Hodgkin lymphoma in pregnancy is a malignant lymphoproliferative disease with damage to B—lymphocytes of lymph nodes, lymphoid structures and extranodular tissues, transferred before gestation, occurred or recurred during pregnancy. It is manifested by an increase in lymph nodes, causeless fever, night sweating, weight loss, weakness, itching, signs of compression of various organs. It is diagnosed by MRI, ultrasound, chest X-ray, lymphoid tissue biopsy. Mono- or polychemotherapy is used for treatment, supplemented by irradiation of the affected areas.
C81 Hodgkin disease [lymphogranulomatosis]
In the structure of malignant neoplasms detected in pregnant women, Hodgkin lymphoma in pregnancy(lymphogranulomatosis, malignant granuloma, Hodgkin disease) ranks fourth. The disease is detected with a frequency of 1:1,000 — 1:6,000 pregnancies and affects mainly young Caucasian women aged 20-29 years. The use of modern methods of treatment of hemoblastosis with the achievement of stable remission or complete recovery has led to an increase in the number of situations when patients who have previously undergone lymphogranulomatosis come under the supervision of obstetricians and gynecologists. At the same time, the risk of recurrence of lymphoma in pregnant women with complete remission lasting more than 3 years is 9%, and in patients who became pregnant less than 3 years after the end of therapy reaches 44%.
The etiology of Hodgkin lymphoma in pregnancy has not been definitively established. Most specialists in the field of hematology, obstetrics and gynecology do not consider gestation to be the cause or provoking factor in the occurrence or recurrence of Hodgkin disease. The local transformation of B cells, characteristic of malignant granuloma, can probably be triggered by the action of factors such as:
- Infection with Epstein-Barr viruses. In 40-70% of cases, EBV-positive B-cell lymphoma. The pathogen is a type 4 herpesvirus (HHV4), is tropic to B-lymphocytes, as a result of long-term latent persistence, it is able to have a transformative effect on immune cells with the expression of membrane proteins and the triggering of apoptosis mechanisms. Some authors also name Mycobacterium tuberculosis, type 6 herpesviruses, and HIV among the pathogens that cause oncotransformation of B cells.
- Exposure to mutagens. In EBV-negative forms of lymphoma, the influence of other adverse environmental factors is not excluded. Gene aberrations that contribute to the malignancy of lymphoid tissue can occur under the influence of occupational hazards (work with industrial poisons), chemo- and radiation therapy, some medications (phenytoin and analogues). Presumably, a number of patients may have a genetically inherited defect of tumor transformation and growth containment systems.
The likelihood of B-cell lymphoma increases when taking immunosuppressants after organ transplantation. The risk group also includes pregnant women with congenital immune disorders (Wiskott-Aldrich disease) and autoimmune disorders (rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, celiac disease).
The mechanism of development of Hodgkin lymphoma in pregnancy is similar to oncogenesis occurring outside the gestational period. Under the influence of Epstein-Barr viruses and other mutagenic factors, a number of immunohistochemical processes occur that allow degenerated B cells to avoid apoptosis and cytolytic action of T-killers, to suppress the immune response of the tissue microenvironment to neoplasia. According to most oncogematologists, germinative lymphoid B-cells that originate from the germinal center of the follicle of the lymph node undergo degeneration.
The pathogenesis of Hodgkin disease is represented by complex changes at the level of transcription factors, TNF proteins, chemokines, cytokines. The loss of regulatory mechanisms of apoptosis leads to uncontrolled reproduction of degenerated B-lymphocytes — unicellular progenitor cells of Hodgkin and giant multinucleated Reed-Berezovsky-Sternberg cells. Cancer proliferation is accompanied by deterioration of humoral immunity and a reactive response in the form of connective tissue proliferation. In most pregnant women with lymphogranulomatosis, the insufficiency of T-cell immunity progresses, which subsequently leads to the development of intercurrent bacterial, viral, fungal, protozoal infections complicated by septic conditions.
When systematizing variants of Hodgkin lymphoma in pregnancy, histological features of neoplasia, the stage of the disease, and the severity of intoxication phenomena are taken into account. This approach allows you to most accurately predict the course of malignant granuloma and offer a woman the optimal solution, taking into account the possible prolongation of pregnancy. The outcome of the disease and gestation largely depends on the type of tumor. Oncologists distinguish:
- Lymphogranulomatosis with nodular sclerosis. It is determined in 60.3% of pregnant women with malignant granuloma. The lymph nodes of the mediastinum are mainly affected, the lymphoid tissue is divided into separate sections (“nodes”) by fibrous strands. The disease usually has a favorable prognosis. Classical multinucleated and lacunar cells are determined in the preparation.
- Mixed-cell variant of Hodgkin disease. During pregnancy, it is diagnosed in 32.8% of sick patients, and proceeds less favorably. As a rule, several groups of lymph nodes in different areas are involved in the process, general clinical symptoms are expressed. Histologically it is manifested by polymorphism of cellular elements.
