Justification of the Feasibility of Resections of Scar-Changed Tissues of the Pancreas in Chronic Pancreatitis

The dissertation is dedicated to the justification of the feasibility of resections of scar-changed tissues of the pancreas in chronic pancreatitis. The research is based on the analysis of clinical data, results of reohepatographic studies of splanchnic blood flow, and morphological and histochemical study of resected sections of the pancreas. The work reveals pathomorphological features of scar-changed sections of the gland, including proliferative and sclerotic processes, altrophic changes, the state of neural structures, and the arterial vascular bed. The previously unknown phenomenon of arterial invagination in scar-changed tissues was established, which is of key importance for understanding the mechanisms of chronic pancreatitis exacerbations and for justifying organ-preserving surgical tactics.

Relevance of the Research. Chronic pancreatitis (CP) is one of the most complex problems of theoretical and practical medicine. The young and middle age of patients (25-50 years), the steady increase in morbidity in recent years [N.B. Gubergrits, T.N. Khristich, 2000; O.V. Kokueva et al., 2000; V.I. Onopriev, N.V. Korochanskaya, 2003], the frequent combination of pancreatic cancer (PC) with this pathology [Lovenfels et al., 1999; Talamini et al., 1999; Isla, 2000; Ditte et al., 2002], high complication rates [Byrne et al., 2002] and mortality [Thuluvath, 2003] indicate the relevance of studying this problem.

Periodically occurring exacerbations of CP leave behind foci of pancreatic parenchymal destruction due to its death, as a result of which pancreatic exocrine insufficiency (PE) increases [V.V. Vinogradov et al., 1974; L.I. Geller et al., 1989; Loeser, 1998]. The destroyed sections of the PE undergo sclerosis, and scar fields are formed at their sites, in whose fibrotic tissue preserved anatomical structures (blood vessels, nerve trunks, pancreatic ducts) are enclosed, as well as newly formed structures in the form of small ducts, regeneration nodules from endocrine and exocrine parenchyma [A.I. Abrikosov, 1957; I.V. Davydovsky, 1957; I.S. Derizhanova, 1991]. With the formation of scar fields, pathology of the ductal system develops, cyst formation, stone formation, as well as metaplastic and dysplastic changes of the epithelium occur [Bockman et al., 1997; Cylwik et al., 1998; Tannapfel et al., 2001; Byrne et al., 2002]. Chronic recurrent pancreatitis with pronounced sclerotic changes in the gland, according to some authors, may be the pathogenetic basis for the development of a tumor process [D.F. Blagovidov, 1973; A.S. Loginov et al., 1992; Calvo et al., 1981].

Therapeutic measures are often insufficient in the treatment of CP, prevention of complications and disease exacerbation, surgical treatment is delayed and often proves ineffective. Mortality after emergency operations for severe complications exceeds that after planned pancreatic operations by dozens of times. Therefore, one of the ways to improve treatment outcomes is the expansion of planned surgical activity in relation to patients at high risk of exacerbations and the presence of concomitant pathology [Witzigman et al., 2001], as well as the improvement of surgical techniques [M.L. Rogal, 1999; V.I. Onopriev et al., 2006]. Organ-preserving resection methods [Beger et al., 1980; Buchler et al., 1990, 1997; Friess et al., 2002], successfully implemented in the work of the Russian Center for Functional Surgical Gastroenterology by Professor V.I. Onopriev and his students, best meet this recommendation. However, the new direction in the surgical treatment of CP in the form of organ-preserving operations has not yet found a satisfactory morphofunctional justification for the necessity of removing the fibrosed focus of the pancreas due to the absence of any significant morphological investigations in this area. In this regard, pathomorphological investigations of scar-changed sections of the pancreas, together with the analysis of clinical data, can play a substantial role in affirming and further developing the organ-preserving direction in surgery of the pancreatoduodenal complex [V.I. Onopriev, 2007].

