Vol 48, No 2 (2020)

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Full Issue


In remembrance of Irina A. Kazantseva (02.09.1938 – 27.02.2019)


Almanac of Clinical Medicine. 2020;48(2):75-77
pages 75-77 views


Key VEGF signaling system components and matrix metalloproteinases in the diagnosis and prognosis of overall survival of patients with renal cell cancer

Kushlinskii N.E., Gershtein E.S., Kolpakov A.V., Bezhanova S.D., Mushtenko V.V., Korotkova E.A., Pushkar D.Y., Bazaev V.V.


Background: Evaluation and search for new molecular markers of renal cell cancer, first of all, associated with angiogenic and invasive activity, continue to be highly relevant. In our previous publications, we have assessed the potential diagnostic value of matrix metalloproteinases (MMP) 2, 7, 8, and 9, their tissue inhibitor type 1 (TIMP1) and components of the VEGF signaling system in renal cell cancer. Aim: To assess the role of serum VEGF, VEGFR1, VEGFR2, MMP2, 7, 8, 9, and TIMP1 levels in renal cell patients as diagnostic and prognostic markers of overall survival. Materials and methods: 99 renal cell cancer patients (94 primary and 5 at progression) were recruited into the study. The control group included 97 healthy control blood donors. Ninety three (93) primary patients with renal cell cancer were followed for 1 to 45 (median, 26) months for assessment of their overall survival. Serum concentrations of the study proteins were measured by direct immunoenzyme analysis (Quantikine® ELISA kits, R&D Systems, США). Results: Serum VEGF, VEGFR1, VEGFR2, MMP7, MMP8, and TIMP1 levels in renal cell cancer patients are significantly higher than those in the control group. The diagnostic characteristics of the markers are considerably different, the most reliable marker with 84% sensitivity at 87.5% specificity being MMP7. VEGFR1, MMP7, MMP8, and TIMP1 were positively associated with disease stage and TNM indices. MMP7 and TIMP1 levels also increased with a higher tumor grade. MMP7 was found to be a significant unfavorable prognostic factor for overall survival: the 3-years survival in those with low (< 6.3 ng/ml) marker level amounted to 93%, whereas with high, 51% (p < 0.001). MMP7 prognostic value remained significant also in stage I renal cancer: after 3-years' follow-up, all patients with low MMP7 were alive, while survival of those with high marker levels was 72% (p=0.02). Increased serum MMP8 level (> 51 ng/ml) also had an unfavorable prognostic value in the whole renal cell cancer patient group, with 3-years' survival being 78 and 58% for low and high levels, respectively (p < 0.01). The components of VEGF signaling system, MMP2, MMP9, and TIMP1 had no significant prognostic values. Conclusion: MMP7 should be viewed as the most promising diagnostic and prognostic renal cell cancer marker. VEGF and its soluble receptors could be useful for monitoring of patients receiving anti-angiogenic treatments and prediction of their sensitivity to these agents.

Almanac of Clinical Medicine. 2020;48(2):78-83
pages 78-83 views

The pathological anatomy of alcoholic disease

Paukov V.S., Erokhin Y.A.


The problem of alcohol abuse is high on the agenda for the whole world both medically and socially. However, the fight against this disease is less than effective, mostly due to the fact that its solution has been left to psychiatrists and experts in narcology. They are making attempts to treat alcoholism, a disease which results from long-term, chronic alcohol intoxication and alcohol dependence. What is missed here is a long period of excessive use of hard drinks characterized by alcohol cravings with no alcohol dependence; this period is called “excessive alcohol consumption”. Based on the results of 1113 autopsies of patients aged 18 to 73 years who died at home or in a hospital, the authors propose the concept of the alcohol disease, whose pathogenesis consists of 3 stages: stage 1, episodic alcohol intoxication, stage 2, excessive alcohol drinking, and stage 3, alcoholism and its complications. The article describes the changes over time that can be found in the liver, vessels and other organs. The authors emphasize that the formation of Mallory bodies (auto-antigens), mainly in the stage of alcoholism, triggers an irreversible autoimmune inflammatory reaction explaining an extremely poor effect of alcoholism treatment. In this regard, excessive alcohol drinking is being suggested as a separate stage, which should be treated by internists.

