[The relationship between Sjogren's syndrome, systemic sclerosis and lymphoproliferative diseases].

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature. AIM: To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs). MATERIALS AND METHODS: In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD. RESULTS: Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs. CONCLUSION: pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

[Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers].

OBJECTIVE: To determine the genetic forms of follicular cell thyroid carcinoma (FCTC) (papillary and follicular thyroid carcinoma (PTC and FTC)), to identify criteria to individually predict the development of the same disease for relatives, and to assess the role of molecular markers in the diagnosis, prognosis, and treatment of this disease. SUBJECTS AND METHODS: One hundred and ninety adult patients aged 20 to 84 years with histologically verified PTC and FTC and 20 children (12 patients with PTC and 8 with benign thyroid tumors) aged 2 to 16 years were examined. To assess the role of the BRAF gene as a molecular marker for thyroid carcinoma, DNA was isolated from the thyroid tumor tissue of 29 patients, which had been obtained by fine-needle aspiration biopsy (FNAB) and scraping and swabbing the cytological specimen previously showing an area containing tumor cells. A BRAF c.1799T>A (p.V600E) mutation in the FNAB specimens was tested by allele-specific ligation, followed by PCR amplification. RESULTS: The examinees' families were found to have a segregation of benign thyroid tumor and nontumor diseases (13.6%). Neoplasias of different sites were observed in 15% of the patients' relatives. Multiple primary tumors were detected in 6.1% of the patients and in 25% of the examined children (3/12). PTC was ascertained to accumulate as two clinical forms in the families. One form belongs to familial PTC (FPTC) in which two or three generations of relatives in the family are afflicted by only PTC and have a more severe phenotype of the disease. The other includes an association of FPTC with papillary kidney cancer. Furthermore, FPTC and PTC may be a component of multitumor syndromes, such as multiple endocrine neoplasia type 1, Cowden syndrome, and familial adenomatous polyposis. The familial hereditary forms of FCTC were generally revealed in 4.2% of the patients. BRAF v600E mutations were found in only 3 patients with Stages II and III PTC and were not in all the 12 children with PTC. CONCLUSION: The found clinical manifestation of the hereditary forms of FCTC permits the identification of people at high risk for this disease. No correlation between somatic BRAF mutations with a less favorable course in PTC can be noticed because there are few observations. Analysis of published data on the role of molecular markers in FCTC has shown that the existing specific somatic changes complement information in the differential cytological diagnosis when examining FNAB specimens.

[Differential diagnosis of rheumatic diseases and blood cancers involving the nasal cavity and accessory sinuses].

AIM: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS). SUBJECTS AND METHODS: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis. RESULTS: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD. CONCLUSION: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4-RD.

[Morphological features of pulmonary and thymic carcinoid tumor].

Morphological features of atypical and typical subtypes of pulmonary and thymic carcinoid tumors have been studied by pathohistological, immunohistochemical and electron-microscopic methods. There are the main principles of differential diagnostics in the article.

[Choosing combined or complex treatment approach in oral SCC patients].

The aim was to determine the different regiments of adjuvant therapy after radical surgery in patients with oral cancer based on the prognostic factors. 2-years disease-free survival in group with adjuvant chemoradiotherapy was 71.4%; in the adjuvant radiotherapy group - 66.2%. The neoadjuvant chemoradiotherapy demonstrated only 57% 2-years disease-free survival. Our results demonstrate that adjuvant radiotherapy or chemoradiotherapy combined with cisplatin is more effective in treatment of the patients with oral cancer.

[Importance of proliferative potential (as the ratio of a proliferative cells number and duration of mitosis) in diagnoses of malignant degree and prognosis of adrenocortical cancer].

The aim of research has been the estimation of a proliferative potential as simultaneous detection of a proliferative cells number (Ki-67 index) and duration of mitosis (nucleolar argyrophilic protein expression--B23/nucleophosmin and C23/nucleolin) at patients with adrenocortical cancer. In according to lifetime of patients after operation 2 groups had been sorted out. The first one included patients surviving 56.12 months, the second one--9.25 months. We've found out that different aspects of tumor diagnosis as well distinction of benignant or malignant tumor growth, a malignant degree of tumors, a prognostic criteria of illness, survival of patients etc. must be characterized by total research both a proliferative cells fraction (Ki-67 index) and a rate of mitosis (expressions of B23/nucleophosmin and C23/nucleolin).