Taking the above into account, the aim of the work was to justify the feasibility of resections of scar-changed tissues of the PE in the surgical treatment of CP, based on the analysis of clinical data and the results of morphological and histochemical study of resected sections of the PE.

To achieve the stated goal, the following tasks were set:

1. To investigate by reohepatography the features of blood flow in the celiac trunk basin in patients during CP exacerbation.

2. To analyze complicated forms of CP, applied surgical technologies, and results of surgical treatment.

3. To demonstrate the significance of original histochemical methods in obtaining new data on structural changes of the PE in CP and PC.

4. To study the morphological manifestations of regenerative processes in scar-changed tissues of the PE in CP.

5. To study changes in the pancreatic ducts in resected sections of the PE in CP.

6. To study structural changes in nerve formations in the sclerosed peripancreatic tissue, as well as in scar fields of the PE in CP.

7. To study the morphofunctional features of the arterial vascular bed in CP. To analyze the significance of vascular changes in CP exacerbation and its progression.

8. To conduct a comparative analysis of the severity of sclerotic and proliferative processes in scar-changed tissues in CP and PC.

9. To analyze the obtained data in terms of the feasibility of removing scar-changed tissues in the surgical treatment of CP.

Novelty of the Research Results

1. We have established for the first time the pathological character of regenerative processes in scar-changed tissues of the PE in CP, concerning exocrine and endocrine parenchyma in the form of formation of regeneration nodules, as well as numerous newly formed ducts. Morphological signs of metaplasia and dysplasia of the newly formed ductal epithelium were identified.

2. The morphofunctional state of nerve ganglia in the peripancreatic tissue, as well as nerve trunks in the scar field in CP, was characterized for the first time. The nature of changes in nerve structures indicated their hypoxic genesis and simultaneously became one of the morphological equivalents of the pain syndrome in patients with CP.

3. The morphofunctional characterization of the arterial vascular bed in the scar field of the PE was given for the first time, making it possible to document the presence of a phenomenon of local arterial hypertension with periodically occurring vascular crises.

4. The phenomenon of arterial invagination in scar-changed tissues of the PE in CP was discovered for the first time, consisting in the embedding of a spasmed proximal section of the artery into the lumen of the parietally dilated distal part with blockade of arterial blood flow. This phenomenon was recognized as a scientific discovery (diploma for scientific discovery No. 229 of 2003). It was established that with arterial invagination, the development of the most severe forms of CP exacerbation with pronounced altrophic and hemorrhagic processes and the presence of morphological signs of local coagulopathy is associated. Thus, for the first time, the important role of the vascular component in the recurrent course of CP was established.

Basic Propositions of the Dissertation for Defense

When performing operations for CP, the scar-changed segment of the PE is subject to removal in connection with the fact that it:

- is a source of exacerbation of the chronic process, as it forms arterial invaginations causing acute ischemia and altrophic changes;

- is a site of pronounced deformation of the ductal system with impaired outflow of pancreatic juice, leading to ductal hypertension and capable of initiating exacerbation of chronic pancreatic pathology;

- is a site where nerve trunks are subject to pronounced degenerative changes, which is reflected in the clinical course of the disease in the form of a pain syndrome;

- is a site where regeneration can take on a pathological character and proceed in the form of dysregulation with formation of foci of dysplasia, which increases the risk of developing oncological pathology.

Theoretical Significance of the Research The principles are formulated in the work that justify the necessity and feasibility of resections of scar-changed tissues of the PE in CP. The previously unknown phenomenon of arterial invagination in scar-changed tissues of the PE was identified, indicating the significance of the vascular component in the occurrence of CP exacerbations. Morphological and reohepatographic evidence of the presence of local arterial hypertension in the splanchnic blood flow system in CP was obtained, against the background of which vascular crises occurred, causing focal altrophic changes in pancreatic tissues. This made it possible to regard them as a source of disease exacerbation as well as the occurrence of complications. Local arterial hypertension, being a source of chronic progressive ischemia of the organ, determines the course of regenerative processes in scar-changed tissue of the PE in the form of pathological regeneration and dysregulation, which increases the risk of developing oncological pathology in scars.

