For the Pacific College of Oriental Medicine Sept 2019

1. Neil Theise, MD
Department of Pathology
New York University School of Medicine
New York City
What Lies Between:
Interstitium, Fascia, &
Questions of Culture and Practice

2.  Full disclosures:

3.  Full disclosures:
• “Allopathic” trained physician

4.  Full disclosures:
• “Allopathic” trained physician
• Liver Pathologist

5.  Full disclosures:
• “Allopathic” trained physician
• Liver Pathologist
• Jewish, Zen Buddhist, Shamanic practitioner

6.  Full disclosures:
• “Allopathic” trained physician
• Liver Pathologist
• Jewish, Zen Buddhist, Shamanic practitioner
• Human with Ehlers-Danlos who has benefited
therapeutically (and humanly) from Iyengar
yoga, osteopathy, acupuncture, tai chi, and
physiotherapy.

7. The “allopathic” view of histologic anatomy

9. What is Optical Biopsy ? 9
Physical Biopsy
Optical Biopsy
En-face view
In-vivo
Microscopic
Minimally invasive
Instantaneous imaging
9
Transverse view
Ex-vivo
Microscopic
Invasive
Delayed imaging

10. Probe based Confocal Laser Endomicroscopy
How it works:
 Fluorescein: extracellular contrast
 492 nm absorption spectrum
 Depth of focus; ~70 mM

11. pCLE fixed focal depth
Esophagus

12. pCLE fixed focal depth
Stomach

13. pCLE fixed focal depth
Small Intestine

14. pCLE fixed focal depth
Large Intestine

15. But in the biliary and pancreatic ducts,
something weird appears by pCLE…
The “reticular pattern.”

16. Normal Common Bile Duct

17.  Arteries? Veins?
 Muscularis mucosae?
 Mucosal crypts?
 Peribiliary glands?
 Submucosal capillaries?
Normal Common Bile Duct

27. Real spaces
NOT artifactual spaces!

28. CD34: endothelial cells of blood vessels but not lymphatics
CD31 (PECAM-1): diverse endothelial cells
LYVE-1: lymphatic vascular endothelial cells
D2-40: lymphatic vascular endothelial cells

29. CD34 Vimentin
frozen frozen
fixed fixed

30. Negative markers:
(D2-40)
CD31
ERG
LYVE-1
Smooth Muscle Actin
CD117 (c-kit)
Nuclear b-catenin

35. Implications
 Invasion into submucosa potentiates metastasis
 Circumferential compression:
• outward, by impacted stone or tumor
• inward, by tumor or nodes
 Sclerosis (e.g. PSC, biliary atresia) activation of
endothelial/fibroblastic cells?

36. Implications
 Invasion into submucosa potentiates metastasis
 Circumferential compression:
• outward, by luminal tumor or stone
• inward, by extrinsic tumor or nodes
 Sclerosis (e.g. PSC, biliary atresia) activation of
endothelial/fibroblastic cells?

37. Implications
 Invasion into submucosa potentiates metastasis
 Circumferential compression:
• outward, by luminal tumor or stone
• inward, by extrinsic tumor or nodes
 Sclerosis (e.g. PSC, biliary atresia) activation of
endothelial/fibroblastic cells?
Intrahepatic features
of LBDO

41. Space of Mall

42. Space of Mall

43. Space of Mall

44. Space of Mall

45. Implications
 Invasion into submucosa potentiates metastasis
 Circumferential compression:
• outward, by luminal tumor or stone
• inward, by extrinsic tumor or nodes
 Sclerosis (e.g. PSC, biliary atresia) due to activation
of CD34+ fibroblastic cells?

46. Is this something special about the bile duct…?

47. 10x CD34, 40x

48. Digestive Tract: Implications
 Submucosal compressibility creates “shock absorber” functionality
 Peristalsis drives lymphatic flow along the digestive tract
 Lymphatic flow parallels luminal flow: communication? Other
functionalities?
 Tumor invasion into submucosa potentiates metastasis
 Endothelial/fibroblastic cells may mediate peri-tumoral sclerosis.
 Sclerosis (e.g. PSC, biliary atresia) activation of
endothelial/fibroblastic cells?