[Interdigitating dendritic cell sarcoma].

The paper presents a case of the extremely rare tumor--interdigitary dendritic cell sarcoma in a 47-year-old woman with buccal soft tissue lesion that has been immunohistochemically and electron microscopically verified.

[Prognistic value of a study of the expression of argyrophilic nucleolar organizer region associated proteins in case of papillary thyroid cancer].

The prognosis in papillary thyroid cancer (PTC) is usually good. Ten-year survival can be seen in 90-98% of patients. Immunohistochemical study (antigen K-67) ascertained that a female patient with PTC had a low number of proliferating cells, which is usually seen in the favorable course of the disease. However, in the presented case, PTC was highly aggressive and showed a significant invasive growth, provided regional and distant metastases, rapidly progressed and, despite the performed surgical treatment, the patient died due to disease progression 3 months after surgery. This discrepancy between the number of proliferating cells and the aggressive course of PTC should be explained by the high expression of argyrophilic nucleolar organizer region associated proteins nucleofozmin and nucleolin, detected by immunohistochemical study, which is known to cause an increase in the rate of a mitotic cycle rate and to promote intercellular adhesion and enhancement of invasive growth and metastatic spread. Various factors involved in the regulation of proliferation of cells and their capacity for invasion and metastasis should be studied to make the most objective estimation of the degree of malignancy of a tumor and its prognosis.

[Diagnostic value of study of bone marrow trepanobiopsy imprints in patients with non-Hodgkin's lymphomas].

Bone marrow (BM) trepanobiopsy imprints were studied in 85 patients with non-Hodgkin's lymphomas (NHL) and they were compared with aspirates. All the patients were divided into 2 groups, depending on the presence (n=17) and absence (n=65) of BM lesion established on the basis of the data of histological and immunohistochemical studies of trepanobiopsy specimens. The trepanobiopsy imprints allow one to more clearly evaluate BM cellularity and to determine peripheral blood dilution. The composition of myelograms in the imprints was similar to that of aspirates. Histologically verified BM lesion was observed in the imprints of 16 patients and less frequently in the aspirates of 14 patients. Studies of trepanobiopsy imprints present a means of reading the myelogram and reveal BM lesion more rapidly than a histological finding is obtained.

[Immunohistochemical diagnosis of metastases of small round cell carcinomas with undetected primary focus].

17 small round cell tumors of unkown primary site were studied. The main location was lymph nodes and brain. Immunohistochemical study was performed. One of the following diagnosis was obtained in 14 cases (82.4%): small cell carcinoma, Merkel cell carcinoma, melanoma, Ewing sarcoma family tumor. In other three cases (17.6%) tumor histogenesis was not determined definitively.

[Askenazi (Hurtle) cell tumors of the thyroid].

Oncocytic adenomas have primarily follicular structure; trabeculas, solid areas, necrosis are rare. They may possess malignant potential as their malignant transformation occurs in 35% cases against 5% in adenomas of follicular cells. Oncocytic follicular carcinomas can be hardly distinguished from oncocytic adenomas. Tumors larger than 4-5 cm in diameter are considered to be malignant. Main difference with adenomas is invasion into the capsule surrounding thyroid or into the vessels. They can be well or poorly differentiated or anaplastic. Oncocytic papillary carcinoma and oncocytic medullary carcinoma are rare. The clinical course of oncocytic tumors is more aggressive than that of tumors from follicular cells. Of key importance in differential diagnosis is electron microscopy (EM) and immunohistochemistry with antimitochondrial antibodies. EM may be also useful in determination of the degree of oncocytic tumors maturation.

[Insullar cancer. Diagnosis and place in the structure of thyroid carcinoma].

15 cases of thyroid insullar carcinoma in patients aged from 10 to 65 years are described. It is shown that the tumor has aggressive histological signs and represents a prognostically important form of thyroid carcinoma.

