SUMMARY OF THE DIAGNOSTIC EVALUATION AND TREATMENT OF LOST
IN THE FOG DURING HIS STAY AT THE UC DAVIS SCHOOL OF
VETERINARY MEDICINE, AND RECOMMENDATIONS FOR FUTURE
TREATMENT
Prepared by Dr. W. David Wilson
Director of Large Animal Clinical Services
Veterinary Medical Teaching Hospital, University of California-Davis
Background:
Lost in the Fog, a 4-year-old Thoroughbred racehorse, presented to the Equine
Emergency and Critical Care Service at the UC Davis Veterinary Medical
Teaching Hospital (VMTH) at approximately 6:30 PM on the evening of Sunday,
August 13th. The horse was reported to have been in full training until 4 days
previously and had raced as recently as mid-July. He was reported to have
started to show intermittent low-grade fever and lethargy, starting on 8/09/06.
Two days later he became more lethargic, had a reduced appetite, and showed
signs consistent with mild abdominal discomfort (stretching, looking at his flanks,
laying down more often than normal).
Blood samples collected for further
diagnostic testing by Dr. Donald Smith, Lost In The Fog’s regular veterinarian,
revealed a mild anemia; otherwise, results of other tests performed on these
samples were unremarkable. The horse initially responded positively to
symptomatic treatment administered by Dr. Smith, and the excellent care
provided by Lost In The Fog’s trainer, Mr. Greg Gilchrist, and his experienced
staff. Signs of abdominal discomfort (colic) recurred during the afternoon of
8/13/06. When Dr. Smith examined Lost In The Fog at that time, he found that
his gastrointestinal sounds were absent and that his spleen was larger than
normal. Recognizing the need for the more advanced diagnostic capabilities
provided by specialists at the VMTH, Dr. Smith arranged for emergency referral
by contacting Dr. Gary Magdesian, a board-certified specialist in Equine Internal
Medicine and Critical Care, and Chief of the VMTH’s Equine Medical Emergency
and Critical Care Service. Dr. Smith administered an analgesic prior to loading
Lost In The Fog on the trailer in order to assure his comfort during the 90-minute
journey from Golden Gate Fields to the VMTH.
Examination and diagnostic work-up at the VMTH
Lost In The Fog arrived at the VMTH in excellent condition and appeared
comfortable, although he had an elevated heart rate and was mildly dehydrated.
He was examined immediately by Dr. Jonathan Anderson, a senior resident
veterinarian in the Equine Surgical Emergency and Critical Care Service, by Dr.
Magdesian, and by Dr. Julie Dechant, a board-certified equine surgeon who
specializes in abdominal surgery and the management of colic. At that time, Lost
In The Fog was evaluated and triaged in a manner similar to that used for all
horses that present to the VMTH with a history of, or active signs of, “colic” in
order to quickly determine the cause of the discomfort and determine the optimal
approach to treatment. Blood samples were collected immediately for analysis in
the ICU Lab, a complete physical examination and examination of the abdomen
per rectum were performed, a nasogastric tube was introduced into the horse’s
stomach to relieve potential pressure created by build up of gas or fluid, and a
catheter was placed in one jugular vein for intravenous administration of fluids
and electrolytes to correct dehydration and support circulatory function. In
addition, a detailed abdominal ultrasound examination was performed and a
sample of peritoneal fluid, collected from Lost In The Fog’s abdominal cavity by
introducing a catheter through his body wall at the lowest part of the abdomen,
was analyzed. Abdominal X-rays were also taken to help rule out accumulated
sand, foreign bodies, or enteroliths (hard intestinal stones formed by deposition
of minerals around a central core) as the cause of the horse’s discomfort.