49. Digestive Tract: Implications
 Submucosal compressibility creates “shock absorber” functionality
 Peristalsis drives interstitial and therefore lymphatic flow along the
digestive tract
 Lymphatic flow parallels luminal flow: communication? Other
functionalities?
 Tumor invasion into submucosa potentiates metastasis
 Endothelial/fibroblastic cells may mediate peri-tumoral sclerosis.
 Sclerosis (e.g. PSC, biliary atresia) activation of
endothelial/fibroblastic cells?

50. Digestive Tract: Implications
 Submucosal compressibility creates “shock absorber” functionality
 Peristalsis drives interstitial and therefore lymphatic flow along the
digestive tract
 Submucosal space is compressible and distensible
 endothelial/fibroblastic cells?

51. Digestive Tract: Implications
 Submucosal compressibility creates “shock absorber” functionality
 Peristalsis drives interstitial and therefore lymphatic flow along the
digestive tract
 Submucosal space is compressible and distendible
 Tumor invasion into submucosa potentiates metastasis
 endothelial/fibroblastic cells?

52. Digestive Tract: Implications
 Submucosal compressibility creates “shock absorber” functionality
 Peristalsis drives interstitial and therefore lymphatic flow along the
digestive tract
 Submucosal space is compressible and distendible
 Tumor invasion into submucosa potentiates metastasis
 CD34+ fibroblastic cells may mediate peri-tumoral sclerosis.
 endothelial/fibroblastic cells?

53. Is this something special about the digestive tract…?

56. PREDICTS

57. Seen in:
Perivascular stroma

58. Seen in:
Urinary bladder submucosa

59. Seen in:
Bronchial submucosa and
peri-cartilagenous soft tissue

60. Debby Green
Iyengar Yoga Instructor
Certified Rolfer

61. Seen in:
Fascia

62. Skin

63. So if its not vascular and not lymphatic, what is it?

64. Pre-obstructed bowel (incarcerated hernias)
 Specimens from 6 patients

65. Pre-obstructed bowel (incarcerated hernias)
 Immunostains positive for plasma proteins:
IgG, IgM, IgA, C-reactive protein, albumin, A1AT

66. Pre-obstructed bowel (incarcerated hernias)
 Immunostains positive for plasma proteins:
IgG, IgM, IgA, C-reactive protein, albumin, A1AT
Lymph?

67. Wiki:
Lymph is the fluid that circulates throughout the lymphatic system. The
lymph is formed when the interstitial fluid (the fluid which lies in the interstices of all
body tissues) is collected through lymph capillaries.
It is then transported through lymph vessels to lymph nodes before
emptying ultimately into the right or the left subclavian vein, where it mixes back with
blood.
Since the lymph is derived from the interstitial fluid, its composition
continually changes as the blood and the surrounding cells continually exchange
substances with the interstitial fluid.

70. Therefore this space links to the lymphatics.

71. Ulcerated surface CA of stomach
Invasive
tumor

74. Dermal invasion of melonoma

77. So if its neither vascular nor lymphatic,
but pre-lymphatic,
it must be the interstitium!

78. Function of Interstitial Spaces and Matrix
• Regulates fluid flow
– Cell nourishment and health
– Morphogenesis, regeneration,
cell function in general
• Permeability and movement
– Cells
– Liquids and solutes
• Mechanical properties
(resistance to compression)
Interstitial flow
Swartz and Fleury, Ann Rev Biomed Eng 2007