Almanac of Clinical Medicine. 2020;48(2):84-93
pages 84-93 views

Clinical and morphological analysis of dysplasia in Barrett's esophagus and columnar-lined esophagus

Mikhaleva L.M., Voytkovskaya K.S., Fedorov E.D., Birukov A.E., Gracheva N.A., Shegoleva N.N., Chigrai L.V., Shidii-Zakrua A.V.


Background: Barrett's esophagus (BE) is a precan-cerous disease of the esophagus. The risk of adenocarcinoma in BE patients increases with the extension of segment length and with the presence of dysplasia. Columnar-lined esophagus (CLE) devoid goblet cells is also associated with dysplasia and adenocarcinoma, however, with a lower risk. Aim: To perform clinical and morphological analysis of patients with BE with goblet cells and CLE devoid goblet cells on the presence or absence of dysplasia. Materials and methods: This prospective clinical morphological study included 78 patients with columnar-lined esophagus at EGDS, among them 20 patients with a long segment, 58 patients with a short segment. Biopsy specimens from the CLE area of the distal part of the esophagus were stained by hematoxylin and eosin and standard PAS-reaction with Alcian blue. Histological examination showed BE with goblet cells in 49 patients and CLE devoid goblet cells in 29 patients. In those with BE, the morphometric analysis of the goblet cells density was performed and the number of the affected crypts was counted in dysplastic fragments. Results: In the short segment group, the male to female ratio was ~ 1:1.1, and CLE devoid goblet cells was found in 53% of cases (27/58 patients), and BE with goblet cells in 57% of cases (31/58 patients). In the long segment group, the male to female ratio was ~ 2.3:1, along with predominance of BE with goblet cells cases (18/20 patients, 90%) and high density of goblet cells (11/18 patients, 61%). The rates of goblet cells detection increased with the extension of the segment length (p < 0.05). The relative goblet cells density in the patients with the long BE segment was also significantly higher than in the short segment group (p < 0.001). Advanced inflammatory infiltration was found in 22 of 58 (38%) cases with the short segment and in 13 of 20 patients with the long one (65%, p = 0.012). The rates of erosion in the long segment group were 1.62-fold higher and ulcerations 3.87-fold higher (p = 0.014). Esophageal dysplasia was identified in 10 of 20 cases (50%) with the long segment and in 2 of 58 cases (3.4%) with the short segment. In 10 of 12 cases (83.3%) dysplasia was multifocal and involved from 2 to 10 crypts (in total, up to 25 crypts). Conclusion: The long segment of metaplasia was associated with higher rates of active chronic esophagitis, higher presence of goblet cells and their higher density. Dysplasia was found in 10 patients with three and more risk factors of progression (male gender, long segment, hiatal hernia, etc.). In most cases, the biopsy samples showed multiple foci of dysplasia.

Almanac of Clinical Medicine. 2020;48(2):94-101
pages 94-101 views

Specifics of type IV collagen expression in basal cell skin carcinoma

Khlebnikova A.N., Belova L.A., Gurevich L.E., Selezneva E.V., Sedova T.G.


Rationale: Type IV collagen is the main component of the basal membrane ensuring its integrity. Basal membrane destruction is associated with absent type IV collagen expression being directly related to an increased tumor invasion risk. Specifics of the protein expression in various morphological types of basal cell carcinoma have not been well described. Aim: To study the association between type IV collagen expression and basal cell carcinoma morphological structure and invasion potential. Materials and methods: We performed an immunohistochemistry analysis with anti-type IV collagen antibodies on 30 biopsy specimens of the skin involved with basal cell carcinoma. Results: The superficial multicentric type of basal cell carcinoma differed from the solid, micronodular, and infiltrative types by linear continuous type IV collagen expression (р < 0.0083). Most often, there was no type IV collagen expression in the micronodular and infiltrative basal cell carcinomas; however, no significant difference of the solid type and each of the abovementioned types was found. Aggressive basal cell carcinoma types (micronodular and infiltrative, taken together) were significantly different (р = 0.033) from the solid type by the absence of type IV collagen expression. Linear continuous expression was seen exclusively in basal cell carcinomas with the invasion of < 0.825 mm. Conclusion: We have identified the difference in type IV collagen expression depending on the morphological type of basal cell skin carcinoma, prevailing linear continuous expression in the superficial multicentric type and its absence in the micronodular and infiltrative types.

