Hodgkin disease (Hodgkin lymphoma)

Cliché thoracique de face d’un patient atteint de maladie de Hodgkin mettant en évidence une volumineuse masse polylobée se développant dans le médiastin supérieur. Le rapport médiastino-thoracique en D5/D6 est supérieur à un tiers

Diagnosis:

A- Definition, epidemiology, etiology:

Hodgkin’s disease is now considered a particular type of lymphoma, characterized by proliferation of large cells called Reed-Sternberg cells in a lymphoid tissue reaction characteristic architecture. The disease is more common in men (2-5 cases per 100 000 population per year) than in women (1-2 cases per 100 000 population per year). Its incidence seems generally stable or slightly decreasing in the last 20 years. It can be observed at all ages, but with a peak occurred during the third decade and affect again increasing among people over 70 years. Several recent studies indicate that a number of Hodgkin’s diseases develop from lymphocytes of the B lineage The Epstein-Barr virus (EBV) can be detected in the Reed-Sternberg cell, in a highly variable proportion of cases and there is no evidence of its role in the occurrence of the disease.

B- Circumstances of Discovery:

Hodgkin’s disease was found in about 4 out of 5 by peripheral lymphadenopathy often painless cervical or supraclavicular seat. In about 10% of cases, it is discovered to mediastinal lymphadenopathy identified on a chest radiograph (Fig. 1) made fortuitously or during compression signs (cough, dyspnea, pain). Finally, in 10-20% of cases, the disease is revealed by the presence of general symptoms, such as fever, weight loss, night sweats, and more rarely pruritus.

C- Positive diagnosis of Hodgkin’s disease:

The diagnosis of Hodgkin’s disease must be established on a pathological examination of a lymph node biopsy. If FNA can sometimes highlight of Reed-Sternberg cells, it is not sufficient to establish the diagnosis because the cell is not pathognomonic of the disease. Finally, in the very rare hematological forms without lymph node involvement, the diagnosis can be worn on the bone marrow biopsy or splenectomy room. The Reed-Sternberg cell is a giant cell, about 40 mm in diameter, bright nucleus, mono- or sometimes lobed with a mirrored aspect, multi-nucleolus.Cytological variants of the Reed-Sternberg cell can also be encountered (deficient cells, Hodgkin cells, tumor giant cells). The usual phenotype Sternberg cells in classical Hodgkin’s disease is characterized by expression of the CD30 surface molecule, optionally sometimes CD20 CD15 antigens. Four histological subtypes were usually distinguished according to the classification of Lukes-Rye

– Hodgkin’s disease with nodular sclerosing and organization (nodular sclerosis type 2) is the most classic form of Hodgkin’s disease, found in 80% of cases, preferentially affecting the young and the above-diaphragmatic nodes;

– The mixed cellularity (type 3) represents 15-20% of cases and occurs more readily in the elderly, with general signs of scalability or in carriers of HIV (HIV) Hodgkin’s disease patients;

– Beside these two classic forms, shape lymphocyte depletion (type 4) is rare, often associated with border prologie with anaplastic lymphoma. Finally, the shape lymphocytic (type 1) and architecture is now more diffuse considered Hodgkin’s disease but as lymphoma; while the nodular form is individualized as the nodular nodular paragranuloma of the characteristics and evolution are distinct classical Hodgkin’s disease. Immunohistochemical analysis of lymph node biopsy is needed when the diagnosis is not obvious in the 2 classical forms (types 2 and 3), or when atypical forms is suspected, given the boundaries of these forms with certain Non-Hodgkin lymphomas.

D- Differential Diagnosis:

The clinical picture of Hodgkin’s disease revealed by a superficial lymphadenopathy fact discuss other causes of superficial lymphadenopathy, especially other lymphomas, lymph node metastasis of cancer, viral or bacterial infections (tuberculosis) accompanied by adenomegaly the systemic diseases. After lymph node biopsy, only a problem forms the borders between Hodgkin’s disease and lymphoma subtypes 1 and 4 of the classification of Lukes-Rye.

International Classification prognostic:

Hodgkin’s disease is one of the first cancers being cured, first by radiation therapy used alone broad fields and chemotherapy, used alone or in combination with radiotherapy. However, it is clear that these treatments exposed to immediate and long-term complications, and should be optimal use. This is why the treatment of Hodgkin’s disease today is based on a very precise staging of patients to best use these different therapeutic weapons.

