non hodgkin's lymphoma

Hodgkin lymphoma

Hodgkin's lymphoma (LH) or Hodgkin's lymphoma (as opposed to non-Hodgkin's lymphoma) is a type of lymphoma (cancer of the lymphatic system) characterized by the presence of large atypical cells, Reed-Sternberg cells. The fact that it is the first well-characterized lymphoma has led to the exclusion of non-Hodgkin lymphomas (NHL), all other types of lymphoma.

The Reed-Sternberg cell is indispensable for diagnosis, but it is not totally specific, and can be found (rarely) in other types of lymphoma (peripheral T lymphomas in particular). Its nature has long been debated but it is now well established that it is a cell of the lymphoid lineage B1.

Its synonyms include "Hodgkin's disease-Paltauf-Sternberg", "Hodgkin", "Hodgkin's Lymphoma", "Malignant granulomatosis", "Malignant lymphogranuloma" and "pathophysiology ganglion cancer"

Distribution of lymphatic drainage areas (Hodgkin's lymphoma)
The origin of the characteristic cells of Hodgkin's lymphoma, Hodgkin's cells (mononuclear) and Reed-Sternberg cells (multinucleate), was for a very long time debated and it was only at the turn of this century that it was formally Established that these cells were of lymphoid origin B1. This late identification, more than 150 years after the description of the disease, is due to the fact that these tumor cells usually represent only 1% of the tumor mass, mainly consisting of a reaction cellular infiltration. Moreover, these cells do not express markers typical of lymphoid origin B or T.

The demonstration that all tumor cells carry rearrangements of immunoglobulin genes with presence in addition to somatic mutations characteristic of lymphogenèse B reflects the fact that these cells originate from the Centers Germ of the ganglion. In a significant proportion of cases, these somatic mutations are characterized as unfavourable, which should have led to the removal by apoptosis of these cells; This non-elimination is the cause, in some cases, of the malignant transformation of these B1 lymphocytes.

Finally, many recent studies have shown that tumour cells are characterized by a very significant change in the normal pattern of gene expression: most of the genes normally expressed in B lymphocytes are no longer, While many transduction or transcription pathways are dérégulées1.

Clinical Signs
The increase in lymph node size (adenopathies) is the most common sign; The adenopathies are firm, but painless (apart from the classics but rare alcohol ingestion) and not inflammatory. They are most often located at the ganglion cervical, sus-supraclavicular or axillary areas. The examination can also find adenopathies of the inguinal or crural areas, a splenomegaly or a hepatomegaly.

Some symptoms may be secondary to the presence of deep ganglia, in particular pulmonary signs: chronic cough and dry or even dyspnea, and cardiac signs: Upper cave syndrome, in case of adenopathies mediastinal compressive (Rare situation in Hodgkin's lymphoma).

About one third of the patients also have general signs (so-called "B" signs or symptoms): slimming (significant if it is greater than 10% of body weight), asthenia, fever (significant if > 38 ° for at least 7 days), or night sweats and Abundant (significant if they impose a change of clothes). An isolated pruritus is a classical sign and sometimes precedes much the date of diagnosis.

Diagnosis

The diagnosis of Hodgkin's lymphoma can be evoked on a puncture of a ganglion. Analysis of a ganglionic juice smear may indeed reveal the presence of Sternberg cells.

But the formal diagnosis of Hodgkin's lymphoma is based on the anatomopathologic study of a ganglion. This requires a biopsy of a lymphadenopathy performed either surgically (resection of a ganglion), or by biopsy puncture to the trocar of a ganglion, made by external means, by a radiologist, under the control of an ultrasound or a scanner.

The Anatomopathologic examination reveals the association of the presence of large malignant cells (so-called Reed-Sternberg [RS]), Binucleate, with prominent Nucleoli, and a destruction of the normal lymph node architecture. There is also an important cellular reaction of T lymphocytes, histiocytes, and eosinophils. In this anatomopathologic study, a study of the immunophénotype of tumor cells will be coupled. The cells are typically CD15 + and CD30 +, often CD25 +, and in almost half of the LMP + cases (a marker that the Reed-Sternberg cells contain the Epstein-Barr virus genome); The CD20 (marker B) is most often negative; Its positivity should evoke a Popemma lymphoma, must be verified against it.

