José Luis Fedele
Lymphomas are clonal expansions of cells that derive from their normal counterparts, lymphocytes, located in their normal functional compartments, that is, lymph nodes, spleen, bone marrow, and mucosa-associated lymphatic tissue.
In the next chapter, an overview of this heterogeneous group of tumors will be given.
Hodgkin's Lymphoma (HL) is a malignant disease of the lymphatic system with distinctive characteristics that have made it a prototype disease within neoplasms, both due to its evolutionary characteristics and its response to treatment.
Over the past 40 years, advances in chemotherapy and radiation therapy have greatly improved survival rates and, in many cases, cure rates of the disease. Today it can be said that more than 80% of the new cases of LH in those under 60 years of age are cured of this disease.
Approximately 7,500 new cases of LH are diagnosed each year in the USA.
It is estimated that in Argentina there are between 750 to 800 new cases each year
The incidence of the disease varies considerably, since it has a bimodal presentation patent in relation to age; with two peaks of frequency of presentation, one in young adults and the other in those over 55 years of age.
LH-related causes remain obscure. Familial factors (genetic-hereditary), viral exposure and immune suppression have been implicated.
In favor of the first, there is the higher incidence of cases in twins of patients with HL. In relation to viral exposure, this theory is supported by the detection of the Epstein-Barr virus genome in LH tumor specimens, as well as its association with HIV infection, and presentation in these cases, of more advanced disease at the time of detection and poor response to conventional therapy, which in turn is related to immune suppression.
Symptoms and signs
Classically, LH was divided into four subtypes, separated according to histological characteristics.
At present, according to a new WHO classification, the disease is considered to be composed of 2 different clinico-histological entities:
The classic variant, composed of 4 already known subgroups (Nodular Sclerosis - Mixed Cellularity - Lymphocyte Depletion - Rich in Lymphocytes), and a new variant, separated from the previous ones, with a rarer presentation: Nodular with Lymphocyte Predominance.
Painful lymphadenopathy is the most common clinical manifestation of the classic form of LH, however, each histologic subtype has distinctive clinical features.
Nodular sclerosis, the most common subtype, tends to affect adolescents and young adults and has a predilection for the cervical, supraclavicular, and mediastinal regions.
The mixed cellularity subtype is more prevalent in the pediatric population and in elderly patients, and is commonly associated with advanced disease at the time of diagnosis and poor prognosis.
The incidence of lymphocyte depletion is much lower than initially reported and many cases were reclassified as Non-Hodgkin's Lymphoma. This subtype occurs frequently in elderly patients and is associated with the absence of peripheral lymphadenopathy and disseminated viceral disease from the beginning. This variant is the most frequently associated with HIV.
The lymphocyte-rich subtype is a recently incorporated variant, similar to the predominantly lymphocytic one.
With respect to the Nodular variant with a predominance of lymphocytes, it constitutes a unique clinicopathological entity that differs significantly from the classic forms.
Pathologically, this variant shows loss of the typical Reed-Stenberg cells, and instead a population of large cells is observed, with lobed nucleoli, which, unlike classical cells, in immunostaining, are CD20 (+) and commonly CD30 and CD15 (-), the latter elements, characteristic of classical forms.
Clinically, it presents with localized nodal disease, frequently in the cervical region, and constitutional symptoms are rare. The natural history is one of a more indolent evolution with a tendency to late relapses.
Immunological traits and natural clinical history are elements that relate it more to indolent Non-Hodgkin's Lymphomas than to the classic Hodgkin's disease. Therefore, it could be anticipated that initial aggressive treatment would not be necessary in many cases.
More than 80% of patients present to the consultation with adenopathies, which are generally above the diaphragm, commonly compromising the anterior mediastinum. It is common to find cervical, supraclavicular, and axillary lymphadenopathy on physical examination, but the inguinal lymph nodes are usually less involved.
One third of patients present with B symptoms (fever - night sweats - weight loss). A characteristic and distinctive symptom of this disease is chronic pruritus. These latter symptoms occur more frequently in elderly patients and are associated with a poor prognosis.
Furthermore, LH can affect extranodal sites by direct invasion or by hematogenous spread. The organs most commonly affected by this spread are the spleen, liver, lungs, and bone marrow.
For the diagnosis of LH, only a lymph node biopsy may be necessary.
Due to frequent reactive hyperplasia of affected nodes, multiple node biopsies are sometimes required to confirm the diagnosis.
Fine needle aspiration is inadequate since the lymph node architecture is extremely important for proper diagnosis and histological sub-classification.
To confirm the diagnosis, it is necessary to identify the Reed-Sternberg cells within a suitable cellular environment, composed of reactive normal lymphocytes, eosinophils, and histiocytes. LH is the only malignant disease in which malignant cells constitute a minority of the tumor cell population.
