They threw me off the hay truck at noon

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They threw me off the hay truck at noon
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Tumor-to-Tumor

• Steven Sorscher

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Case

• 37 y/o female
• 1975 (age 5) retinal hemangioma and
  blindness
• 1987 balance difficulties, endolymphatic
  tumor
• 1994,1996 hemangioblastomas resected
• 1999 pancreatic neuroendocrine (NE) tumor,
  whipple, Dx with von Hippel-Lindau
• 2002 Liver recurrence, NE tumor
• 2006, 2008 Surgery for hemangioblastomas
  seeded with neuroendocrine tumor

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Tumor-to-tumor

• Von Hippel-Lindau An eponymic disease
• Overview of metastases
• Tumor-to-tumor metastases
• CNS tumor-to-tumor
• Novel treatment considerations

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Von Hippel-Lindau (VHL)

• Germline mutation or deletion in VHL gene
  (3p25-26)
• 20 founder mutation
• Tumor suppressor gene mechanism (Knudson 2-hit)
• Hypoxia-inducing factor (HIF-1) expression and
  angiogenesis (VEGF) in response to hypoxia
• Mutated VHL gene product does not degrade HIF-1,
  therefore
• Chronic HIF activation causes increased VEGF and
  vascular proliferation
• Death is usually due to RCCA, brain lesions or
  pheochromocytoma complications

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Arch Nemeses

• Superman
  VHL gene product
• Humbert
  Lex Luther
• Federer
  NY Yankees
• Professor Moriarity
  Nadal
• HIF
  Sherlock Holmes
• Boston Red Socks
  Clare Quilty

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• I grow old ... I grow old ...
• I shall wear the bottoms of my trousers rolled.
•  
• Shall I part my hair behind? Do I dare to eat a
  peach?
• I shall wear white flannel trousers, and walk
  upon the beach.
• I have heard the mermaids singing, each to each.
• TS
  Elliott
• To Create a monument that would have lasting
  significance..a landmark for our time
• 
  Eero Saarinen

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VHL complications

• Visceral
• Renal Cell Carcinoma (RCC)
• Renal cysts
• Pheochromocytoma (missense mutation in 40 of
  families)
• Pancreatic neuroendocrine tumors
• Cystadenomas of the epididymis or broad ligament
• CNS
• Hemangioblastoma
• Cerebellar tumors
• Brain stem, spinal cord, retina
• Endolymphatic sac tumors

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Von-Hippel Lindau

• 1904 Eugen von Hippel, angiomas of the eye
• 1927 Arvid Lindau, angiomas of the cerebellum,
  spine
• Eugen von Hippel (August 3, 1867 - September 5,
  1939) was a German ophthalmologist who was born
  in Königsberg. He studied medicine in Heidelberg
  under ophthalmologist Theodore Leber (1840-1917)
  and neurologist Wilhelm Heinrich Erb (1840-1921).
  In 1897 he attained the title of "professor
  extraordinary" at Heidelberg, and in 1909 became
  a professor at the eye clinic in Halle. In 1914
  he became a professor of ophthalmology in
  Göttingen.
• In 1904, Hippel described a rare disorder of the
  retina, and in 1911 discovered the anatomical
  basis of this disease, which he named
  "angiomatosis retinae". However it wasn't until
  1926 that Swedish pathologist Arvid Lindau
  recognized an association between angiomatosis of
  the retina with hemangioblastomas of the
  cerebellum and other parts of the central nervous
  system. This condition is known today as the Von
  Hippel-Lindau Disease (VHL).
• Hippel contributed several writings to textbooks
  regarding anatomy and diseases of the eye. He was
  the son of Arthur von Hippel (1841-1916), a
  pioneer in corneal transplantation, and an uncle
  to German-American physicist Arthur R. von Hippel
  (1898-2003).
• Type 1 VHL angiomatosis w/o pheochromocytomas
• Type 2 angiomatosis with pheochromocytomas
• 2A Low RCCA risk
• 2B high RCCA risk
• 2C Pheochromocytomas only no
  angiomatosis or RCCA risk

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Eugen von Hippel

• "To those who met von Hippel briefly, he appeared
  reserved and withdrawn but whoever came to him
  with a real human need, be it as a patient
  seeking advice from him, as a pupil returning to
  him, or as a co-worker seeking with him the same
  goal in a clinical and scientific task, that
  person would find in Dr. von Hippel a rich
  helpful attitude and an unlimited and unshakeable
  confidence."
• Dr. Baurmann, Karlsruhe Klinische
  Monatsblätter für Augenheilkunde, 1993, 103
  632-634.