The pathologist will also classify Hodgkin's lymphoma into one of its histological subtypes (see infra), knowing that this classification does not, in most cases, alter the treatment to be administered.

Histological subtypes

Hodgkin's lymphoma can be classified into four histological subtypes according to the Anatomopathologic examination data.

The ranking established by Rye in 1965 distinguishes four types2:

Type 1 rich in lymphocytes or predominantly lymphocyte (PL);

Type 2 lichen-nodular (SN) associated with the presence of multiple sclerosis;

Type 3 with mixed cellularity (CM);

Type 4 with lymphocyte depletion (DL).

More recently, the WHO classification has excluded from this framework the nodular forms rich in lymphocytes, now considered as a separate entity (NLPH of the Anglo-Saxons, Popemma lymphoma, paragranulome of Popemma and Lennert). According to this classification3 it is now question of classical Hodgkin lymphoma with as sub-entities:

form with nodular sclerosis;

The form rich in lymphocytes;

The form with mixed cellularity;

The form with lymphoid depletion.

Finally, the form with Nodular sclerosis is subdivided into two subgroups based on rarity (NS1) or richness (NS2) in Sternberg cells.

Extension balance

The diagnosis posed with certainty, the hematologist must carry out an extension assessment of the disease. This balance sheet requires:

A full clinical examination

Imaging examinations: Chest X-ray, abdominal ultrasound, CT, thoracic, and Pelvic CT scans: Ct. The lymphography is no longer practiced. A positron emission tomography (PET) at 18f-FDG is now systematic; Extremely sensitive, it detects unsightly attacks by classical imaging exams and thus avoids substage of patients. The pet has replaced the gallium scan that is no longer performed. Cardiac ultrasound may be necessary to clarify whether or not the pericardium is affected;

A blood test with a dosage of LDH, a CBC, a hepatic checkup, a martial balance, a protein electrophoresis and an inflammatory balance; It allows to gather the elements of the prognostic index (see infra);

A ostéomédullaire biopsy (BOM) is especially indicated in forms with B-signs or extended forms; The interest of this BOM is currently rediscussed because pet allows to identify most often ostéomédullaires attacks;

More rarely, further examinations may be necessary to clarify the extent of the disease: liver biopsy (PBH), puncture or pleural biopsy, etc. These "aggressive" exams will be especially necessary in cases where their positivity changes the stage of the disease.

Other initial exams

A number of other tests will be carried out in the diagnosis, essentially to ensure that there is no prior organ injury or contraindication to the use of certain medications. An electrocardiogram and a transthoracic cardiac ultrasound are performed prior to any chemotherapy by anthracycline. Respiratory functional tests are performed prior to chemotherapy by bleomycin.

A sperm freezing in a Centre for the study and conservation of human eggs and semen is systematically offered to adolescents and adult men as some chemotherapy used in Hodgkin's lymphoma are sterilizing for Male patients.

Stages

At the end of the extension balance, the stage of the disease according to the ANN Arbor classification will be determined; This one distinguishes:

Stage I: A single ganglionic area is reached;

Stage II: At least two ganglion areas, on a single side of the diaphragm, are reached;

Stage III: Attainment of ganglion areas on either side of the diaphragm;

Stage IV: Attainment of one or more lymph organs (lung, liver, bone, bone marrow, etc.).

NB1: The spleen counts as a ganglionic area; The invasion of the spleen may be marked by an "s"; Liver damage on the other hand defines a stage IV as well as the impairment of other organs.

NB2: The invasion of an extra-lymphatic organ or serous (Pleura, pericardium) by adjacency from an invaded ganglion (e.g., invasion of the pulmonary parenchyma or anterior thoracic wall from a lymphadenopathy Mediastinal) is noted by an "E".