Almanac of Clinical Medicine. 2020;48(2):102-109
pages 102-109 views

Clinical and morphological characteristics IgG4-associated retroperitoneal fibrosis

Lishchuk S.V., Dubova E.A., Pavlov K.A., Borbat A.M., Udalov Y.D.


Background: Retroperitoneal fibrosis (RF) is a rare disease with inflammation and fibrosis of the retroperitoneal soft tissues and adjacent organ involvement. At present, a proportion of RF cases are believed to be IgG4-associated. Aim: Clinical and morphological comparison of the IgG4-associated and idiopathic (non-IgG-associated) RF. Materials and methods: The study was based on a comprehensive morphological assessment of surgical and biopsy samples taken from 12 RF patients. In addition to hematoxylin eosin stained specimens, we performed immunohistochemistry (IHC) with determination of absolute CD138+ counts, IgG+ and IgG4+ cells in the inflammatory infiltration, as well as IgG4/IgG and IgG4+/CD138+ ratios. Results: The proportion the IgG4-associated RF was 66.7% (8/12). The majority of IgG4-associated RF patients were men, with the mean age of 54.9 ± 10.3 years. Idiopathic RF was found without any gender imbalance in the younger patients. In all cases of IgG4-associated RF, the adjacent organs were also involved, whereas in those with idiopathic RF the aortic wall was involved in only half of the cases. Morphological specimen investigation in IgG4-associated RF showed signs characteristic for an IgG4-associated disorder, such as advanced lymphoplasmocytic infiltration, storiform fibrosis, and obliterating phlebitis. IgG4+ plasma cells numbers in the infiltrates was at least 25 per high-power field, and the IgG4+/IgG+ and IgG4+/CD138+ ratios exceeded 50% in all cases. No signs of an IgG4-associated disease were found in idiopathic RF, with significantly lower numbers of IgG+ and IgG4+ plasma cells in the infiltrations and the IgG4+/IgG+ ratio below 10%. Conclusion: A big proportion of RF is IgG4-associated, being an intrinsic feature of a systemic autoimmune IgG4-associated disease. The differential diagnosis should be based on the morphological assessment and immunohistochemistry results with obligatory identification of CD138, IgG, and IgG4 expression in the involved tissues. In some cases, it allows for avoidance of an unnecessary surgery. Reliable and accurate diagnosis would determine the subsequent treatment strategy of these patients.

Almanac of Clinical Medicine. 2020;48(2):110-116
pages 110-116 views

Patient-derived xenograft model of well-differentiated pancreatic neuroendocrine tumor in immunodeficient Balb/c Nude mice

Trifanov V.S., Maksimov A.Y., Goncharova A.S., Lukbanova E.A., Karnaukhov N.S., Kit S.O., Volkova A.V., Protasova T.P., Tkachev S.Y., Khodakova D.V., Zaikina E.V., Mindar M.V., Akulshina I.M.


