Faculty Bibliography

Bodies have continuous reticular networks, comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, through all tissues and organs. Fibrous coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently validated fluid flow through human fibrous tissues, though whether these interstitial spaces are continuous through the body or discontinuous, confined within individual organs, remains unclear. Here we show evidence for continuity of interstitial spaces using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. Hyaluronic acid, a macromolecular component of interstitial spaces, was also visualized. Both techniques demonstrate interstitial continuity within and between organs including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest that there is a body-wide network of fluid-filled interstitial spaces that has significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.

Background: Neuroendocrine tumors (NETs) have been well studied and most organs have criteria which allow for neuroendocrine hyperplasia (NH) or a preneoplastic state before a neuroendocrine proliferation is defined a neuroendocrine tumor. In the lung, neuroendocrine proliferations <5mm are designated tumorlets. In the stomach, neuroendocrine proliferations range from NH to neuroendocrine dysplasia, and the designation of NET does not occur unless the proliferation is >5mm. In the pancreas, neuroendocrine proliferations with a diameter of <5 mm are termed neuroendocrine microadenomas. However in the appendix, there is no provision for NH and there are no established minimal size criteria for appendiceal NETs in the current 5th edition WHO book, which considers all NETs to have malignant potential. Also the current CAP protocol applies to all appendiceal NETs regardless of size, forcing pathologists to diagnose NETs despite studies demonstrating small appendiceal NETs (<1cm) to be indolent.
Design(s): A single institution database of adult patients with appendectomies containing the word "neuroendocrine" and "carcinoid" was queried from January 2004 to December 2012. Patients with neuroendocrine carcinoma, goblet cell carcinoid, and patients without follow up were excluded.
Result(s): 32 patients were included in the study. The mean age at diagnosis was 40.3 years (18-79). Females represented 59.3 % (19/32) of all patients. All appendiceal NETs were incidentally identified in a background of acute appendicitis. Tumor size ranged from 1 mm to 17 mm and the depth of extension ranged from submucosa to mesoappendix. One patient underwent a right hemicolectomy because of tumor size > 1cm. In long term follow up (7-15 years), none of these patients had disease recurrence. (Table presented)
Conclusion(s): The majority of appendiceal NETs are small incidental findings associated with acute appendicitis. In this setting, neural proliferation and mucosal expansion can often be seen and it is reasonable for NH to also represent inflammatory/reactive changes rather than a neoplastic process given their indolent behavior and long term survival rate (100%). In the appendix, we propose NH is part of the inflammatory process and should not be classified as a NET unless it is >5mm. We advocate the terminology of appendiceal NH in neuroendocrine proliferations <5mm in keeping with size criteria in other organs. This change in terminology from NET to NH may reduce unnecessary medical surveillance, overtreatment, and patient anxiety

Background: Fibroconnective tissues of the body are traditionally conceived as layers of densely compacted collagen. Recent in vivo microscopy, however, demonstrates that at least some, including visceral submucosae, dermis, fascia, adventitia and perineurium, are actually a reticular network of fluid-filled sinuses supported by a complex scaffold of thick collagen bundles (Benias et al Sci Rep 2018: 8). The interstitial fluid is rich in hyaluronic acid (HA). Whether these large scale interstitial spaces are continuous between tissues/organs or separate is unclear. Continuity was investigated by two methods: 1. movement of non-biological pigment (tattoo pigment, colloidal silver) in colon and skin specimens; 2. localization of HA by IHC.
Design(s): H&E-stained sections of FFPE tissues from resected colons following endoscopic submucosal tattoo for malignant polyps (n=5) and from skin biopsies with either cosmetic tattoos (n=3) or colloidal silver (n=2) were examined. Location of particles was assessed. The slides were then scanned, decolorized, and stained by multiplex chromogenic IHC assay (Discovery Ultra, Ventana) for HA-binding protein (brown), vimentin (magenta) and CD34 (teal) to label interstitial lining cells.
Result(s): Tattoo pigment and colloidal silver within the interstitial spaces was identified in the dermis (Fig. 1) and colonic submucosa and in the dependent mesenteric and subcutaneous fascias. In all colon specimens HA IHC highlighted the spatial continuity of all layers of the colon from lamina propria through muscularis mucosae to submucosa (Fig. 2A), then through the muscularis propria into mesenteric fascia (Fig. 2B, C). Continuity between these spaces and perivascular stroma/adventitia and perineurium in the bowel wall was also evident. Continuity of HA-filled spaces is also demonstrated from papillary to reticular dermis and then to subcutaneous fascia interface. (Figure presented)
Conclusion(s): Interstitial spaces are neither virtual nor a result of processing artifact, but are filled with physiologically relevant fluid rich in HA. Their continuity across tissue compartments is demonstrated by movement of non-biological pigments and by spatial continuity of HA. The implications of such multisystem continuity are protean, but may particularly explain commonly observed modes of discontinuous cancer spread through tissue planes, such as mesenteric tumor deposits in colon cancer and subcutaneous in-transit melanoma metastasis, and spread of infection (e.g. necrotizing fasciitis)

Weight loss through lifestyle intervention remains the mainstay treatment for nonalcoholic steatohepatitis (NASH). Nevertheless, only a minority of patients undergoing lifestyle intervention are able to achieve the weight loss threshold that reverses NASH histologic features. This case report demonstrates a minimally invasive method of treating NASH using an intragastric balloon. With endoscopic ultrasound-guided liver biopsy at the time of intragastric balloon removal, we demonstrate a significant improvement in NASH histologic features including steatosis, ballooning, lobular inflammation, and fibrosis. This endoscopic method may offer an alternative solution to patients with NASH who fail lifestyle intervention.