The absence or presence of general signs is notified by adding an "a" or a "B". The "a" or "B" cases can be classified according to the presence or not of biological signs of inflammation (this classification is no longer used at present).

Thus, the so-called localized forms (stages I and II) and the extended forms (Stages III and IV) which are covered by different intensity treatments are distinguished. The possible stages go from IA to IVBE. Note that the presence of B signs, or an extension by adjacency, can alone impose a change of therapeutic group. A IIBE form will thus be more severe prognosis than a form IIIA.

Prognosis factors

The main prognostic factor is the degree of extension of the disease. Other prognostic factors are also considered and can be used for the statification of patients:

The importance of tumor syndrome (bulky character of the Anglo-Saxons): Some protocols take into account the presence or not of very large adenopathies (> 6 cm or > 10 cm) or the presence or not of a large mediastinum (defined by a ratio mediastinum/thorax > 0.33 or > 0.45);

The existence or not of an extension by adjacency;

An international study identified seven factors with prognostic value for AVANCÉS4 stages in 1998:

Male sex;

Age ≥ 45 years;

Stage IV of the disease (versus stage III);

Hemoglobin < 10.5 g/DL;

Number of lymphocytes < 600/μl or < 8%;

Number of white blood cells ≥ 15 000/μl;

Albumin < 4.0 g/dl.

In this study a patient with none of these factors has a chance of survival at 5 years of 84%. The prognosis then decreases according to the number of factors present, 5-year survival falling to 42% for patients with 5 of these factors.

The inflammatory character is sometimes more simply taken into account by the degree of increase in the rate of sedimentation at the first hour (> 30 mm or > 50 mm).

The histological type "nodular sclerosis" is considered to be a more severe prognosis and may intervene in stratification as well.

Finally the tumor response is also taken into account. It is evaluated in two ways: the volumetric decrease of the tumor (the measurements of the tumor masses are quantified by a CT) and the persistence or not of a positive fixation to the toe. This assessment can be done in an early stage (after only 2 cures) or at the end of treatment. Depending on the quality of the response observed, it will be decided, according to the protocols, to lighten or intensify the treatment. For example, many of the current protocols propose not to irradiate patients who have a very good response to chemotherapy.

Treatment

With appropriate treatment, more than 90% of Hodgkin's disease is curable [ref. needed]. Treatment typically combines chemotherapy and/or radiation therapy with the knowledge that the latter is less and less used. The therapeutic choice takes place at a multidisciplinary consultation meeting (as with any cancer). As treatments are in progress, it may be suggested that the patient integrate a therapeutic protocol (cf: targeted therapies).

Chemotherapy

The intensity of chemotherapy will depend on the degree of spread of the disease. Depending on the stratification chosen by the protocol, patients are divided into therapeutic groups according to the stage and whether or not certain prognostic factors are present.

The most widely used cancer chemotherapy for adult patients is the ABVD that combines Adriamycin, bleomycin, Vinblastine, and Dacarbazine. Developed in Italy in the years 1970, the ABVD remains the gold-standard to which other types of treatment must compare. The cures of ABVD are repeated every 28 days for a total of 3 to 8 cures according to the degree of extension and the protocols.

Other types of cures are used:

The BEACOPP-type cures (developed by the German group), which are more intensive, are used mainly by European groups. The BEACOPP said climbed is even heavier;

In pediatrics, the use of anthracyclines will be restricted; Cures of the type OEPA, COPP, COPDAC, etc. are used;

The classic cures of MOPP (Méthylchlorétamine, vincristine, procarbazine and prednisone) are no longer used, at least in the first line.

In case of relapse, chemotherapy treatments bringing unused agents to the front line are used. The main cures are IVA, ICE, Ptwi, mine, etc.

Radiotherapy

Hodgkin's lymphoma is a highly radiosensitive disease (that is, it "responds" well to radiation therapy). Unfortunately, radiation therapy is also the main source of secondary sequelae to treatment, which is why medicine seeks to reduce its indications and intensity.

