Diagnosis of lymphohistiocytosis

The most important laboratory characteristics of lymphohistiocytosis are: changes in the peripheral blood picture, some biochemical parameters and moderate pleocytosis of the cerebrospinal fluid of a lymphocytic-monocytic nature. Anemia and thrombocytopenia are most often detected. Anemia is usually normocytic, with inadequate reticulocytosis, caused by intramedullary destruction of red cells and the inhibitory effect of TNF. Thrombocytopenia is a more diagnostically significant element, allowing us to assess the degree of activity of the syndrome and the activity of treatment. The number of leukocytes may vary, but leukopenia with a neutrophil level of less than 1 thousand per μl is most often detected; atypical lymphocytes with hyperbasophilic cytoplasm are often detected in the leukocyte formula.

Peripheral blood cytopenia is usually not associated with hypocellularity or dysplasia of the bone marrow. On the contrary, the bone marrow is rich in cellular elements, excluding late stages of the disease. According to G. Janka, 2/3 of 65 patients show no changes in the bone marrow or specific changes without disruption of maturation and hypocellularity. The phenomenon of hemophagocytosis is not detected in all patients, and often only repeated studies of the bone marrow and other affected organs allow detecting hemophagocytic cells.

Changes in the biochemical composition of the blood are more diverse. The dominant ones among them are the indicators characterizing disorders of lipid metabolism and liver function. Thus, disorders of lipid metabolism, detected in 90-100% of patients, are indicated by hyperlipidemia due to an increase in the level of triglycerides, an increase in the fraction of very low density prelipoproteins of type IV or V and a decrease in high-density lipoproteins, which is probably associated with the suppression of TMF synthesis of lipoprotein lipase, which is necessary for the implementation of lipid hydrolysis of triglycerides. An increased level of triglycerides is a reliable criterion for disease activity.

The frequency of hypertransaminasemia (5-10 times the norm) and hyperbilirubinemia (up to 20 times the norm), increasing as the disease progresses, is detected in 30-90% of children. Common changes characteristic of various inflammatory processes are often present, such as increased levels of ferritin, lactate dehydrogenase (LDH), hyponatremia and hypoproteinemia/hypoalbuminemia.

Of the hemostasis system parameters, a decrease in fibrinogen levels is diagnostically significant, detected in the early stages of the disease in 74-83% of children. Hypofibrinogenemia is presumably associated with increased production of plasmagen activators by macrophages. At the same time, abnormalities in coagulogram parameters that allow one to suspect DIC syndrome or a deficiency of prothrombin complex factors are usually not detected. Hemorrhagic syndrome in hemophagocytic lymphohistiocytosis is caused by thrombocytopenia and hypofibrinogenemia.

Immunological disorders are represented by a decrease in the activity of cellular cytotoxicity, primarily due to a decrease in the activity of NK cells. During remission, their function can partially normalize, but is fully restored only after BMT. In the active phase of the disease, an increased number of activated lymphocytes (CD25+HLA-DR+) and cytokines (IFNy, TNF, soluble receptors IL-2, 1L-J, C-6) are determined in the blood.

Pathomorphological changes

The morphological substrate of lymphohistiocytosis is diffuse lymphohistiocytic infiltration with hemophagocytosis, mainly in the bone marrow, spleen, lymph nodes, central nervous system, liver, and thymus.

Histiocytes carry markers of mature ordinary macrophages and have no cytological signs of malignancy or increased mitotic activity. Hemophagocytosis is the main but nonspecific pathomorphological sign of hemophagocytic lymphohistiocytosis. Histopathological assessment is difficult in 30-50% of patients due to the absence of hemophagocytosis in the early stages of the disease or its disappearance under the influence of therapy. Some authors associate the degree of lymphohistiocytic infiltration and the presence of hemophagocytosis with the patient's age and the duration of the disease.

As a rule, given the presence of cytopenia and splenomegaly, which are mandatory signs of hemophagocytic lymphohistiocytosis, bone marrow is examined in a timely manner. During the initial examination of bone marrow, hemophagocytosis is detected only in 30-50% of patients. Trepanobiopsy is mandatory in case of negative results of bone marrow puncture, but its diagnostic capabilities are also limited. At "advanced" stages of the disease, the cellularity of bone marrow is noticeably reduced, which can be mistakenly interpreted in favor of aregenerative blood diseases or taken as a side effect of chemotherapy.

Hemophagocytosis is also rarely detected in lymph nodes, with the exception of late stages of the disease. The diagnostic capabilities of morphological examination of the liver are quite limited: hemophagocytosis is rarely detected, proliferation of Kupffer cells is moderate, but the general histological picture, reminiscent of chronic persistent hepatitis, in the presence of other manifestations of the disease, can become an important additional criterion for hemophagocytic lymphohistiocytosis. Hemophagocytic activity is almost always detected in the spleen, but due to technical difficulties, spleen biopsy is performed extremely rarely.

