations and assessment of the response to therapy.

CT and ultrasoundCT and ultrasound provide the most useful ways to assess abdominal and retroperitoneal lymphadenopathy

ultrasound has the advantage of being less expensive and not requiring radiation exposure.

MRI and gallium scanningMRI and gallium scanning are not first-line studies for the assessment of lymphadenopathy


Gallium scansGallium scans

presence of active lymphoma in patients with lymphadenopathy and a proven diagnosis

Fine-needle aspirationFine-needle aspiration

currently popular and is often an accurate way to diagnose infection or carcinoma

it is inappropriate as an initial diagnostic maneuver for lymphoma.

Cutting needle biopsiesCutting needle biopsies

will occasionally provide sufficient material for an unequivocal diagnosis and subtyping of the lymphom

excisional biopsyexcisional biopsy,

which is most likely to provide the pathologist with adequate material to perform histologic, immunologic, and genetic studies, is the most appropriate approach.


AN APPROACH TO THE PATIENT WITH LYMPHADENOPATHY

1. Does the patient have a known illness that causes lymphadenopathy?Treat and monitor for resolution.

2. Is there an obvious infection to explain the lymphadenopathy (e.g., infectious mononucleosis)?Treat and monitor for resolution.

3. Are the nodes very large and/or very firm and thus suggestive of malignancy?Perform a biopsy.

4. Is the patient very concerned about malignancy and unable to be reassured thatmalignancy is unlikely? Perform a biopsy.

5. If none of the preceding are true, perform a complete blood count and if it isunrevealing, monitor for a pre-determined period (usually 2 to 6 weeks).If the nodes do not regress or if they increase in size, perform a biopsy.



come to medical attention in several ways

felt a lymph node in the neck, axilla, or groin

an unexpected finding on routine physical examination or as part of the evaluation of another complaint.

Finally, patients might be found to have unexpected lymphadenopathy on imaging studies of the chest or abdomen.

The approach to a patient complaining of newly discovered lymphadenopathy in the neck, axilla, or groin will depend on the size, consistency, and number of enlarged lymph nodes and the patient's general health

a biopsy might be done more quickly in a patient who is very anxious about malignancy or who needs a definitive diagnosis expeditiously.



Biopsy might be done more quickly in a patient who is very anxious about malignancy or who needs a definitive diagnosis expeditiously.


Hodgkin's diseaseHodgkin's disease

The cell of origin of

suggests that most are of B cell origin.

Hodgkin's disease is more common in whites than in blacks

more common in males than in females

A bimodal distribution of age at diagnosis has been observed,

with one peak incidence occurring in patients in their 20s

and the other in those in their 80s

younger age groups diagnosed in the United States largely have the nodular sclerosing subtype

Elderly patients, patients infected with HIV, and patients in third world countries more commonly have mixed-cellularity Hodgkin's disease or lymphocyte-depleted Hodgkin's disease

Infection by HIV is a risk factor for developing Hodgkin's disease. In addition, an association between infection by EBV and Hodgkin's disease has been demonstrated

GENERAL ASPECTS OF LYMPHOID MALIGNANCIES

ETIOLOGY AND EPIDEMIOLOGY

non-Hodgkin's lymphomas

have increased in frequency in the United States at the rate of 4% per year since 1950.

more frequent in the elderly and more frequent in men

Patients with both primary and secondary immunodeficiency states are predisposed to developing non-Hodgkin's lymphomas.

HIV infection;

patients who have undergone organ transplantation

patients with inherited immune deficiencies,

the sicca syndrome

rheumatoid arthritis




various subtypes differ geographically

T cell lymphomas are more common in Asia

follicular lymphoma are more common in western countries.

angiocentric nasal T/natural killer (NK) cell lymphoma has a striking geographic occurrence, being most frequent in Southern Asia and parts of Latin America.

human T cell lymphotropic virus (HTLV) I is seen particularly in southern Japan and the Caribbean.




environmental factors

infectious agents,

chemical exposures

medical treatments

Patients treated for Hodgkin's disease can develop non-Hodgkin's lymphoma

agricultural chemicals




HTLV-I infects T cells

directly to the development of adult T cell lymphoma (ATL) in a small percentage of infected patients.

cumulative lifetime risk of developing lymphoma in an infected patient is 2.5%.

transmitted by infected lymphocytes ingested by nursing babies of infected mothers, blood-borne transmission, or sexually

The median age of patients with ATL is about 56 years, emphasizing the long latency.