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Hatfield vs McCoy Feud

• The Hatfields and McCoys have a storied and
  deadly history dating to Civil War times in the
  1860s. Their generations of fighting over land,
  timber rights and even a pig are the subject of
  dozens of books, songs and countless jokes.
  Unfortunately for rural Appalachia, the mountain
  area stretching from southern New York state to
  northern Mississippi, the feud is one of its
  greatest sources of fame. The spat officially
  ended with the formal truce declaration along the
  Kentucky-West Virginia border in 2003.
• McCoys reportedly harbor a VHL mutation with
  high propensity to pheochromcytomas causing
  excess epinephrine, exposive tempers
• Feud reportedly related to rage disease
  (Vanderbilt University, associated press)

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Metastasis Overview

• Clonal Expansion vs Rare Variant
  model
• Clonal Expansion A rare variant becomes the
  dominant primary/majority cancer cell by out
  competing the others (Darwinian selection)
• c/w common mutations in the primary and
  metastasis
• Rare Variant A rare cell has no selective
  growth advantage, but is a highly metastatic
  variant and will not become the majority in the
  primary (punctuated equilibrium)
• c/w Fidlers isolation of rare variants by
  subcloning in vitro or in vivo

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Clonal Dominance Theory of Cancer Progression

• A synthesis of clonal expansion and rare variant
  proposals
• Kerbel tumor cells clones and tagged either with
  random or single site and innoculated into
  animals
• Restriction length polymorphism analysis (RLPA)
  used to monitor primary and metastases
• 1 innoculation of a single clone will dominate
  the primary (clonal expansion) and metastasize
  (rare variant)

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Seed and Soil Donor factors

• Subclone acquires specific characteristics
  (metastatic cascade)
• Collagenases,proteases
• Adhesion molecules (eg E-cadherin loss) or
• CD44 involved in adhesion to hyaluronan (HA)
  expression is related to prognosis, metastatic
  potential
• Angiogenesis (eg VEGF expression)
• Integrins mediate cell, extracellular matrix
  interaction (eg loss of PTEN results in integrin
  alterations)
• ECM exerts an influence on both normal and
  neoplastic cells which affects the
  assembly/disassembly of the matrix (eg dynamic
  reciprocity)

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For example, the seed

• Hypoxia induces
• Reduced e-cadherin (loss of adhesion)
• Plasminogen activating receptor expression
  (invasion)
• Hepatocyte growth factor (HGF-MET) and cell
  migration to blood/lymphatics
• Increased VEGF for angiogenesis and dissemination
  (and establishment of metastatic foci)
• For VHL
• Like Hypoxia, VHL mutation in RCC causes
  increased HIF, decreased e-cadherin, both
  re-established with WT VHL or dominant negative
  HIF. (Sullivan, Cancer Met
  Rev,2007)

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Recipient Factors

• Anatomical considerations
• Vascularity
• Potential for immune reaction
• Changing micro-enviromental factors
• eg curative resections and prolonged TT recur

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For example, the soil

• Bone marrow and a pre-metastatic niche
• Clusters of hematopoietic progenitors cells
  express VEGFR-1 ( flt-1 ) and home to primary
  tumors to help growth.
• These same cells are found at tumour specific
  premetastatic sites before tumor cells arrive
• These cells express VLA-4 (an integrin) which
  allows a permissive environment for tumor
  colonization
• This is prevented by antibodies to those cells or
  removal of those cells from WT mice either
  intervention prevents metastases
• 
  (Kaplan, Nature, 2005)