It is important to take this aspect into account since, even an adequate biopsy, may fail to include malignant cells in the specimen to be studied.
Recent studies have confirmed that Reed-Sternberg cells originate from B lymphocytes and a simple PCR test confirmed that these cells arise from center-follicular B lymphocytes.
In recent years, the introduction of immunology and genetic studies have provided a very important tool in the diagnostic arsenal of oncohematological pathologies.
In the case of LH, the detection of CD30 (+) and CD15 (+) are unequivocal elements of the presence of LH. As mentioned above, in the Nodular variant with Lymphocyte Predominance, there may be negativity for these classic markers and positive, on the other hand, for typical markers of non-Hodgkin's Lymphoma, such as CD20.
For an adequate therapeutic approach, it is critical to properly establish the stage of the initial disease.
The staging system for patients with HL is based on the number of compromised sites, if the nodules are on one or both sides of the diaphragm, if the compromised site is “bulky” (tumor mass greater than 10 cm in diameter), if there is contiguous extranodal involvement or distant extranodal spread and if there are the typical systemic symptoms (Symptoms B). (Table I).
The initial study of a patient with HL includes: Chest X-ray; CT of the chest, abdomen, pelvis and neck (the latter when indicated); laboratory tests that include complete blood count, erythrocyte sedimentation rate, kidney and liver function tests, serum albumin and lactate dehydrogenase measurement.
A bone marrow aspirate and biopsy should be performed, except with the possible exception of female patients, with stage I or IIA, which involves the neck, who have been shown to have a very low incidence of bone marrow involvement.
In the past, diagnostic laparotomies were used to be performed, but today, with the improvement of diagnostic imaging techniques, as well as the inclusion of chemotherapy regimens in patients with early stage, this technique is rarely used today.
Recently, the incorporation of 18 F fluorodeoxyglucose positron emission tomography (FDG-PET), also known as PET Scan, has emerged as a powerful technique in the initial staging and post-treatment controls of HL.
The sensitivity of detection of sites with LH reaches 91%, and the use of this technique in the initial study of the patient, leads to a change of stage in approximately 15 to 25% of patients.
Additionally, the PET Scan has an important role in post-treatment controls.
A negative PET scan at the end of treatment results in a 2-year relapse-free rate of 85-95%; while the same positive study at the end of treatment, even with a negative conventional CT, has a significantly high recurrence rate. With these data, the PET Scan has become a tool that cannot be replaced by other methods for the initial and post-treatment evaluation of LH.
Since this is a potentially curable disease, patients are at risk of "overtreatment" in an attempt to achieve that goal. To properly select the patients who should be treated more aggressively, a risk classification or "score" was performed.
The German LH Study Group (GHSG), together with the European Organization for the Study and Treatment of Cancer (EORTC), designed a score of prognostic factors for the early stages of LH. According to these groups, the prognosis is unfavorable if the following criteria are met: large mediastinal mass (bulky), elevated erythrocyte sedimentation, involvement of 4 or more sites, age greater than 50 years, extranodal involvement, or massive splenic disease.
The International Prognostic Factor Project established the following poor prognostic factors: age older than 45 years, stage IV disease, male gender, white blood cell count greater than 15,000 mm3, absolute lymphocyte count in peripheral blood less than 600 cells / mm3, level of serum albumin less than 4.0 g / dl, hemoglobin less than 10.5 g / dl. Patients with 5 or more of these factors have a progression-free survival at 5 years of 42%, while those without negative prognostic factors have a progression-free survival at 5 years of 84%.
For the treatment of HL, strategies have been designed that differ depending on whether they are patients with early disease without adverse prognostic factors, early disease with adverse factors, or late disease.
Although, as mentioned above, prognostic factors define the clinical outcome, in general, the elements that continue to be taken into account when selecting treatment are the anatomical stage of the disease, the presence of constitutional symptoms, and the presence of "bulky" mass.
As a general rule, patients with early stages of disease are treated with combined modalities of shortened chemotherapy courses alone or combined with radiation therapy of the compromised fields. For those with advanced disease, prolonged courses of chemotherapy without radiation therapy are indicated.
In patients with primary refractory disease, defined as intra-treatment disease progression, or relapse before 90 days after the end of the treatment, the option is high doses of chemotherapy followed by Bone Marrow Anthology Transplantation. Not all patients are good candidates or can benefit from Bone Marrow Transplantation, for example the elderly. In these, the option is medical treatment, and its choice must take into account the complications that the elderly usually present during the course of more aggressive chemotherapies.
In this special group of patients, who themselves have a poor prognosis, effective treatment strategies have not yet been determined.