EBV

Burkitt's lymphoma in Central Africa and the occurrence of aggressive non-Hodgkin's lymphomas in immunosuppressed patients in western countries

EBV infection is strongly associated with the occurrence of extranodal nasal T/NK cell lymphomas in Asia and South America.




HIV

predisposes to the development of aggressive, B cell non-Hodgkin's lymphoma

overexpression of interleukin 6 by infected macrophages

Helicobacter pylori

Infection of the stomach by the bacterium

induces the development of gastric MALT (mucosa-associated lymphoid tissue) lymphomas.

The bacterium does not transform lymphocytes to produce the lymphoma; instead, a vigorous immune response is made to the bacterium and the chronic antigenic stimulation leads to the neoplasia.




Chronic hepatitis C virus

lymphoplasmacytic lymphoma

Human herpesvirus 8 is associated with primary effusion lymphoma

in HIV-infected persons and multicentric Castleman's disease, a diffuse lymphadenopathy associated with systemic symptoms of fever, malaise, and weight loss.



TABLE 179–2. COMPARISON OF THE WORKING FORMULATION AND THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF LYMPHOID NEOPLASMS

WORKING FORMULATIONWHO CLASSIFICATION

B-Cell Neoplasms T-Cell Neoplasms

Low Grade

A. Small lymphocytic consistent with CLL B-cell CLL/SLL

B. Follicular, predominantly small cleaved cell Follicular lymphoma, grade I

C. Follicular, mixed small cleaved and large cell Follicular lymphoma, grade II

Intermediate Grade

D. Follicular, large cell Follicular lymphoma, grade III

E. Diffuse, small cleaved cell Mantle cell lymphoma

F. Diffuse, mixed small and large cell Large B-cell lymphoma (rich in T cells) Peripheral T cell, unspecified

G. Diffuse, large cell Diffuse large B-cell lymphoma Peripheral T cell, unspecified

High Grade

H. Large cell immunoblastic Diffuse large B-cell lymphoma Peripheral T cell, unspecified

I. Lymphoblastic Precursor B lymphoblastic Precursor T lymphoblastic

J. Small non-cleaved cell Burkitt's Non-Burkitt's

Burkitt's lymphoma

CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma.

TABLE 179–1. WORLD HEALTH ORGANIZATION CLASSIFICATION OF NEOPLASTIC DISEASES OF THE HEMATOPOIETIC AND LYMPHOID TISSUES: LYMPHOID NEOPLASMS

B-Cell NeoplasmsPrecursor B-cell lymphoblastic leukemia/lymphoma*Mature B-cell neoplasmsB-cell chronic lymphocytic leukemia/small lymphocytic lymphomaB-cell prolymphocytic leukemiaLymphoplasmacytic lymphomaSplenic marginal zone B-cell lymphomaHairy cell leukemiaExtranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue typeMantle cell lymphomaFollicular lymphomaNodal marginal zone lymphoma with or without monocytoid B cellsDiffuse large B-cell lymphomaBurkitt's lymphomaPlasmacytomaPlasma cell myelomaT-Cell NeoplasmsPrecursor T-cell lymphoblastic lymphoma/leukemiaMature T-cell and NK cell neoplasmsT-cell prolymphocytic leukemiaT-cell large granular lymphocytic leukemiaNK cell leukemiaExtranodal NK/T-cell lymphoma, nasal and nasal typeMycosis fungoides/Sézary syndromePrimary cutaneous anaplastic large cell lymphomaSubcutaneous panniculitis-like T-cell lymphomaEnteropathy-type intestinal T-cell lymphomaHepatosplenic / T-cell lymphomaAngioimmunoblastic T-cell lymphomaPeripheral T-cell lymphoma (unspecified)Anaplastic large cell lymphoma, primary systemic typeAdult T-cell lymphoma/leukemia (HTLVI+)

NK = natural killer; HTLV = human T-cell leukemia virus.

*The most common B- and T-cell malignancies are in bold.

Modified from Jaffe E, Bernard C, Harris N, et al: Proposed World Health Organization classification of neoplastic diseases of hematopoietic and lymphoid tissues. Am J Surg Pathol 21:114, 1997.

TABLE 179–4. ANN ARBOR STAGING SYSTEM

Stage I Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE)

Stage II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site (IIE)

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic organ or site (IIIE), the spleen (IIIS), or both (IIISE)

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement

Identification of the presence or absence of symptoms should be noted with each stage designation. A = asymptomatic; B = fever, sweats, or weight loss greater than 10% of body weight.