Background: Orthotopic patient-derived xenografts (PDX) in immunodeficient mice are recognized as the most adequate neoplastic model due to their ability to maintain primary tumor properties after implantation. They can be used to study anti-neoplastic effects of pharmacological substances in vivo and to investigate characteristics and mechanisms of carcinogenesis. Results of preclinical studies of pharmacological substances obtained with PDX models are virtually no different from those of subsequent clinical trials. Aim: To develop an orthotopic PDX model of a highly differentiated human pancreatic neuroendocrine tumor (pNET) by implanting a fragment of the patient's tumor into the pancreas of immunodeficient mice. Materials and methods: A tumor fragment was obtained from a patient with a highly differentiated pNET G2 and liver metastasis. Fifteen (15) male immunodeficient Balb/c Nude mice with a mass of 22-24 grams were used to establish the orthotopic PDX model of human well-differentiated pNET. A fragment of primary pNET was orthotopically transplanted into the pancreas of 10 animals. A fragment of the metastatic lesion was transplanted into the liver of 5 animals. The animals were followed for up to 45 days. In vivo monitoring of the tumor growth was performed with a magnetic resonance imaging (MRI) system (ClinScan, Bruker BioSpin, Rheinstetten, Germany). At the end of the experiment, animals were euthanized and autopsies were performed, with routine histopathological examination and immunohistochemical study with antibodies to human chromogranin A, synaptophysin, and the marker of proliferative activity (Ki-67) of both original donor tumor and orthotopic pancreatic and liver xenografts. Results: Obvious changes in the mice condition were noticed at 30 days after surgery. They manifested as an increase in abdominal distension, swelling, and cyanosis in the projection of the pancreas. MRI showed a homogeneous neoplasm in the pancreas. At autopsy, the engraftment rate was 73% of all study animals, with yellow masses with even contours and a volume of about 100 cm3 present within the yellow-pink pancreatic tissues. The morphological assessment showed histological similarity between the original patient's tumor and patient-derived xenografts, which were identified as highly differentiated G2 pNETs. At immunohistochemical assessment, the patient's primary and metastatic tumor tissue specimens expressed anti-chromogranin A (full-blown cytoplasmic reaction) and anti-synaptophysin (mild cytoplasmic reaction) antibodies. Ki-67 was positive in 5.2% of the cells. An immunohistochemical study of the orthotopic tumor fragments and heterotopic tumor fragments showed moderate cytoplasmic staining with antibodies to chromogranin A and synaptophysin. The rate of Ki-67 in the orthotopic pNET model and metastatic model does not exceed 5% and 8%, respectively. Conclusion: Engraftment of tumor material after transplantation of human pancreatic cancer was observed in 73% of the cases, which should be considered a good first passage implantation result. The morphological studies confirmed that the orthotopic PDX was a well-differentiated pNET, histologically corresponding to the donor tumor. The model created in the experiment mirrors the histological characteristics of the donor tumor and can be used in preclinical studies of new treatments for well-differentiated pNETs, including those of antitumor activity of new pharmacological substances.

Almanac of Clinical Medicine. 2020;48(2):117-124
pages 117-124 views


Merkel cell carcinoma (neuroendocrine carcinoma of the skin): a lecture with a brief overview of 19 cases and demonstration of two clinical observations

Gurevich L.E., Grishina E.E.


The lecture deals with epidemiology, clinical morphological and genetic characteristics of a rare aggressive neuroendocrine carcinoma of the skin, or Merkel cell carcinoma (MC). We describe the algorithms for the differential diagnosis of these tumors and their treatment approaches, and focus on the main unresolved issues, such as delayed and erroneous diagnosis, the search for new diagnostic markers and targets for the development of more effective treatment methods. We provide a brief clinical and morphological analysis of 19 own observations of MC in 10 men and 9 women aged 40 to 85 years (57.9% of the patients were above 60 years, 31.6% from 50 to 60 years, and 10.5%, below 50 years). In 42.1% of the cases, the tumors were located in the head, in 15.8% in the limbs, and in 15.8% in the trunk and soft tissues; in the rest of the cases the primary tumor location was not identified. Only in 4 cases MC was diagnosed immediately; in all other cases, the initial diagnoses had been wrong. The diagnosis of MC was established after the analysis of medical files, histological and immunohistochemical biopsy studies and was confirmed by immunohistochemistry. All the tumors were expressing synaptophysin, chromogranin A, CD56; in all cases except one, cytokeratin 20 of the dote-like type, type 2A somatostatin receptors in 66.7%, nuclear survivin in 100%, p53 in 88.9%, CD117 in 57.1%. To illustrate the topic, we present 2 clinical observations of MC. The first case was an 82-year old man who had been living for a long time in the territory with increased sun radiation. A bright red tumor developed on his left upper eyelid, becoming gigantic (5 cm in diameter) within 2 months and bleeding. Despite the radical excision of the tumor, at 2 months after the surgery he developed local recurrence and metastases in regional lymph nodes. Thereafter, he underwent the orbital exenteration and lymphodissection of the affected lymph nodes. The second observation was a 63-year old man. At 10 years after he had had his renal transplant, he developed a mixed skin tumor on the anterior neck surface. The tumor was represented by MC and porocarcinoma with signs of squamous and sebaceous differentiation. These observations demonstrate MC rapid growth, its aggressive potential and such risk factors as prolonged high insolation and long-term drug immunosuppression after organ transplantation. Conclusion: At present, the rarity and low understanding of MC, its rapid growth, late diagnosis, aggressive biological potential and the lack of uniform treatment standards do not allow for cure in most such patients. The solution to the problem lies in the search for the cellular targets that would allow for the development of new effective targeted treatments for these aggressive tumors. In addition, integration of any results obtained in multicenter studies of the disease is essential.