A- Assessment of extension:

Hodgkin’s disease extension record begins with an interrogation in search of general symptoms: fever over 38 ° C for more than 8 days, weight loss of more than 10% of body weight during the last 6 months profuse night sweats.Clinical examination aims to explore all the lymph nodes, to detect splenomegaly or hepatomegaly. The presence of extranodal localizations of Hodgkin’s disease is relatively rare but bone lesions revealed by focal pain are not exceptional in extended forms of the disease. The chest radiograph is necessary for the possible identification of a large mediastinal mass, celleci being considered significant when the largest tumor diameter, measured at D5-D6 is greater than or equal to one third of the thoracic transverse diameter, measured same level (Fig. 1). Computed tomography of the chest complete search of hilar and mediastinal lymphadenopathy, the existence or not of pleural or pericardial effusion whose specificity must be documented if possible.

CXR face of a Hodgkin's disease patient reaches demonstrating a large mass polylobée developing in the upper mediastinum. The mediastinal-thoracic ratio D5 / D6 is greater than one third
CXR face of a Hodgkin’s disease patient reaches demonstrating a large mass polylobée developing in the upper mediastinum.The mediastinal-thoracic ratio D5 / D6 is greater than one third

Regarding sub-diaphragmatic extension, the exploration of the abdomen and pelvis is currently performed by a CT scan (abdomen + pelvis) which replaced lymphography. Abdominal ultrasound ensures the homogeneity of the splenic parenchyma, possibly indicate the presence of liver damage. The exploratory laparotomy has no place in the balance sheet of standard extension of Hodgkin’s disease. The minimum balance must be supplemented by an ENT examination in cases of cervical lymph node involvement, and by performing a bone marrow biopsy which can not be omitted for the limited stages with favorable characteristics (see below). The necessary laboratory tests include a complete blood count, a measure of the erythrocyte sedimentation rate, liver function tests (looking particularly of cholestasis or cytolysis that could move towards hepatic parenchymal disease), a virus serology human immunodeficiency. The realization of a protein electrophoresis, a dosage of lactate dehydrogenase (LDH), b2-microglobulin, fibrinogen and ferritin can be made, their disturbances are associated with a worse prognosis of the disease. Finally, depending on the interpretation of previous examinations and clinical call points a liver biopsy may be performed, and a bone scan, magnetic resonance imaging (MRI), or any other examination for documenting a specific impairment of Hodgkin’s disease.

B- classical prognostic factors:

To adapt the treatment strategy, patients are first stratified using the Ann Arbor classification resulting from the interpretation of the staging. In the various subgroups identified by this classification, other prognostic factors are sometimes necessary for therapeutic decisions. After this classification, patients will be grouped schematically as follows: the limited stage (I and II) supra-diaphragmatic; limited stages (I and II) subdiaphragmatic; stage IIIA; IIIB-IV stages. As for stages I and II supra-diaphragmatic, several international studies have identified some independent prognostic factors (age, presence of constitutional symptoms, elevated sedimentation rate, mass and tumor extension) for separating 2 prognostic groups, the a favorable evolution, the other adverse developments (Table II).These two groups usually receive different treatment strategies (therapeutic protocols of the European Research Organization treating cancer, EORTC). Many other prognostic factors have been described, whether poor prognosis associated with a type of mixed cellularity histology (versus nodular sclerosis), male and many other biological signs (elevated LDH, b2-microglobulin, decreased albumin, hyper leukocytosis, iron deficiency …).

Clinical stage expansion according to the classification of Ann Arbor
Clinical stage expansion according the classification of Ann Arbor

Evolution:

A- Evolution under treatment:

The main treatment goal is to achieve complete remission after the first treatment, because this determines remission obtaining a favorable long-term therapeutic outcome. Upon initiation of appropriate treatment (chemotherapy or radiation), clinical signs (fever, sweating) quickly disappear in a few days.Superficial lymph nodes or moderate size regress within weeks. The evaluation of the therapeutic response in patients with large lymph node masses, particularly in the mediastinum, is more difficult. Indeed, some of these lesions decreased initially in treatment, but persist on plain radiographs or CT scan. It comes in a number of cases of simple non-scalable fibronécrotiques residues.The realization of complementary techniques such as gallium scan or magnetic resonance imaging could help discern these residual masses scalable tumor residues.