Non-Hodgkin's Lymphomas (NHL) constitute a very heterogeneous variety of lymphoid neoplasia and are, as a whole, the neoplastic entity that has perhaps suffered the most variations in terms of its classification in recent years.
This, added to the advent of new drugs for their treatment, has transformed the management of these neoplasms into a difficult task for the physician.
The incidence of NHL varies considerably between countries, but is approximately between 5 and 10 new cases per 100,000 population / year.
In the United States, it represents the seventh cause of cancer mortality with almost 45,000 new cases diagnosed in 1999. Its frequency has increased every year without interruption for several decades and has suffered a significant increase since the appearance of NHL in patients with Acquired Immune Deficiency Syndrome.
In relation to Hodgkin's disease, it is four times more frequent when adjusted for age and does not present the typical bimodal pattern of presentation, showing an ever-increasing incidence as age advances with a maximum peak between 50 and 70 years.
As with LH, the etiology of NHL remains obscure.
External agents, added to pre-existing genetic abnormalities, play an undoubted role, but these processes have not yet been able to be accurately identified.
Exposure to radiation is a known risk factor. The presence of chromosomal instability syndromes (Sme. Boolm, Fanconi anemia, Ataxia-Telangiectasia, etc.) are also predisposing factors.
Immunodeficiency, as mentioned before, facilitates the development of these neoplasms, as occurs in patients undergoing solid organ transplantation or those infected with the Human Immunodeficiency virus.
The association of viruses with NHL has been unequivocally demonstrated between Epstien-Barr virus and Burkit's Lymphoma by molecular biology techniques in endemic cases. Another indisputable association is that of the HTLV-1 virus with adult T-Leukemia-Lymphoma.
Another association between lymphomas and infections has been shown between Mucosal Associated Lymphomas (MALT) and chronic Helicobacter Pilory infection.
Cytogenetic alterations and the participation of various oncogenes can be described in different types of NHL, where they undoubtedly play a pathogenic role.
NHLs represent, as mentioned before, the pathological counterpart of the different types of lymphatic cells that can be observed in the lymph node, before and after antigenic stimulation.
To understand the genesis of the different types, the reader is suggested to refer to the reading of the histological evolution of the lymphopoietic system, which is beyond the scope of this chapter.
Many classifications have been proposed (Bennet - Rappaport - Gérard-Marchant, etc). This abundance of classifications reflects the difficulty in finding a single, internationally accepted and clinically validated system.
The classification most used today is the one issued by the US National Cancer Institute, also called Working Formulation (WF). (Table I)
The WF establishes 10 categories (A to J), which are divided into 3 degrees of malignancy (low-intermediate-high).
It is a classification that fundamentally aims to define entities with different natural history, prognosis and response to treatment, which makes this a classification with an eminently practical purpose.
The previous classifications (Rappaport - Kiel) had a different basis; the first pathological and the second immunological, which, although they accurately describe the original cells, had little practical reproducibility, especially with regard to prognosis and response to treatment.
As expected, there was no shortage of criticism of this classification, but the fact that it is preferred by the majority of clinicians and hematologists who routinely treat these pathologies, clearly speaks of its practicality.
An analysis of prognosis and its dependence on the histological subtype and clinical stage of WF, showed that the survival at 10 years was 45, 26 and 20% for the low, intermediate and high degree of malignancy respectively, demonstrating once again that WF is a useful and simple measure to assess prognosis, select treatment, and make clinical comparisons.
The great limitation of all current classifications is that they must permanently incorporate new clinicopathological entities that are emerging.
B CELL NEOPLASMS
Symptoms and signs
The symptoms of NHL classically include B symptoms (night sweats, weight loss, marked asthenia) and the appearance of lymphadenopathy in different regions of the body, often painful.
However, according to their degree of evolution (high, intermediate or low grade), there may be different degrees of presentation.
The extranodal presentation with or without general symptoms is a less frequent form of presentation, but when it occurs in this way, it tends to express more aggressive forms, with disseminated disease and a worse prognosis. The most common sites of extranodal involvement are: digestive tract, skin, bone marrow, paranasal sinuses, CNS.
Bone marrow involvement is common and is sometimes associated with cytopenias.
Splenomegaly is present in 30–40% of patients but is rarely the only site of disease involvement.
The clinical history is essential to reveal the presence of B symptoms, as well as to determine antecedents (autoimmune diseases, Immunodeficiencies, etc.) and belonging to different risk groups (HIV infection).
There are no effective methods for the detection (screening) of patients with lymphoma, and the population of patients at high risk for lymphomas is changing.
Typically, patients are identified after they develop lymphadenopathy or other symptoms associated with the disease.
Despite the advancement in imaging techniques for the detection of lymphoma, histology remains the central method in the diagnosis of this pathology.