One of the ways to reduce the intensity of radiation therapy is to associate it with chemotherapy. Thus the attitude of choice is most often a treatment called combiné5.

The dose of radiotherapy delivered was classically important: 36 or even 40 Gray; Gradually this is reduced to 25 or 20 Gy.

Irradiation fields were also reduced over time: Total lymphoid irradiation or extensive irradiation (e.g., conventional mantle), the Radiotherapist switched to an involved-field or IFRT irradiation (only the area irradiated), or even "nodular" or INRT irradiation (only the affected ganglion is irradiated).

Currently, it is considered that a localized form should not be treated by exclusive radiotherapy (combined treatment allows for less intensive irradiation); Whereas the extended forms, stage IV in particular, should be treated most often, at least in adults, by exclusive chemotherapy (in order to avoid extensive irradiation); And that good answering patients early to chemotherapy may probably not be irradiated (evaluation underway).

Irradiation is done in several sessions (it is a matter of fractional irradiation).

The SUS-diaphragmatic zone (mantle, etc.) must be irradiated, and then, if necessary, the sub-diaphragmatic zone (inverted, lumbosacral-splenic bar, etc.). An irradiation SUS or under diaphragmatic usually extends for 2-3 weeks depending on the total dose delivered.

The main side effects of radiation therapy are: the lack of growth of the irradiated area in the child, thyroid damage (hypothyroidism, cancer), ovarian failure (early menopause and even sterility when the ovaries are In the irradiation field and have not been moved before it), coronary artery stenosis (angina, myocardial infarction), etc. but also malignant tumours (breast cancer, osteosarcoma, etc.) and acute leukemias Myéloblastiques or myélodysplasies (the risk of secondary malignant hemopathy is also increased by some chemotherapy, alkylating in particular).

The expected frequency of these complications in the current protocols will, a priori, be much lower than that observed in the old protocols given the changes in the management done over time.

Marrow grafts

The autograft is performed from a autologous marrow swab, or more often here from a circulating hematopoietic stem cell (CSH) collection obtained by Cytaphérèse after mobilization by a suitable chemotherapy treatment and a Growth factor of the granular line (G-CSF). This is to play on a "dose effect": very intensive chemotherapy, whether or not associated with total body irradiation, is administered to the patient and the CSH is then reinjected, which will allow the patient to leave aplasia within an average time of 3 Weeks after the reinjection.

The autograft is indicated on the front line for refractory patients or with very pejorative initial prognostic criteria and in case of relapse. Some protocols use a double-grafting approach.

The marrow allograft remains experimental in the treatment of Hodgkin's lymphoma, but a Hodgkin's anti-lymphoma graft effect is well established: the risk of relapse is decreased (compared with an autograft) by a allogeneic effect: Elimination of any residual tumor cells by the donor's immune cells. Allograft is indicated especially in patients who relapse after autografting. The methods of implementation are the same as an autograft: conditioning (intensive chemotherapy associated with or not total body irradiation) and then re-injection of CSH. For some fragile patients the conditioning at the transplant will be attenuated (then referred to as "mini-graft"). The suites of a allograft are longer and potentially more complicated than those of an autograft. The prevention of graft disease against the host requires, in particular, prolonged immunosuppression, and graft disease against the poorly controlled host considerably increases the graft's aftermath. The control of graft disease is important for the success of the allograft: it is desirable because its occurrence is associated with a decrease in the risk of relapse, but it must not be too toxic to the patient. Finally, post-allograft mortality is higher than that of the autograft. All of this explains why Allograft is generally proposed for more severe cases.

Targeted Therapies

Many new drugs are currently being studied (phases II and III) in Hodgkin's lymphoma: monoclonal antibodies (anti-CD30) or inhibitory drugs of histone deacetylases (Panobinostat) or M-TOR6. The SGN-35 or brentuximab vedotin, anti-CD30 coupled with chemotherapy, aurostatine, thus appears very prometteur7.