B- Evolution after relapse:

Patients who relapse after initial treatment may still benefit from effective treatment. We distinguish:

– Relapses occurring after radiotherapy alone which can be made up a significant proportion of cases with a single chemotherapy alone;

– Late relapses some of which can be treated successfully for several years, particularly since they occur with a long delay compared to the initial push; – Early relapses occurring within one year after the initial treatment that are very poor prognosis and are treated by intensive chemotherapy with possible bone marrow transplant. If the course of the disease is not controlled, Hodgkin’s disease often takes a feverish form and cachexia resulting in patient death.

C- specific clinical forms:

Some elderly are disseminated forms with general signs whose evolution is severe. The possible occurrence of a Hodgkin’s disease during pregnancy poses special therapeutic problems.

D- Late effects of treatment and long-term complications:

1- Immunosuppression:

Hodgkin’s disease is a disease of the immune system, in which an alteration of cellular immunity in the disease is observed. The various therapies implemented worsen the immunosuppression, and patients frequently present infectious complications during or subsequent to processing thereof. In particular, we must emphasize the frequency of gram-positive bacteria infections in splenectomized patients (or who received irradiation on the splenic area) and the occurrence of herpes virus infections (shingles several months after the end of treatment).

2- Cardiovascular complications, pulmonary, and other:

• Cardiovascular complications are frequently reported, whether heart failure, pericarditis or especially of coronary diseases. Mediastinal irradiation and cardiotoxic drugs (doxorubicin) play an important role in the occurrence of these complications are the cause of excess cardiac death in patients treated for Hodgkin’s disease.

• Pulmonary complications related to irradiation and use of bleomycin have also been reported. The digestive complications sousdiaphragmatiques irradiation are rare, unless patients had exploratory laparotomy before.Endocrine complications are represented by thyroid deficiency primarily related to irradiation, and abnormalities of reproductive function of patients. These are primarily related to the use of alkylating agents (cyclophosphamide, procarbazine) or nitrogen mustard (caryolysin). Thus, male infertility is almost constant in patients receiving more than 6 courses of MOPP (see below); the risk of early menopause occur with the same treatment increases from 10% to 100% with the age of the patient. This leads us to consider less toxic chemotherapy regimens on gonadal lineage.There is no established data about an increased risk of second cancer or genetic defects in children of patients treated for Hodgkin’s disease.

3- Occurrence of second cancers:

• The acute myeloid leukemias and myelodysplasia side are related to the use of chemotherapy with alkylating or combined treatments (their impact may reach 1 to 10% to 10 years).

• Non-Hodgkin’s lymphoma also have an increased risk of development, with a cumulative incidence at 10 years 1 to 5%. Factors contributing to their occurrence, however, remain unclear (immunosuppression, 2nd true cancer, Hodgkin’s disease relapse in a different form?).

• Finally, more recently, attention was drawn to solid tumors occur later (10-20 years) in patients treated for Hodgkin’s disease, especially in irradiated areas. This increase relates to both skin cancer, cancers of the lung, the breast cancer, and cancers of various organs when it came to children treated. This now leads to limiting the dose and radiation fields for the initial treatment of the disease.

Principles of treatment:

A- Radiotherapy:

Radiation therapy is the first therapeutic weapon used successfully in the treatment of Hodgkin’s disease. Patients should now benefit from the most modern radiation techniques (high energy photons). Large irradiation fields are defined supradiaphragmatic by irradiation mantle (2 supraclavicular regions, axillary, mediastinal and hilar) which can optionally be extended to the chest wall or the adjacent lung volume. The mantle may also be reduced, without mediastinal or myocardial protection. As regards the sousdiaphragmatiques volumes, irradiation is carried out in inverted Y comprising the latero-aortic region; External iliac lymph node chain, right and left; bilateral inguinal regions; the spleen and splenic hilum. These large fields are used in the exclusive irradiation or during treatment of advanced stages of the disease. In localized stages, the current trend is the use of fields reduced to initially invaded territories or territories with strong initial tumor masses. A dose of 40 Gy is delivered on initially invaded territories, and a dose of 30-36 Gy on irradiated territories prophylactically.