With fairly vivid and frequent neurological symptoms, its morphological basis is usually represented by lymphohistiocytic infiltration of the meninges and brain matter. In itself, it is devoid of any specific signs. Hemophagocytosis is not always pronounced; in particularly severe cases, multiple foci of brain matter necrosis are detected without pronounced vascular occlusion.

In other organs, the picture of hemophagocytosis is rarely detected.

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Diagnostics

As shown above, it is extremely difficult to objectify the presumptive diagnosis of hemophagocytic lymphohistiocytosis. The difficulty of diagnosis is associated with the lack of specific clinical and laboratory symptoms. Establishing a diagnosis requires a scrupulous comprehensive assessment of all anamnestic, clinical, laboratory and morphological data.

Given the lack of pathognomonic signs of the disease, the International Society for the Study of Histiocytic Diseases proposed the following diagnostic criteria (1991).

Diagnostic criteria for hemophagocytic lymphohistiocytosis, 1991.

Clinical criteria:

1. Fever over 7 days > 38.5 degrees.
2. Splenomegaly 3 or more cm from under the costal margin.

Laboratory criteria:

1. 1. Peripheral blood cytopenia with damage to at least 2 germs in the absence of hypocellularity or myelodysplastic changes in the bone marrow: (hemoglobin less than 90 g/l, platelets less than 100 x 10 ⁹ /l, neutrophils less than 1.0 x 10 ⁹ /l).
2. 2. Hypertrigleciridemia and/or hypofibrinogenemia (trigleciridemia > 2.0 mmol/l; fibrinogen < 1.5 g/l).

Histopathological criteria:

1. Hemophagocytosis in the bone marrow, spleen, or lymph nodes.
2. No signs of malignancy.

Note: The diagnosis of familial hemophagocytic lymphohistiocytosis is established only in the presence of a family history or in consanguineous marriages.

Comments: the presence of mononuclear pleocytosis in the cerebrospinal fluid, histological picture in the liver of the chronic persistent hepatitis type and decreased activity of natural killers can be used as additional criteria. Other clinical and laboratory signs, which in combination with other symptoms may indicate in favor of the diagnosis of hemophagocytic lymphohistiocytosis, are the following: neurological symptoms of meningoencephalitis type, lymphadenopathy, jaundice, rash, increased liver enzymes, hyperferritinemia, hypoproteinemia, hyponatremia. If manifestations of hemophagocytosis are not found, it is necessary to continue the search for morphological confirmation. Accumulated experience shows that if puncture and/or trephine biopsy of bone marrow are not diagnostic, it is necessary to perform a puncture biopsy of another organ (spleen or lymph node), and repeated bone marrow studies are justified to confirm the diagnosis.

According to these diagnostic criteria, 5 criteria are required to diagnose primary hemophagocytic lymphohistiocytosis: fever, cytopenia (in 2 of 3 lines), splenomegaly, hypertriglyceridemia, and/or hypofibrinogenemia, and hemophagocytosis. A positive family history or consanguineous marriage is required to confirm the familial form of the disease.

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Differential diagnostics

The range of diseases differentiated from hemophagocytic lymphohistiocytosis is quite large. These are viral infections, bacterial infections, leishmaniasis; blood diseases - hemolytic and aplastic anemia, myelodysplastic syndrome, combined immunodeficiencies. Hemophagocytic lymphohistiocytosis can also occur under the guise of severe CNS lesions.

In differential diagnosis with histiocytosis and other types, the most attention should be paid to the variant of Langerhans cell histiocytosis, which occurs with multisystem lesions. Both hemophagocytic lymphohistiocytosis and the multisystem variant of hemophagocytic lymphohistiocytosis affect infants and young children, but there is always no family history with hemophagocytic lymphohistiocytosis. Of the clinical differences, the most characteristic are bone lesions in hemophagocytic lymphohistiocytosis, which are never found in hemophagocytic lymphohistiocytosis, and a characteristic rash (like seborrhea), which also does not occur with lymphohistiocytosis. CNS damage, which occurs in 80% of cases with hemophagocytic lymphohistiocytosis, is extremely rare in hemophagocytic lymphohistiocytosis. One of the most reliable differences in PHHLH and LCH is the morphological and immunohistochemical characteristics. In the infiltrate in hemophagocytic lymphohistiocytosis there is monoclonal proliferation of CL, there is no admixture of lymphocytes and histiocytes, as well as signs of lymphoid atrophy and hemophagocytosis. The cells contain CDla antigen, S-100 protein, Brenbek granules.

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