Almanac of Clinical Medicine. 2020;48(2):125-139
pages 125-139 views


Primary thyroid-like follicular renal carcinoma: a clinical case and literature review

Volchenko N.N., Goeva N.S., Vorobyev N.V., Muradyan A.G., Ratushnaya V.V.


Primary thyroid-like follicular renal cell carcinoma is an extremely rare type of renal cell cancer with low malignancy potential and relatively good prognosis. It has not been included into the World Health Organization classification of renal tumors. This tumor is characterized by morphology similar to primary thyroid follicular cancer, but with different immune phenotype, which is important for morphological diagnosis. Surgery has been recognized as the only curative treatment. We describe our own observation of follicular renal carcinoma in a 68-year old man, in whom renal tumor was identified during his regular examination due to past colon cancer. The disease was asymptomatic. The patient had elective laparoscopic nephrectomy. At pathological assessment, the tumor looked like a follicular thyroid neoplasm. Immunohistochemistry revealed no expression of RCC, TTF-1, thyroglobulin, CD-10, synaptophysin, and chromogranin A. The differential diagnosis included metastatic primary thyroid malignancy as the most probable diagnosis, as well as highly differentiated neuroendocrine tumor and the so-called “thyroid kidney” that might occur in long-standing chronic pyelonephritis. Conclusion: The case of primary follicular renal carcinoma illustrates that this rare renal tumor is heterogeneous both in its structure and tumor cell immunophenotypes. Longer follow-up and accumulation of larger numbers of the disease is needed. This would allow for a more objective assessment of its prevalence in the population, of its clinical characteristics and morphological variability.

Almanac of Clinical Medicine. 2020;48(2):140-145
pages 140-145 views

Myxoid adrenal cortical carcinoma, a rare type of adrenal cortical cancer. A case report

Korosteleva P.A., Krivosheev A.V., Vorontsova S.V., Voronkova I.A., Britvin T.A., Krivosheeva Y.G.


Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex with aggressive clinical behavior and an unfavorable prognosis. Its estimated annual incidence is 0.5 to 2 cases per 1,000 000. The unfavorable prognostic factors include its rare variants, such as myxoid ACC. This ACC type was first reported as early as in 1979; however, its low prevalence hinders any reliable assessment of its prognostic value. Few published data indicate more than 2-fold lower median survival of patients with myxoid ACC, compared to that in classical ACC. Here we present a rare clinical case of myxoid ACC in a 56-year old woman with Cushing's syndrome, invasion of the adjacent tissues and organ by the time of diagnosis, rapid progression of the disease with fatal outcome. We discuss the variations of the myxoid component, associated with different cellular growth patterns in ACC. This clinical case demonstrates the aggressive course of myxoid ACC type, compared to the classical one, and is aimed at drawing the attention of various medical specialists to rare ACC variants.

Almanac of Clinical Medicine. 2020;48(2):146-152
pages 146-152 views

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