B- Chemotherapy:

The first chemotherapy protocol developed was MOPP (caryolysin, vincristine, procarbazine, prednisone) and its variants. Thereafter, the ABVD protocol (doxorubicin, bleomycin, vinblastine, dacarbazine), introduced in the 70s, allowed the achievement of better results, both as regards the control of the disease than the long-term complications. Protocols MOPP and ABVD alternating protocols or mixing the drugs these 2 protocols were developed with comparable efficacy, but perhaps a higher toxicity.

C- Therapeutic indications:

They must be posed in terms of prognostic criteria defined above. Before treatment should be offered sperm cryopreservation for male patients; oral contraceptives is offered to women of childbearing age; Finally, if a sub-diaphragamatique irradiation is considered in a patient, a oophoropexy (displacement of the ovaries in the abdominal cavity) may be considered to preserve fertility.

In the above-diaphragmatic localized stages, patients with a disease with favorable characteristics (Table II) will be treated with exclusive radiotherapy (cloak), or by a combination of 3 or 4 courses of chemotherapy followed by a limited irradiation invaded areas (the latter method is becoming the reference). The current trend is the reduction of radiation doses and the use of an isolated chemotherapy is being tested in these patients. In the forms of poor prognosis, it is the realization from April to June of chemotherapy followed by irradiation with initially territories which constitutes the reference protocol. Complete remission is obtained in 85 to 100% of cases. In favorable shapes, more than 90% of patients are surviving to 10 years whereas in the negative forms, the 10-year survival is 70 to 90%.In extended forms of Hodgkin’s disease (stages IIIB and IV), patients can be treated with 6 cycles of chemotherapy for obtaining a complete remission, consolidated therapeutic result by issuing additional 2 courses of chemotherapy or an extended irradiation. The under investigation protocols based on the use of more intensive chemotherapy doses close followed by irradiation with limited fields. Complete remission was achieved in the majority of patients (approximately 75%) but relapses are frequent with a long-term survival of 40 to 65%. In other presentations of Hodgkin’s disease (I and II subdiaphragmatic and stage IIIA) treatment generally includes the use of chemotherapy (4-6 courses) and a localized radiotherapy.

Prognostic classification of localized stages above-diaphragmatic (I and II)
Prognostic classification stadiums localized above-diaphragmatic (I and II)

CONCLUSION:

If significant therapeutic advances have been achieved in Hodgkin’s disease through the use of combined treatments (chemotherapy and radiotherapy), the current trend is to optimize treatment based on evolutionary characteristics of each sub-group of patients, to limit Long-term complications, responsible for an excess mortality from toxicity of treated patients. The concern of this excess mortality has to prefer the use of validated chemotherapy regimens, and discuss therapeutic indications with specialized teams. Changes in relation to these standards can only be achieved through clinical trials subjected to a rigorous evaluation of short- and long-term results.

Highlights to include:

• Hodgkin’s disease is part of the lymphatic system cancers, as other lymphomas, but its histological, scalable and therapeutic characteristics are unique.

• The diagnosis is focused on the presence of Reed-Sternberg cells in a characteristic nodal architecture.

• The spread of the disease is done step by step by ganglion territories shall be specified by a careful staging.

• The so-called in Ann Arbor stage classification is an indispensable element prognosis, plus age, sedimentation rate, and mediastinal-thoracic ratio for infringement mediastinal.

• Therapeutic modalities generally utilize a combination of chemotherapy and radiation therapy (combination therapy).

Strong Points to remember:

• The most common clinical presentation of Hodgkin’s disease is that of a cervical or supraclavicular lymphadenopathy.

• The node biopsy necessary for diagnosis, to distinguish Hodgkin’s disease from other lymphomas. Both conventional histological forms are scléronodulaire shape and form mixed cellularity.

• The questioning search for the presence of general signs while the clinical examination and CT scan of the thorax, abdomen and pelvis specify ganglion rarely met or extranodal. Laboratory tests and a bone marrow biopsy complete this staging.

• Clinical classification of Ann Arbor separates localized stages I and II supra-diaphragmatic extensive and developmental stages (stages IIIB and IV), the other presentations (I – II sousdiaphragmatique first, second stage IIIA) being much rarer.

• The combination of chemotherapy and radiation therapy provides a sustained complete remission after 5 years in 80-95% of localized tumors, and 40 to 60% of extended forms.

• The risk of late complications of chemotherapy and radiotherapy leads to use these two treatment arms in a limited way.