Lymphangioleiomyomatosis (LAM) affects exclusively women of reproductive age, involves the lungs and axial lymphatic system, and is frequently complicated with renal angiomyolipomas. LAM lesions are generated by the proliferation of LAM cells with mutations of one of the tuberous sclerosis complex (TSC) genes. Recent studies indicate that LAM cells can migrate or metastasize to form new lesions in multiple organs, although they show a morphologically benign appearance. In the previous study, we reported LAM-associated lymphangiogenesis and implicated its role in the progression of LAM. In this study, we further focused on the lymphatic abnormalities in LAM: LAM-associated chylous fluid (5 pleural effusion and 2 ascites), surgically resected diaphragm (1 patient), and axial lymphatic system including the thoracic duct, lymph nodes at various regions, and diaphragmatic lymphatic system (5 autopsy cases). We demonstrated that LAM cell clusters enveloped by lymphatic endothelial cells (LCC) in all chylous fluid examined. We identified LAM lesion in the diaphragm (2 of 5 autopy cases and one surgical specimen), thoracic duct (5 of 5), and lymph nodes (retroperitoneal (5 of 5), mediastinal (4 of 5), left venous angle (5 of 5) with total positive rate of 68% to 88% at each region of the lymph node, but less frequent or none at remote lymph nodes located away from the axial lymph trunk (cervical [1 of 5] and axillary [0 of 5]). LCCs were identified in intra-LAM lesional lymphatic channels where LAM cells proliferate along lymphatic system. In in vitro culture system, LCC can fragment into each proliferating LAM cell. These findings suggest that LAM-associated lymphangiogenesis demarcates LAM lesion into bundle- or fascicle-like structure and eventually shed LCC into the lymphatic circulation and that LCCs play a central role in the dissemination of LAM lesion.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare inflammatory tumor-like lesion composed of vascular nodules and non-neoplastic stroma including spindle cells and inflammatory cells. The focus of our study was on the stromal proliferating process in SANT. Nine cases of SANT were examined. All cases showed alpha-smooth muscle actin (alpha-SMA) and vimentin on the spindle cells but not CD21, CD31, CD34, CD68, desmin, S100, human herpes virus-8, or anaplastic lymphoma kinase-1. In one case, 20-30% of the myofibroblasts in Epstein-Barr-virus (EBV)-positive spindle cells were detected using double-labeling immunohistochemistry for alpha-SMA and EBV-encoded small RNA in situ hybridization. A quantitative analysis of IgG and IgG4-positive plasma cells (pPCs) in SANT was performed. The median densities of IgG-pPCs and IgG4-pPCs in SANT were approximately four-fold and 13-fold higher than those in the normal spleens, respectively. In addition, there was a statistically significant increase of IgG4/IgG-pPCs ratio in SANT in comparison to the control specimens. In conclusion, the fibrogenesis in a subset of SANT may be associated with EBV-infected myofibroblasts in an overlapping immune reaction indicated by the presence of infiltrating IgG4-pPCs. Further investigation is needed to elucidate the association between SANT and IgG4-related sclerosing disease.

The most frequently recognized presentation of autoimmune pancreatitis (AIP) is that mimicking pancreatic cancer. It is also known that at some stage during the disease process chronic pancreatitis clinically presents as a tumorous swelling, often suspected of being a carcinoma. In Japan, this stage has also been proposed clinically to be tumor-forming pancreatitis. Hence, tumor-forming pancreatitis shows at least two distinct types: a reparative process for centriductal acute inflammation with a background of chronic pancreatitis, which is considered to have given rise to the tumor at some stage of chronic pancreatitis, and a lymphoplasmacytic infiltration with lymphoid and fibrous proliferation in normal pancreatic tissue, which corresponds to autoimmune pancreatitis. These tumorous lesions may be changeable along the disease process.

The authors investigated the role of activated perilobular, not periacinar, pancreatic stellate cells, in fibrogenesis in chronic pancreatitis, based on the distribution of myofibroblasts. Twenty-four patients with clinically diagnosed chronic alcoholic pancreatitis were studied histopathologically, immunohistochemically and quantitatively. In all cases, fibrosis was patchily distributed in the perilobular, or interlobular, areas, accompanied by a cirrhosis-like appearance; it had extended into the intralobular area in advanced cases. Seven patients had a massive or confluent loss of exocrine tissue, resulting in extensive interlobular fibrosis; the more extensive the interlobular fibrosis, the smaller the lobules. Immunoreactivity to alpha-smooth muscle actin, a myofibroblast marker, was found mostly in the same areas of the fibrosis, mainly the interlobular, and less often the periacinar, areas; the average percentage area of perilobular myofibroblasts was significantly higher than that of periacinar myofibroblasts in 20 randomly selected lobules (P > 0.001), in which the average value for the former was 38.03% (range: 13.54-61.32%; SD, 13.8%) and that for the latter was 4.85% (range 0.90-9.57%; SD, 2.22%). Fibrosis also immunostained positive for collagen types I and III. In conclusion, activated perilobular, not periacinar, pancreatic stellate cell contribute to fibrogenesis in chronic pancreatitis.

No abstract