HODGKIN'S DISEASE

Nodular Lymphocyte-Predominant Hodgkin's Disease

CLASSIC HD

LP

NST

MCT

LD

APPROACH TO THE PATIENT SPLENOMEGALY

the largest lymphatic organ

function

the primary immune response

filter for the blood

removing from the circulation senescent red cells,

Removing blood cells and other cells coated with immunoglobulins

Red pulp

occupies more than half the volume of the spleen

is the site where senescent red cells are identified and destroyed and red cell inclusions are removed by a process known as pitting

In the absence of splenic function, inclusions known as Howell-Jolly bodies are seen in circulating red blood cells White pulp

of the spleen contains macrophages, B lymphocytes, and T lymphocytes, participates in the recognition of microorganisms and foreign proteins, and is involved in the primary immune response

PHYSIOLOGY AND ANATOMY.


TABLE 178–6. CAUSES OF SPLENOMEGALY

Infection

Bacterial (e.g., endocarditis, brucellosis, syphilis, typhoid, pyogenic abscess)

Mycobacterial (e.g., tuberculosis)

Fungal (e.g., histoplasmosis, toxoplasmosis)

Parasitic (e.g., malaria, leishmaniasis)

Rickettsial (e.g., Rocky Mountain spotted fever)

Viral (e.g., Epstein-Barr virus, cytomegalovirus, HIV, hepatitis)

Benign disorders of the immune system (e.g., rheumatoid arthritis with

Felty's syndrome, systemic lupus erythematosus, drug reactions such as

to phenytoin, Langerhans' cell histiocytosis, serum sickness)



TABLE 178–6. CAUSES OF SPLENOMEGALY Malignant disorders of the immune system (e.g., acute or chronic myeloid

or lymphoid leukemia, non-Hodgkin's lymphoma, Hodgkin's disease,Waldenström's macroglobulinemia, angioimmunoblastic-like T-celllymphoma, malignant histiocytosis)

Other malignancies (e.g., melanoma, sarcoma)Congestive splenomegaly (e.g., portal hypertension secondary to liver disease,

splenic or portal vein thrombosis)Hematologic disorders (e.g., autoimmune hemolytic anemia, hereditary

spherocytosis, thalassemia major, hemoglobinopathies, elliptocytosis,megaloblastic anemia, extramedullary hematopoiesis)

Storage diseases (e.g., Gaucher's disease)Endocrinopathies (e.g., hyperthyroidism)Miscellaneous (e.g., sarcoidosis, amyloidosis, tropical splenomegaly, cysts)



EVALUATION OF SPLENIC SIZE AND FUNCTION.

TABLE 178–7. METHODS FOR EVALUATION OF THE SPLEEN

Physical examination

Imaging

Ultrasonography

Computed tomography

Liver-spleen scanningGallium scanning

Positron emission tomography

BiopsyNeedle aspiration

Splenectomy

Laparotomy (total or partial splenectomy)

Laparoscopy



an important skill, but it is not easily learned

the existence of a splenic rub on inspiration can lead to the diagnosis of splenic infarct.

In general, a splenic "biopsy" involves splenectomy, which can be performed at laparotomy or with laparoscopy

a splenectomy done via laparoscopy leads to maceration of the organ and reduces the diagnostic information.



AN APPROACH TO THE PATIENT WITH SPLENOMEGALY

1. Does the patient have a known illness that causes splenomegaly(e.g., infectious mononucleosis)? Treat and monitor for resolution.

2. Search for an occult infection (e.g., infectious endocarditis), hematologicdisorder (e.g., hereditary spherocytosis), occult liver disease (e.g., cryptogeniccirrhosis), autoimmune disease (e.g., systemic lupus erythematosus),or storage disease (e.g., Gaucher's disease). If found, manage appropriately.

3. If systemic symptoms are present and suggest malignancy and/or focal replacement of the spleen is seen on imaging studies and no other site is available for biopsy,splenectomy is indicated.

4. If none of the above are true, monitor closely and repeat studies until thesplenomegaly resolves or a diagnosis becomes apparent.



AN APPROACH TO THE PATIENT WITH SPLENOMEGALY

presentation

left upper quadrant pain or fullness or

of early satiety

catastrophic symptoms of splenic rupture

unexplained cytopenias

incidentally on physical examination

The presence of a palpable spleen on physical examination is almost always abnormal.

The one exception to this rule is a palpable spleen tip in a slender, young woman

In general, the presence of a palpable spleen should be considered a serious finding and an explanation should be sought.

approach to the patient with lymphadenopathy and splenomegaly

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