Practical Significance of the Research The feasibility and sufficiency of removal of scar-changed sections of the PE in CP are justified, since these pathologically changed tissues are the site of occurrence of arterial invaginations causing exacerbation recurrences of the disease. These same scar-changed tissues may contain foci of dysplasia and therefore they are a factor of increased risk of developing oncological pathology in scars.

Methods of postoperative pharmacotherapy aimed at preventing and treating regional vascular crises pathogenetically associated with CP, which lead to exacerbation of CP, have been proposed for development. Taking into account the important role of the vascular component in the genesis of altrophic processes in CP, in addition to standard treatment, mandatory implementation of therapeutic measures to improve regional blood flow and prevent vascular crises is recommended.

Local calcium antagonists (beta-adrenoblockers).

The original methods of histological and histochemical processing of material developed and used in the work are of practical importance: the method of combined aldehyde-fuchsin chromotrope - aniline blue staining, which made it possible to effectively identify histological structures of the vascular wall, contributing to the establishment of the phenomenon of arterial invagination; the method of alcian blue - neutral red staining for detecting dystrophically changed nerve trunks and neurons, as well as the method of hematoxylin - basic fuchsin - picric acid staining, adapted for detecting early damage to the muscular tissue of arterial walls of hypoxic origin. This method was published in the article by R.A. Serov et al. (1977).

Of practical importance is the proposed method for obtaining the dye - aldehyde-fuchsin, superior to the analog in staining properties, as well as increasing the yield of the target product. The use of this dye expands the diagnostic possibilities of morphological investigations. The method is patented (patent for invention No. 2223117 of 10.02.2004).

The diagnostic significance of reohepatographic investigations of splanchnic blood flow in patients with CP for detecting features of local arterial hypertension has been demonstrated.

Information on Practical Use of the Research Results

The phenomenon of local arterial hypertension and the phenomenon of arterial invagination in chronic diseases of the digestive organs have been proposed and are used as teaching material when lecturing to students and during practical sessions in the course of pathological anatomy and internal diseases (see Appendix 3).

The feasibility of using reohepatographic investigations of splanchnic blood flow in patients with CP for diagnostic purposes in the Russian Center for Functional Surgical Gastroenterology to detect local arterial hypertension and vasospastic reactions in the celiac artery basin has been demonstrated.

The developed methods of histological and histochemical processing of biological tissue are used in conducting scientific research in the Laboratory of Functional Morphology of the Department of Clinical Physiology of the Digestive System of the Russian Center for Functional Surgical Gastroenterology and are recommended for use in the pathological anatomy departments of hospitals (see Appendix 2).

Based on the results of the research, 22 printed works have been published (see Appendix 1), including 1 diploma for scientific discovery (see Appendix 4) and 1 Russian Federation patent for invention (see Appendix 5).

Concluding the introductory part of the dissertation, I would like to express sincere gratitude to my scientific supervisor, Doctor of Medical Sciences, Professor Vladimir Ivanovich Onopriev, for providing the research topic and creating all conditions for conducting scientific research in the Russian Center for Functional Surgical Gastroenterology that he leads. I also express my gratitude to the head of the course of pathological anatomy of the Kuban Medical Institute, Doctor of Medical Sciences, Professor Leonid Alexandrovich Faustov, for assistance in conducting morphological analysis of the operative material. I express my gratitude to the head of the Department of Clinical Physiology of the Digestive System of the Russian Center for Functional Surgical Gastroenterology, Doctor of Medical Sciences, Georgiy Gennadievich Korotko, for assistance in conducting reohepatographic investigations, as well as the head of the Center for Pancreatic Diseases of the Russian Center for Functional Surgical Gastroenterology, Doctor of Medical Sciences, Mikhail Leonidovich Rogal, for providing illustrative material on surgical technologies.

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