- Lymphoid exhaustion. A rare unfavorable variant of lymphogranulomatosis in pregnant women. It is detected in 1.4% of cases. The dissemination of cancer cells with extralymphatic damage and significant suppression of immunity is characteristic. The biopsy contains layers of malignated cells and fibrous strands, there is no normal lymphoid tissue.
Low-grade and prognostically most favorable lymphoma with lymphoid predominance (lymphohistiocytic variant of the disease) and undifferentiated types of neoplasia during gestation occur extremely rarely. When developing tactics of pregnancy support, obstetricians and gynecologists necessarily take into account the stage of the oncological process. Taking into account the number and localization of the affected areas, structures (spleen, thymus gland, lymphatic periaryngeal ring, Peyer’s plaques, appendix), extranodular tissues, severity of clinical symptoms, size of neoplasia, 4 stages of Hodgkin disease are distinguished. In general, the prognosis of pregnancy worsens as the disease progresses.
In most cases, the first sign of lymphogranulomatosis is enlarged, painless, densely elastic lymph nodes that are not soldered to surrounding tissues and can form conglomerates. In 70-75% of patients, the cervical and supraclavicular areas are affected, in 15-20% — the axillary and mediastinum, in 10% — the groin. Later, the lesion of mediastinal lymph nodes is detected, which, with a significant increase, compress the bronchopulmonary tissue, causing coughing and difficulty breathing. Generalized skin itching and transient soreness of the affected lymph nodes may occur after taking alcohol.
In 20-30% of pregnant women with Hodgkin lymphoma in pregnancy of stage III-IV, systemic general intoxication symptoms are detected — an unreasonable temperature rise of more than 38 ° C, profuse night sweats, weight loss of 10% or more, decreased appetite, weakness, which serves as a prognostically unfavorable sign. In some patients, there is heaviness and swelling in the left hypochondrium, indicating an increase in the spleen. When the liver is involved in the process, jaundice often occurs, when the vessels are squeezed by the affected inguinal and pelvic lymph nodes, the lower extremities swell. Wheezing and shortness of breath are detected in women with upper respiratory tract compression. In rare cases, neuralgia, paralysis of the upper or lower extremities with loss of motor function, impaired swallowing and speech occur.
The complicated course of pregnancy is determined in 64.7% of women with Hodgkin lymphoma. Most often, gestation is complicated by viral and bacterial infections. In 19.6% of pregnant women, herpes infection worsens, of which 10.8% have genital herpes, 9.8% often have ARVI, 8.8% have gestational pyelonephritis or relapses chronic pyelonephritis. Anemia is detected in 18.6% of patients. The threat of termination of pregnancy in one or all three trimesters is diagnosed in 30.4% of patients, gestosis — in almost 20%. The incidence of fetoplacental insufficiency is 8.8%, fetal development delay are 2.9%, neutropenia and thrombocytopenia are possible in a newborn.
Medication and radiation treatment of lymphogranulomatosis during the first 2 weeks after conception provokes spontaneous miscarriage. During organogenesis (at 2-8 weeks of gestation), drugs with low molecular weight induce congenital malformations, starting from the 3rd month of gestational age – cause fetal growth retardation. The frequency of severe multiple organ defects during polychemotherapy in the 1st trimester of pregnancy reaches 10-25%. The probability of radiation-induced genetic defects increases by 1% with every 1 G of absorbed dose of ionizing radiation. Screening of the abdominal cavity reduces the risk of mutagenesis by half. In women after chemoradiotherapy, the frequency of subsequent multiple pregnancies reaches 12%, which is 10-20 times higher compared to the general population.
With a relapse of Hodgkin lymphoma in pregnancy, the diagnosis does not present any particular difficulties. However, even in the case of a primary disease, despite the limited use of studies using ionizing radiation (computed tomography, lymphangiography), modern diagnostic methods make it possible to detect lymphogranulomatosis in time and correctly establish its stage. The most informative methods are:
- Magnetic resonance imaging. When detecting lymphadenopathy, MRI is comparable in information content to CT, but it determines the affected nodes in the mediastinum somewhat worse. Three-dimensional visualization of the organs of the thoracic and abdominal cavity, retroperitoneal space, pelvis, soft tissues, vessels makes it possible to accurately determine the prevalence of the pathological process. If necessary, an MRI of the whole body is performed.
- Ultrasound examination. Echography is the safest method of examination for a pregnant woman and fetus. Ultrasound of the abdominal cavity and retroperitoneal space is prescribed if malignant degeneration of retroperitoneal lymph nodes is suspected. To correctly determine the stage of the disease, an ultrasound of the spleen is performed, which can be involved in the oncoprocess. With a superficial location, ultrasound of the lymph nodes is performed.
- X-ray examination. Radiography of the OGC in two projections is used only with a possible lesion of the intra-thoracic (mediastinal) lymph nodes. To exclude a negative effect on the fetus, the abdominal cavity is necessarily screened. If there are indications, a CT scan of the thoracic cavity is performed without using contrast.