Examination of the abdomen per rectum and abdominal ultrasound examination
generated the most significant findings. Examination per rectum detected a
markedly enlarged spleen and the edge of an abnormal mass deep within the
abdomen. The presence of a greatly enlarged spleen was confirmed during the
ultrasound examination, and, in addition, a large (25 by 35 centimeter), welldemarcated mass was identified in the lower portion of the spleen. A Doppler
ultrasound study of this mass was then performed to determine whether it
contained large blood vessels that could complicate collection of a biopsy. Large
vessels with active blood flow were not found. The second suspected mass that
had been detected during rectal examination could not be visualized during the
transabdominal ultrasound examination because it was presumably hidden
behind loops of intestine containing gas (gas reflects the ultrasound beam and
does not allow it to penetrate to visualize deeper structures). An additional finding
on the ultrasound examination was a mildly increased amount of peritoneal fluid
within the abdomen.
Within two hours of Lost In The Fog’s arrival at the VMTH on that Sunday
evening, Drs. Magdesian, Anderson, and Dechant had completed a detailed
physical examination and extensive diagnostic work-up and already had the
results of many diagnostic tests at their disposal. Based on their findings, the
doctors were able to rule out those conditions that are most commonly
encountered in horses referred to the VMTH for evaluation of colic. These
include impaction of the intestine with dry feed material, accumulation of sand or
gas in the intestine, enteroliths, colitis (inflammation of the colon), internal
abscess, and displacement or torsion (twist) of the colon or other portions of the
intestinal tract. More significantly, the team of veterinary specialists was able to
render the seemingly unlikely tentative diagnosis of neoplasia (cancer), probably
lymphoma, involving the spleen and potentially other areas of the abdomen,
although a biopsy would be necessary to confirm this diagnosis and rule out
other potential causes of the masses. They quickly devised a plan for continued
emergency care and monitoring and admitted Lost In The Fog to the Equine
Intensive Care Unit (ICU) where his condition could be monitored 24-hours-a-day
by the experienced ICU nursing staff working under their direction. In addition,
Dr. Magdesian formulated a plan for further diagnostic evaluation to confirm the
diagnosis of the splenic mass as quickly as possible, determine whether other
structures in the abdomen and elsewhere were involved, define treatment
options, and project the short-term and long-term prognosis associated with each
treatment option. Many members of UCD’s team of experts would be involved in
this well coordinated effort.
Lost in The Fog’s condition stabilized quickly and he spent a comfortable Sunday
night in the Equine ICU. On Monday morning, Dr. Magdesian planned to repeat
the abdominal ultrasound examination, in part to further investigate the potential
presence of other masses in the abdomen, and in part to perform an ultrasoundguided biopsy of the mass in the spleen. At the VMTH, it is routine practice to
make sure a horse’s blood clotting profile is normal before performing biopsies
on organs such as the spleen, liver, or kidney that have an abundant blood
supply. In Lost In The Fog’s case, one of the clotting times (PTT) was abnormally
prolonged; therefore, a transfusion with 3 units of plasma was administered in
order to minimize the risk of serious hemorrhage during the biopsy procedure. In
addition, a blood cross-match was performed and a matched donor horse was
made available in case Lost In The Fog needed fresh blood. A radiographic (Xray) examination of Lost In The Fog’s thorax was completed at this time to look
for evidence of spread of the tumor to his chest. No evidence of spread to the
chest was found.
As soon as the plasma transfusion had been completed and Lost In The Fog’s
clotting times had been rechecked to make sure the PTT had returned to the
normal range, Dr. Mary Beth Whitcomb, a specialist in equine ultrasound and
chief of the VMTH Equine Ultrasound Service repeated the ultrasound
examination and performed the delicate ultrasound-guided biopsy with an 8-inch
long biopsy needle introduced through a tiny incision in Lost In The Fog’s body
wall on his left side. Dr. Whitcomb’s examination confirmed Dr. Magdesian’s
findings of a cauliflower-like mass in the spleen, approximately 25cm cranial to
caudal (front to back) by 35cm dorsal to ventral (top to bottom) by 20cm deep
(outside to inside). Lost In The Fog tolerated the splenic biopsy procedure well
and did not suffer any hemorrhage or other complications. He was returned to his
stall in the ICU unit where he was maintained on intravenous fluids and had his
condition monitored intensively.