79. Function of Interstitial Spaces and Matrix
Swartz and Fleury, Ann Rev Biomed Eng 2007
Interstitial flow

80. Interstitial spaces x3; Ex: Liver
Intercellular spaces
Space of Disse
Space of Mall

81. Fascia…? Something old or something new?

82. An osteopathic view…
Hugh Ettlinger,
DO, FAAO, FCA
Zina Pelkey,
DO, FCA

83. Grey’s Anatomy 1994

85. Grey’s Anatomy 1994
Grey’s Anatomy 1915

87. Grey’s Anatomy 1994
Grey’s Anatomy 1915
“Teased Rat Dermis”
1889 Gerald Yeo

88. Is this interstitium? (what is interstitium?)
Is this fascia? (what is fascia?)
“The fascial system consists of the three-dimensional continuum of soft,
collagen containing, loose and dense fibrous connective tissues that
permeate the body. It incorporates elements such as adipose tissue,
adventitiae and neurovascular sheaths, aponeuroses, deep and
superficial fasciae, epineurium, joint capsules, ligaments,
membranes, meninges, myofascial expansions, periostea,
retinacula, septa, tendons, visceral fasciae, and all the intramuscular and
intermuscular connective tissues including endo-/peri-/epimysium. The
fascial system surrounds, interweaves between, and interpenetrates all
organs, muscles, bones and nerve fibers, endowing the body with a
functional structure, and providing an environment that enables all body
systems to operate in an integrated manner.”
Stecco C, Adstrum S, Hedley G, Schleip R, Yucesoy CA
Update on fascial nomenclature. J Bodyw Mov Ther. 2018; 22: 354.

89. Is this interstitium? (what is interstitium?)
Is this fascia? (what is fascia?)
“The fascial system consists of the three-dimensional continuum of soft,
collagen containing, loose and dense fibrous connective tissues that
permeate the body. It incorporates elements such as adipose tissue,
adventitiae and neurovascular sheaths, aponeuroses, deep and
superficial fasciae, epineurium, joint capsules, ligaments,
membranes, meninges, myofascial expansions, periostea,
retinacula, septa, tendons, visceral fasciae, and all the intramuscular and
intermuscular connective tissues including endo-/peri-/epimysium. The
fascial system surrounds, interweaves between, and interpenetrates all
organs, muscles, bones and nerve fibers, endowing the body with a
functional structure, and providing an environment that enables all body
systems to operate in an integrated manner.”
Stecco C, Adstrum S, Hedley G, Schleip R, Yucesoy CA
Update on fascial nomenclature. J Bodyw Mov Ther. 2018; 22: 354.
But what about dermis and visceral submucosae?

90. Carla Stecco MD, ... Raffaele De Caro MD,
inFunctional Atlas of the Human Fascial
System, 2015

91. Carla Stecco MD, ... Raffaele De Caro MD,
inFunctional Atlas of the Human Fascial
System, 2015

92. Carla Stecco MD, ... Raffaele De Caro MD,
inFunctional Atlas of the Human Fascial
System, 2015

93.  What lies between: Continuity…

94. Mucosa
Muscularis
Mucosae
Submucosa
Hyaluronic Acid

95. Hyaluronic Acid
Submucosa
Muscularis Propria

96. Muscularis Propria
Subserosa/Mesentery
Hyaluronic Acid

97. Allopathic views… Osteopathic views… Other views…?

98. Chinese medicine…?

99. Acupuncture…?

100. Theise ND.
Now you see it, now you don’t.
Nature, May 2005
“Cell doctrine: modern biology and medicine see the
cell as the fundamental building block of living
organisms, but this concept breaks down at different
perspectives and scales.”

101. Li G, et al.
Physiology and cell biology of acupuncture
observed in calcium signaling activated
by acoustic shear wave.
Pflugers Arch. 2011; 462: 587-97.
“The validity of cell doctrine depends on the scale at
which the body is observed. To limit ourselves to the
perspective of this model may mean that explications of
some bodily phenomena remain outside the capacity of
modern biology. It is perhaps time to dethrone the
doctrine of the cell, to allow alternative models of the
body for study and exploitation in this new, postmodern
era of biological investigation.”

102. Piezo-electricity

103. Piezo-electricity
Chi…?
Prana…?

104. Tibetan pulse diagnosis…?

105. and…?

106. Dept. of Medicine, Digestive Disease Division
Mount Sinai Beth Israel Medical Center
 Petros Benias, MD (now Northwell)
 David Carr-Locke, MD (now Cornell)
 Darren Buonocore
 Markus Miranda
Dept. of Pathology (Electron Microscopy Laboratory)
Mount Sinai Beth Israel Medical Center
 Jason Reidy, PhD
Dept. of Pathology, NYU School of Medicine
 Sue Kornacki, Stella Gordin
Rebecca Wells Laboratory,
Dept. of Medicine, Gastroenterology
University of Pennsylvania
 Jessica Llewelyn, PhD
 Bridget Sackey, PhD
Acknowledgments

107. Henry David Thoreau
“When any real progress is made, we
unlearn and learn anew what we
thought we knew before.”