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Tumor-to-tumor terminology

• Tumor-to-tumor
• Collision tumors
• Piebald tumor

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Case Reports

• The changing face of case reports (eg explosion
  of information, intervention affecting biology,
  nuances of different hosts and tumors)
• -Acinar cancer in HNPCC responding to Gemzar
• -Hepatocellular cancer after RT for Hodgkins
  Lymphoma
• True anomalies versus the extremes of a continuum
• -Jill Price, hyperthymestic
• The individual case should teach us something
  about the whole
• To see the world in a grain of sand

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• To see a World in a Grain of SandAnd a Heaven in
  a Wild Flower,Hold Infinity in the palm of your
  hand And Eternity in an hour.
•                                          -William
  Blake

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Tumor-to-tumor Definition

• More than one primary
• Recipient is true benign or malignant tumor
• Metatastic tumor is true metastasis (not
  collision, piebald, or emboli)
• Excludes lymphoreticular
• 
  (Pamphlett,1984)

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Tumor-to-tumor Considerations

• Slow growing
• Often not resected (eg hemangioblastoma)
• Highly vascular
• -mets tend to distribute to vascular areas (rim
  of ischemia in infarct, cerebral)
• 
  (Duffy, J Urol, 2004)

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Tumor-to-tumor history

• 1829 1st case reported
• 1930 1st CNS case, lung to meningioma
• 1968 22/34 cases, RCC was recipient
• Most common donor lung cancer
• Most common recipient renal cell carcinoma

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Tumor-to-Tumor Sites

• 150 cases reviewed
• Donor
  Recipient
• Lung (40-50)
  RCC (40-70)
• Breast
  Sarcoma
• Prostate
  Meningioma
• Thyroid
  Thyroid
• 
  Pituitary adenoma
• 
  (Constantina, Int. J Path, 2004)

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Tumor-to-CNS Tumor

• Most common recipient meningioma (83)
• Most common donor Lung and Breast (79)
• 23/25 (92) had metastases to other sites
• 
  (Caroli,Neurosurg Rev, 2005)

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Metastases to hemangioblastoma in VHL

• 75 cases of resected hemangioblastoma in patients
  with VHL (2002-2005)
• 5 cases with metastatic RCC to hemangioblastoma
• 1 case neuroendocrine tumor metastatic to
  hemangioblastoma
• 
  (Jarrell,
  2006)

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Renal cell and anti-angiogenesis

• 116 patients, placebo vs low vs high dose
  bevacizumab
• 4 months
  8 months
• PFS(10mg/kg) 64
  30
• Placebo Ab 20
  5
• (Plt0.001)
• Sutent/Sorafenib delay TTP 3-6 months
• 
  (NEJM,7-03,1-07)

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Hemangioblastomas and anti-angiogenesis

• Antiangiogenic agents in hemangioblastoma
• Case Report
• Symptomatic, unresectable hemangioblastoma C3/4
  in VHL patient
• HIF family proteins are expressed (by IHC) in
  hemangioblastoma causing uncontrlloed vascular
  proliferation. High levels of VEGF were also
  detected
• SU5416, VEGF TKI inhibitor led to resolution of
  hypaesthesia.. Spinal lesion was stable after 24
  months (clinical remission also seen in a patient
  with hemangioblastoma involving the optic nerve
  and for a patient with a retinal
  hemangioblastoma) (Schuch, JCO 2005)

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Neuroendocrine tumors and anti-angiogenesis

• Antiangiogenic agents in neuroendocrine tumors
• 48 patients on stable octreotide doses
  randomized
• Bevacizumab
  PEG IFN
• PR 18
• SD 77
  68
• PD 5
  27
• By CT blood flow was unchanged for IFN, but
  49 decrease at D2 for Bev (plt.01)
• 
  (Yao, JCO,2008)

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Conclusions

• More tumor-to-tumor might be expected with
  improved therapies but patterns will remain
  consistent
• VHL tumorigenesis and progression is likely
  mediated by angiogenesis and refined
  antiangiogenic agents will be helpful
• The metastatic phenotype is likely based on
  differing patterns of gene expression and
  individualized therapies may help

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• If you can dream--and not make dreams your
  master,
• If you can think--and not make thoughts your
  aim
• If you can meet with Triumph and Disaster
• And treat those two impostors just the same
  
  
• 
  -R Kipling