Published online Sep 16, 2023. doi: 10.12998/wjcc.v11.i26.6091
Peer-review started: June 25, 2023
First decision: July 18, 2023
Revised: August 16, 2023
Accepted: August 25, 2023
Article in press: August 25, 2023
Published online: September 16, 2023
To date, the literature lacks detailed histoepidemiological, morphological, and immunohistochemical (IHC) studies of the immunophenotype and morphogenesis of multinucleated giant cells (MGCs) in the mucosa and the stroma of the bladder. At the same time, in the non-tumor bladder, this question is insufficiently studied. These questions and difficulties, which pathologists, urologists, and oncologists are exposed to, motivated us to study these problems in more depth, using materials from two geographically different countries-Bulgaria and France.
We believe that it is more reasonable in the present study to determine the exact identification of these cells to use the terms: Mononuclear and MGCs present in the connective tissue of the bladder wall in neoplastic and inflammatory processes.
To establish the function, morphogenesis, and origin of mononuclear giant cells and MGCs in the stroma of urothelial carcinoma (UC) of the bladder in patients samples, as well as to compile a proper differential-diagnostic algorithm from histological, histochemical, and IHC criteria for the diagnosis of MGCs observed in the stroma of the UC of the bladder.
We analyzed retrospectively urothelial bladder carcinomas (n = 104) from 2016-2020 using IHC and histochemical stain examination. Giant cells in the bladder stroma were found in 35.6% of cases, more often in high-grades.
From a pathogenetic point of view, we believe that giant stromal cells in non-tumor and tumor bladder represent a degenerative cellular phenomenon reflecting chronic mucosal bladder irritation (mechanical, chemical, or tumor in nature) and chronic mucosal inflammation. Moreover, we observed a significant correlation between these cells’ presence and the degree of tissue damage (tissue stress). From an oncological perspective, our results show that giant stromal cells in bladder UC are part of the stromal tumor response, although nonspecific and non-immune. This giant cell reaction is probably due to chronic mucosal irritation. It correlates with malignancy and the degree of tumor infiltration. In addition to the above considerations, the positive expression of p16 observed by us is further evidence of the histiocytic nature of the giant cells in the stroma of the bladder UC. In support of this, it is known from the literature that histiocytes and their derived tumor lesions are p16 positive.
Based on the above results, we propose a generalized algorithm of histological, histochemical, and IHC-criteria for the diagnosis of MGCs observed in the stroma of UC of the bladder: MGCs, except in chronic cystitis and other bladder lesions, are localized in the stroma of the bladder carcinoma and the surrounding lamina propria. MGCs are 10 µm to 20 µm in size and star-shaped. Their cytoplasm is eosinophilic and sparse, with the presence of long cytoplasmic growths. The nuclei are rounded, hyperchromatic, and multilobulated, sometimes more or less atypical, but no mitotic figures are observed. Histochemically, MGCs are negative for Perls staining. Immunohistochemically, MGCs are positive for mesenchymal and myofibroblast markers (vimentin, smooth muscle actin, Desmin, and CD34), for the macrophage marker CD68, and the marker of cell aging and degeneration p16.
For the first time, we showed the expression of p16 in giant stromal cells outside the context of granulomatous inflammation. This phenomenon’s probable explanation is the persistent mucosal irritation leading to this protein’s expression in an attempt to find an optimal thermodynamically and biochemically metabolic formula for stromal cells “exhausted” by chronic cellular stress. Similar “dynamic induction” in p16 expression is observed in other processes and other organs: Involution of the glandular parenchyma of the breast, wound healing, nerve regeneration, and chronic inflammation.