Finally, some assess the interest of a monoclonal anti-CD20 (rituximab); Although the Sternberg cell does not express CD20, a current theory assumes that tumor stem cells would be CD20 + and that the elimination of these Stem cells would eliminate the risk of relapse.

The place of these new agents in the treatment of Hodgkin's lymphoma is nevertheless to be defined.

Symptomatic treatments

These treatments are intended to prevent certain complications of chemotherapy. Thus, erythropoietin (EPO) can be prescribed to anemic patients, as well as granulocytaires growth factors (G-CSF) to aplasiques patients. Treatments should also prevent opportunistic infections, vomiting and pain.

Epidemiology

Descriptive epidemiology

Unlike other lymphomas, whose frequency increases with age, Hodgkin lymphomas have a bimodal frequency curve: They occur more frequently in two different age groups, the First age group being that Young adults between 20 and 30 years of age and the second to 70 years. This disease affects men more frequently, except in the case of forms with Nodular sclerosis, a histological subtype that affects women more frequently. According to a recent study of the Lancet Medical Journal, its incidence, of about 4 cases out of 100 000, would increase in young adults. However, this disease is less than 1% of all known cancers.

In France, the report of the Institute of Cancer published in 2009, estimates the number of cases for the year 2005 to 1544 (757 women, 787 men); This makes it a rare cause of cancer: 0.5% of cancers and 24th rank of the 25 locations studied. Since 1980, the annual incidence is declining among men while it is increasing among women: + 3.3% per annum from 2000 to 20058.

The disease is even more rare in the child and mainly concerns children over the age of 10 and adolescents. Among the very few small children reached there is a very strong prevalence of boys. The estimated number of cases of pediatric age is one hundred per year in France.

Analytical epidemiology

The etiology of Hodgkin's lymphoma is not elucidated. Some factors involved in the oncogenesis of this lymphoma were nonetheless identified.

Epstein-Barr virus-responsible for infectious mononucleosis-seems to play a role in some forms of Hodgkin's lymphoma. The EBV virus is present in Reed-Sternberg (RS) cells in 40% of the classical LH cases of patients in developed countries, particularly in mixed cellular and cell-depleted forms; This proportion is greater in children and in emerging countries: 90% of cases, for example, for pediatric cases in Central America or America SUD1.

HIV-infected patients also have an increased incidence of lymphomas, including Hodgkin's lymphoma; At home, the association with EBV is almost constante1.

In the RS cells are expressed three viral proteins (EBNA1, LMP1 and LMPA2) and also two non-encoding RNAs. It is established that these viral proteins play a role in the tumor process; In cases where RS cells do not contain the EBV genome, mutations of a gene, TNFAIP3 could "replace" the VIRUS1.

Maternal exposure to domestic pesticides (insecticides appear to be involved) during pregnancy would be a risk factor for the child (doubled risk), except for Nodular sclerosis type Hodgkin's lymphoma (nodular sclerosis or NSHL for Anglo-Saxon), a form that mainly affects more âgées9 girls.

History

It was first described by Sir Thomas Hodgkin in 183210. Half a century later, Wilms proposes the name of Hodgkin11. In 1902, Dorothy Reed12 and Carl Sternberg13 described the characteristic cells of Hodgkin's lymphoma: Hodgkin's cells, mononuclear, and Reed-Sternberg, polynucléées cells. The origin of Hodgkin's lymphoma has been discussed for a long time: inflammatory, infectious (especially tuberculosis) or tumor.

The first attempt at chemotherapy dates from 1947 with a moutarde14 gas derivative with a very relative success. The prognosis was appalling since the lifespan did not exceed two years after the DIAGNOSTIC15. Very significant progress has been achieved with the development, for the first time in medicine, of polychimiothérapies. The first cure was the MOPP in 196416 (Mechlorethamine, vincristine, procarbazine and prednisone) and then the ABVD (doxorubicin, bleomycin, Vinblastine and Dacarbazine) in the mid-years 1970