[Effect of vaccination of mice with endogenous retrovirus on the development of tumors induced by gamma-irradiation or 7,12-dimethylbenz[a]anthracene]. / Vliianie vaktsinatsii myshei éndogennym retrovirusom na razvitie opukholei, indutsirovannykh gamma-oblucheniem ili 7,12-dimetilbenz[a]antratsenom.

Mouse vaccination with alive endogenous N-tropic virus OA-3 inhibited and decreased the development of the Rauscher leukemia in C57B1/6 mice (B-type) and SWR mice (N-type) as well as the development 7,12-dimethyl benzanthracene (DMBA)-induced tumours in mouse hybrids (neither N-, nor B-types). The effect of vaccination was DMBA- or MLV-P-dose-dependent. Vaccination with the same virus did not affect the incidence of gamma-irradiation-induced leukemia in CBA mice (N-type) and C57B1/6 mice while it increased twice the incidence of radiation leukemia in DBA mice (N-type). However, the incidence of thymomas lowered in radiation leukemia-bearing vaccinated mice of all the 3 strains, which may result from inhibition of murine thymotropic endogenous virus reproduction. The data obtained indicate the participation of murine own endogenous viruses in DMBA- or gamma-irradiation induced carcinogenesis.

[Study of the vaccinating properties of 2 variants of Marek's disease virus]. / Issledovanie vaktsiniruiushchikh svoistv dvukh variantov virusa bolezni Mareka.

The vaccinating properties of two variants of Marek's disease virus, Kekava strain (MDV-Kekava) have been studied. One of them is naturally attenuated, the other has been produced as a result of attenuation of the pathogenic MDV-Kekava by long-term passages in chick embryo fibroblast (CEF) culture. The vaccinating properties of the naturally attenuated strains (MDV-Kekava 83) were first studied in an experiment in which the blood of chicken No. 1683 was used as the vaccine. In paralled. the MDV-Kekava 83 variant was isolated from the blood of this chicken in CEF culture. Vaccination of chickens with the blood of this chicken as well as with 1000-3000 PFU MDV-Kekava 83 which had undergone 16, 24, 45, and 46 passages in vitro produced in the chickens resistance to Marek's disease. According to the combined data of 4 experiments, altogether 9 out of 101 vaccinated chickens developed Marek's disease. Among the controls inoculated with the pathogenic MDV alone 51 out of 137 chickens developed the disease. Attenuation of the pathogenic MDV-Kekava 55 in CEF culture occurred very slowly. The virus of the 45th passage in vitro had no vaccinating properties. Vaccination of the chickens with 1000-2500 PFU MDV-Kekava 56 which had undergone 73 a94 passages in CEF culture produced resistance to Marek's disease. Among the vaccinated chickens 20 out of 113 had Marek's disease whereas in the control group 74 out of 122 were observed to develop the disease. Among the chickens vaccinated with MDV, 3-4% developed the disease. Possible causes of the disease in this group of chickens are discussed.

[Sinus histiocytosis with massive lymphadenopathy]. / Sinusnyi gistiotsitoz s massivnoi limfadenopatiei.

A case of sinus histiocytosis with massive lymphadenopathy in a boy of 13 with multiple subcutaneous tumor-like formations 0.5 to 2.5 cm in diameter is described. The general condition of the patient was not changed despite the 7-month course of the disease. Mild anemia and increased ESR were observed. Microscopically the formations presented massive "dense" infiltrates of lymphoid, plasma cells, and histiocytes-macrophages with foci of fibrosis and xanthomatosis. Since the morphological picture of sinus histiocytosis with massive lymphadenopathy may to some extent imitate the substrate of some tumor diseases of the hemopoietic and lymphoid tissues (malignant histiocytosis, histiocytosis X, lymphogranulomatosis, lymphosarcoma), their differential diagnosis is presented.

[Malignant histiocytosis in children (pathologicoanatomic study of 16 cases)]. / Zlokachestvennyi gistiotsitoz u detei (patologoanatomicheskoe issledovanie 16 sluchaev).

