We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis—e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey–Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)—vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).

Perivascular cells in the pericytic microvasculature, pericytes and CD34+ stromal cells/telocytes (CD34+SCs/TCs), have an important role in angiogenesis. We compare the behavior of these cells depending on whether the growth of endothelial cells (ECs) from the pre-existing microvasculature is toward the interstitium with vascular bud and neovessel formation (sprouting angiogenesis) or toward the vascular lumen with intravascular pillar development and vessel division (intussusceptive angiogenesis). Detachment from the vascular wall, mobilization, proliferation, recruitment, and differentiation of pericytes and CD34+SCs/TCs, as well as associated changes in vessel permeability and functionality, and modifications of the extracellular matrix are more intense, longer lasting over time, and with a greater energy cost in sprouting angiogenesis than in intussusceptive angiogenesis, in which some of the aforementioned events do not occur or are compensated for by others (e.g., sparse EC and pericyte proliferation by cell elongation and thinning). The governing mechanisms involve cell–cell contacts (e.g., peg-and-socket junctions between pericytes and ECs), multiple autocrine and paracrine signaling molecules and pathways (e.g., vascular endothelial growth factor, platelet-derived growth factor, angiopoietins, transforming growth factor B, ephrins, semaphorins, and metalloproteinases), and other factors (e.g., hypoxia, vascular patency, and blood flow). Pericytes participate in vessel development, stabilization, maturation and regression in sprouting angiogenesis, and in interstitial tissue structure formation of the pillar core in intussusceptive angiogenesis. In sprouting angiogenesis, proliferating perivascular CD34+SCs/TCs are an important source of stromal cells during repair through granulation tissue formation and of cancer-associated fibroblasts (CAFs) in tumors. Conversely, CD34+SCs/TCs have less participation as precursor cells in intussusceptive angiogenesis. The dysfunction of these mechanisms is involved in several diseases, including neoplasms, with therapeutic implications.

Several origins have been proposed for cancer-associated fibroblasts (CAFs), including resident CD34+ stromal cells/telocytes (CD34+SCs/TCs). The characteristics and arrangement of mammary CD34+SCs/TCs are well known and invasive lobular carcinoma of the breast (ILC) is one of the few malignant epithelial tumours with stromal cells that can express CD34 or αSMA, which could facilitate tracking these cells. Our objective is to assess whether tissue-resident CD34+SCs/TCs participate in the origin of CAFs in ILCs. For this purpose, using conventional and immunohistochemical procedures, we studied stromal cells in ILCs (n:42) and in normal breasts (n:6, also using electron microscopy). The results showed (a) the presence of anti-CD34+ or anti-αSMA+ stromal cells in varying proportion (from very rare in one of the markers to balanced) around nests/strands of neoplastic cells, (b) a similar arrangement and location of stromal cells in ILC to CD34+SCs/TCs in the normal breast, (c) both types of stromal cells coinciding around the same nest of neoplastic cells and (d) the coexpression of CD34 and αSMA in stromal cells in ILC. In conclusion, our findings support the hypothesis that resident CD34+SCs/TCs participate as an important source of CAFs in ILC. Further studies are required in this regard in other tumours.

We studied telocytes/CD34+ stromal cells (TCs/CD34+SCs) in pathologically affected white adipose tissue after briefly examining them in normal fat. To this aim, we reviewed pathological processes, including original contributions, in which TCs/CD34+SCs are conserved, increased, and lost, or acquire a specific arrangement. The pathologic processes in which TCs/CD34+SCs are studied in adipose tissue include inflammation and repair through granulation tissue, iatrogenic insulin-amyloid type amyloidosis, non-adipose tissue components (nerve fascicles and fibres in neuromas and hyperplastic neurogenic processes) and tumours (signet ring carcinoma with Krukenberg tumour and colon carcinoma) growing in adipose tissue, adipose tissue tumours (spindle cell lipoma, dendritic fibromyxolipoma, pleomorphic lipoma, infiltrating angiolipoma of skeletal muscle and elastofibrolipoma), lipomatous hypertrophy of the interatrial septum, nevus lipomatosus cutaneous superficialis of Hoffman–Zurhelle and irradiated adipose tissue of the perirectal and thymic regions. Two highly interesting issues emerged: (1) whether the loss of CD34 expression in TCs/CD34+SCs is by changes in marker expression or the disappearance of these cells (the findings suggest the first possibility) and (2) whether in some invasive and metastatic malignant tumours, TCs/CD34+SCs that completely surround neoplastic cells act as nurse and/or isolating cells. Further studies are required on adipose tissue TCs/CD34+SCs, mainly in lipomatosis and obesity.

Kaposi sarcoma (KS) is an angioproliferative lesion in which two main KS cell sources are currently sustained: endothelial cells (ECs) and mesenchymal/stromal cells. Our objective is to establish the tissue location, characteristics and transdifferentiation steps to the KS cells of the latter. For this purpose, we studied specimens of 49 cases of cutaneous KS using immunochemistry and confocal and electron microscopy. The results showed that delimiting CD34+ stromal cells/Telocytes (CD34+SCs/TCs) in the external layer of the pre-existing blood vessels and around skin appendages form small convergent lumens, express markers for ECs of blood and lymphatic vessels, share ultrastructural characteristics with ECs and participate in the origin of two main types of neovessels, the evolution of which gives rise to lymphangiomatous or spindle-cell patterns—the substrate of the main KS histopathological variants. Intraluminal folds and pillars (papillae) are formed in the neovessels, which suggests they increase by vessel splitting (intussusceptive angiogenesis and intussusceptive lymphangiogenesis). In conclusion, delimiting CD34+SCs/TCs are mesenchymal/stromal cells that can transdifferentiate into KS ECs, participating in the formation of two types of neovessels. The subsequent growth of the latter involves intussusceptive mechanisms, originating several KS variants. These findings are of histogenic, clinical and therapeutic interest.