As in HL, node removal biopsy is recommended over fine needle puncture in order to be able to assess node architecture.
There are cases in which laparoscopy must be used to ensure the diagnosis (eg, patients with single retroperitoneal involvement).
Although histology continues to be the fundamental stone in the diagnosis of lymphomas, once the samples are obtained, it should be complemented with complementary studies in order to place the patient in the extensive classification expressed above.
For this, immunostaining is used, which allows differentiating, in the first instance, between B and T lymphomas through their specific surface antigens for each group, and genetics, which allows detecting regular clonal translocations, such as for example: t (14; 18) with overexpression of the bcl-1 gene or the t (11; 14) with overexpression of the bcl-2 oncogene.
In the initial evaluation of a patient with Lymphoma, as mentioned above, obtaining a detailed history and physical examination is essential.
The initial laboratory should include complete blood count, kidney and liver function.
The measurement of LDH (lactate dehydrogenase) levels is an element of particular diagnostic value, since it is a marker of cell proliferation and is also used as a prognostic element.
B-2-microglobulin has been shown to be a predictor of response and, at the same time, a marker of treatment failure, which is why it is currently used by most centers to monitor patients already treated.
Positron Emission Tomography with Fluorodeoxyglucose (FDG-PET or PET-Scan) has been shown to have a high sensitivity to detect residual masses, especially for patients with high-grade lymphomas, therefore, it has an undeniable value for monitoring early treatment. A normal PET-Scan at the end of treatment correlates with a very good prognosis for the patient.
An evaluation of the cerebrospinal fluid (CSF) should be performed in patients with high-grade lymphomas and in those with extranodal location, since the presentation of these forms is usually complicated at the beginning or at relapse with CNS involvement.
The clinical presentation of patients with Lymphomas is highly variable.
Histology, morphology, immunostaining, and cytogenetics are major determinants for defining treatment and evaluating the prognosis of each subtype.
Some patients with indolent lymphomas can stay for a long time with minimal or even no treatment. On the other hand, survival in aggressive lymphomas should be measured in weeks, as long as aggressive therapy is not started quickly.
The staging of lymphomas continues to be of vital importance in defining treatment. For this, the Ann-Arbor Classification is used, which is based on compromised sites, the presence or absence of B symptoms, and extranodal involvement. (Table II)
On the other hand, as in Hodgkin's lymphomas, the IPI (International Prognostic Index) is used, based on a few clinical markers that have been determined as independent predictors of survival, namely:
- Age:> 60 years (unfavorable)
- Ann-Arbor stage: III or IV (unfavorable)
- Hemoglobin level: <12 (unfavorable)
- No. of compromised areas:> 4 (unfavorable)
- Serum LDH: Elevated (unfavorable)
On the basis of histology, immunology, cytogenetics, staging and IPI, today it is possible not only to choose the best therapeutic option for each subgroup, but also to predict with a certain degree of accuracy, what will be the medium and long-term evolution of each patient
Non-Hodgkin Lymphomas generally respond to most treatment modalities, including radiation therapy, single or combination agent chemotherapy, immunotherapy, or radio-immunotherapy with significant remission rates.
Despite this, non-Hodgkin's lymphomas are, to this day, incurable diseases, and therefore, taking into account the previous concept, it is logical to anticipate that relapses are the rule of this pathology after an acceptable level of response initial.
Surgery here has a role limited to obtaining specimens for biopsy or special situations such as digestive tract lymphomas when the disease is localized or there is a risk of perforation, or in the case of testicular lymphomas.
Radiation therapy also has a limited role as therapy, but plays an important role in localized disease (spine) or in alleviating symptoms.
In this way, chemotherapy has become the most important therapeutic modality, especially polychemotherapy, conjugated in recent years with immunotherapy and lately with radio-immunotherapy, which has awarded it an important benefit in terms of total survival and survival free of disease.
For the purposes of this chapter, the detail of each therapeutic scheme used is escaped, but it should be mentioned that for most B lymphomas, the CHOP (Cyclophosphamide-Vincristine-Doxorubicin-Prednisone) regimen is used associated with a monoclonal antibody (anti-CD20). called Rituximab.
There is an increasing number of substances with increasingly specific activity against certain epitopes of neoplastic cells, which adds a very interesting seasoning to the treatment scheme to be used.
It should be noted that all these new treatments are extremely expensive, which requires being very precise when diagnosing each subtype.
In the case of T lymphomas, the development of new therapeutic strategies is considerably more delayed than in B lymphomas, perhaps because of their lower frequency, perhaps because of their worse prognosis in general or perhaps because the different biology of T cells, Unknown for a long time, it requires a greater research effort, which the pharmaceutical industry is not willing to face in relation to the number of cases.