They threw me off the hay truck at noon
Tumor-to-Tumor
Steven Sorscher
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
Tumor-to-tumor
• Von Hippel-Lindau: An eponymic disease
• Overview of metastases
• Tumor-to-tumor metastases
• CNS tumor-to-tumor
• Novel treatment considerations
Von Hippel-Lindau (VHL)
Germline mutation or deletion in VHL gene (3p25-26)20% founder mutationTumor suppressor gene mechanism (Knudson 2-hit)Hypoxia-inducing factor (HIF-1) expression and
angiogenesis (VEGF) in response to hypoxiaMutated VHL gene product does not degrade HIF-1,
therefore:Chronic HIF activation causes increased VEGF and
vascular proliferationDeath is usually due to RCCA, brain lesions or
pheochromocytoma complications
Arch Nemeses
• Superman VHL gene product
• Humbert Lex Luther
• Federer NY Yankees
• Professor Moriarity Nadal
• HIF Sherlock Holmes
• Boston Red Socks Clare Quilty
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
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
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
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.
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)
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 Fidler’s isolation of rare variants by subcloning in vitro or in vivo
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)
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)
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)
Recipient Factors
• Anatomical considerations
• Vascularity
• Potential for immune reaction
• Changing micro-enviromental factors
• eg “curative resections” and prolonged TT recur
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)
Tumor-to-tumor terminology
• Tumor-to-tumor
• Collision tumors
• Piebald tumor
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…
• 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
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)
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)
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
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)
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)
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)
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%
(P<0.001)
Sutent/Sorafenib delay TTP 3-6 months
(NEJM,7-03,1-07)
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)
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 (p<.01)
(Yao, JCO,2008)
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
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