- Histological examination of the biopsy. Reliable markers of lymphogranulomatosis are tumor cells — single-core Hodgkin and multi-core Reed-Sternberg. Depending on the histological variant of the disease, they can be isolated, located as foci between fibrous strands or completely replace normal lymphoid tissue. Lacunar cells may also be present in the preparation.
There are usually no specific changes in the general blood test, an increase in ESR indicates an unfavorable course of the process. In the presence of extranodular symptoms of lymphoma, determination of the levels of alkaline phosphatase, AlT, AsT, creatinine, total protein, other laboratory markers of liver and kidney damage, bone marrow biopsy is indicated. Hodgkin disease in pregnancy is differentiated with viral lymphadenitis in rubella, measles, infectious mononucleosis, cytomegalovirus infection, parasitic lesions of lymph nodes (toxoplasmosis, histoplasmosis, echinococcosis, dirofilariasis, leishmaniasis), leukemia, non-Hodgkin lymphomas, tuberculosis, sarcoidosis, lung cancer. According to the patient’s indications, in addition to an obstetrician-gynecologist and an oncohematologist, an infectious disease specialist, a phthisiologist, a pulmonologist, an oncologist, a gastroenterologist, a neurologist, a neonatologist are consulted.
When choosing therapeutic tactics, the aggressiveness of neoplasia, gestational age, and the patient’s desires are taken into account. Regardless of the form and stage of the tumor, one of three possible solutions can be taken: termination of pregnancy, a wait-and-see approach, active antitumor drug-radiation treatment according to general principles. In accordance with the recommendations of the Ministry of Health and Social Development of USA, medical abortion up to 12 weeks is recommended for patients with stage 3-4 lymphoma. At a later date, with an aggressive course of the oncoprocess, the issue of gestation termination is decided by a consultation, taking into account the opinion of the pregnant woman and her relatives.
With indolent (slowly progressing) nodular sclerosis of stages IA-IIA, it is possible to successfully manage most patients without prescribing treatment for some time. In such cases, pregnancy is prolonged until the fetus reaches viability, regular ultrasound or MRI monitoring is provided, and therapy for Hodgkin disease is postponed until the II-III trimesters and even for the postpartum period. Women with a massive lesion, the presence of general clinical B-symptoms, extranodular lesion, subdiaphragmatic spread of the process, rapid progression of lymphogranulomatosis are prescribed:
- Chemotherapy. Before the second trimester, monochemotherapy with alkaloid cytostatics is preferred. Next, the ABVD protocol is applied without alkylating drugs or CHOP-like modes. With refractory forms of Hodgkin disease and relapse of the disease after the first trimester, it is possible to prescribe more active MOPP and MOPP-like schemes. Myelosuppressive treatment should be completed no later than 3 weeks before the expected delivery.
- Radiotherapy. Usually, radiation therapy is postponed until the end of gestation, but no longer than 9 weeks after the last chemotherapy. With clinically diagnosed chemoresistant lymphogranulomatosis or the impossibility of chemotherapy, mantle-shaped or mini-mantle-shaped fields are irradiated, the fetus is protected with a lead apron. The total dose received should not exceed 10 grams.
- B-cell lymphoma is not an indication for surgical delivery. In the absence of obstetric contraindications, pregnancy is completed by natural childbirth. Spinal and epidural analgesia are contraindicated in patients with severe post-chemotherapeutic thrombocytopenia (less than 100 ×109/l) due to the increased risk of puncture hematomas. Caesarean section can be performed in the presence of complications of antitumor therapy — post-radiation cardiofibrosis, cardiopulmonary insufficiency of II-III degree, pathological fractures of the lumbar vertebrae, aseptic necrosis of the hip joint. Breast-feeding is not contraindicated for patients in remission, with active lymphoma, lactation is recommended to be suppressed.
Prognosis and prevention
According to studies, gestation and its preservation do not affect the course of lymphogranulomatosis. The use of polychemotherapy alone or in combination with radiation therapy makes it possible to achieve a cure in 70-80% of pregnant women with newly diagnosed Hodgkin lymphoma. Prognostically unfavorable signs are massive lesion of mediastinal lymph nodes, involvement of 3 or more areas (lymphoid structures) in the process, the presence of extralymphatic lesions, significant acceleration of ESR (in the absence of general clinical symptoms — over 50 mm / h, and in their presence — over 30 mm/ h).
Patients who have received anti-lymphogranulomatous treatment are advised to refrain from conception for 3 years after completion of therapy. Menstrual function, which is often disrupted after the use of chemotherapy drugs, usually recovers in 2-3 years. If the patient was prescribed protocols using high doses of glucocorticoids, it is advisable to perform densitometry before the planned pregnancy to exclude osteopenia or osteoporosis. Pregnant women treated for malignant granuloma are considered to be at high obstetric risk. After being registered in a women’s clinic, they should be examined at least 12 times by an oncohematologist (oncologist). Due to insufficient knowledge of the etiology, no special measures for the prevention of Hodgkin disease have been proposed.