Malignant histiocytosis is a rare neoplastic disease from the group of acute leukemias. Morphological characteristics of the disease are presented on the basis of histological, histochemical, and electron microscopic examinations of section materials from 16 cases of malignant histiocytosis in children of 6 to 14 years. Systemic focal-diffuse proliferation of tumor cells of histiocytic type of various degrees of differentiation was observed in organs and tissues. Most frequently, typical macro- and/or microscopic lesions were detected in lymph nodes, bone marrow of vertebrae, flat and tubular bones, liver, and spleen. The histiocytic nature of tumor cells was judged primarily from such signs as their capacity for phagocytosis detectable by light and electron microscopy, high diffuse cytoplasmic activity on nonspecific esterase and acid phosphatase, and features of the ultrastructure. In the establishment of the diagnosis, malignant histiocytosis had to be differentiated from Letters-Siwe disease, sinus histiocytosis with massive lymphadenopathy, lymphogranulomatosis, immunoblastic lymphosarcoma, melanoma, undifferentiated cancer.

[Histiocytic proliferative diseases]. / Gistiotsitarnye proliferativnye zabolevaniia.

Proliferation of the mononuclear phagocyte system cells is the basis for histiocytic proliferative conditions (malignant histiocytosis, histiocytic "reticulosarcoma" histiocytosis X). Cells of the phagocytosing histiocyte type proliferate in malignant histiocytosis and histiocytic "reticulosarcoma), cells of the Langerhans type proliferate in histiocytosis X. According to Rappaport's classification of 1966, histiocytic "reticulosarcoma" is separated from the heterogeneous group of diffuse histiocytic lymphomas. Its morphological picture is non-distinguishable from that of malignant histiocytosis, particularly at the stage of generalization. The Letterer-Siwe disease due to its course, prognosis and special therapeutical approach should be separated from the group of conditions combined under the term "histiocytosis".

[Lymphomatoid granulomatosis: pathologoanatomical study of three cases with a review of the literature and differential diagnosis]. / Limfomatoidnyi granulematoz: Patologoanatomicheskoe izuchenie trekh sluchaev s obzorom literatury i differentsial'noi diagnostikoi.

Evidence obtained at pathological investigation concerns 3 cases of lymphomatoid granulomatosis. The disease pertains to lymphoproliferative affections and is of rare occurrence. In addition to common involvement of the lungs, liver, kidneys, spleen, adrenals, etc., there was an advanced lymph node and brain lesion with abundant atypical cells in the infiltrate in the first and third case, respectively. The diagnosis rested on autopsy findings in 1 case and was intravital, established upon morphological examination of intraoperative specimens in 2 cases. Samples obtained at bronchoscopy are not fit for verification of the diagnosis in view of profound necrotic and necrobiotic processes in lymphomatoid granulomatosis.

[Diagnosis of papillary thyroid carcinoma]. / K diagnostike papilliarnogo raka shchitovidnoi zhelezy.

The cells of papillary thyroid carcinoma are shown to have the following characteristic morphological features: oval or oval to roundish shape of nuclei, uneven sinuous, folded border of the nuclear membrane, nuclear fissure, intranuclear cytoplasmic inclusions, optically clean nuclei. None of these features is a marker, only combination of more than four of them represents diagnostic value.

[Erythrophagocytic histiocytosis syndrome in a child with a primary immunodeficit]. / Sindrom éritrofagotsitarnogo gistotsitoza u rebenka s pervichnym immunodefitsitom.

The authors described a case of the syndrome of erythrophagocytic histiocytosis in an infant with primary immune deficiency who died at the age of 11 months and 20 days. Microscopic examination revealed focal and diffuse histiocyte proliferation in the bone marrow, lymph nodes, liver, and lung. Histiocytes were found to actively phagocytize erythrocytes and hemosiderin. The changes in the thymus were regarded as congenital primary unclassifiable immunodeficiency. The differential diagnosis of the syndrome was made in comparison with histiocytosis, histiocytosis X and familial erythrophagocytic lymphohistiocytosis.