While awaiting the results of the splenic biopsy, Dr. Magdesian assembled a
team of specialists in equine abdominal surgery, equine anesthesia, and equine
oncology to develop a plan to further explore Lost In The Fog’s abdomen in order
to determine whether the mass had spread beyond the spleen. In addition, this
same group developed a tentative plan for surgical removal of the spleen, and
potentially other tumors, if that was judged to be feasible. When preliminary
histopathology results confirming that the splenic mass was indeed a
lymphosarcoma were reported on 8/16/06, plans were made to hold Lost In The
Fog off feed overnight on 8/17/06 to facilitate a standing exploratory laparoscopic
examination of his abdomen on Friday, August 18th. Two equine anesthesia
specialists, Dr. Robert Brosnan and Dr. Eugene Steffey, chief of the VMTH
Anesthesia Service, planned and implemented a protocol for sedation and
analgesia, while Dr. Larry Galuppo, chief of the Equine Surgery Service, his
equine abdominal surgery specialist colleague, and Dr. Dechant, performed the
laparoscopic examination, assisted by Dr. Anderson. Dr. Galuppo was one of the
early pioneers of this procedure in the horse, describing normal and abnormal
findings in articles published in widely read veterinary journals during the early
1990’s and in presentations at conferences for equine surgery specialists.
Lost In The Fog was sedated, placed in the standing stocks in the Equine
Surgery suite, his flanks were clipped and prepared for aseptic surgery, and local
anesthetic was infiltrated into the areas on each of his flanks where the small
surgical incisions would later be made. Additional amounts of sedative and
analgesic drugs were administered intravenously via an IV catheter to assure
Lost In The Fog’s comfort during the procedure. After creating the portal for
introduction of the laparoscopic instruments, Lost In The Fog’s abdomen was
distended with carbon dioxide, a sterilized telescopic video camera (laparoscope)
was introduced, and the interior of the abdomen was systematically examined
while viewing the image on a large video monitor. The laparoscopic examination
revealed two masses that had not been visible during the earlier ultrasound
examination. One mass was 25 to 30 cm in front of the left kidney, while the
second was located at the base of the cecum high on the right side and
measured 25 x 30 centimeters. Multiple biopsy samples were collected from the
latter mass under direct laparoscopic visualization and submitted for
histopathologic examination, as for the biopsy sample previously collected from
the spleen. Lost In The Fog handled the laparoscopic procedure well, recovered
uneventfully, and was released from the hospital into the care of Mr. Gilchrist and
Dr. Smith, the referring veterinarian, on Sunday, August 20 th, while awaiting the
final results of the specialized tests being performed on the biopsy samples.
Dr. Alain Theon, chief of the Medical and Radiation Oncology Services at the
VMTH and one of the few equine oncology specialists in the world, remained in
close consultation with Dr. Magdesian during Lost In The Fog’s hospitalization at
the VMTH. Dr. Theon was hopeful that if the tumor had not spread beyond the
spleen, Lost In The Fog could have been cured by surgical removal of his spleen
(splenectomy), perhaps together with a short course of chemotherapy, the exact
nature of which would be determined by the pending results of tests on the
biopsies. Considering the size and location of the additional masses found during
the laparoscopic examination, Drs. Theon, Magdesian, Galuppo, and Dechant
deemed that a surgical cure was not to be feasible at this time, although they did
not rule out the possibility of adjunctive surgical treatment if the size of the
masses could be reduced. Nor did they rule out the possibility of chemotherapy.
To this end, they recommended that Lost In The Fog be started on a course of
treatment with Dexamethasone, a corticosteroid immunosuppressive antiinflammatory medication, with the goal of reducing the size of the masses.
Lymphoma in the horse generates a considerable inflammatory response
characterized by influx into the tumor of cells, many of which are reactive
lymphocytes. These inflammatory cells may contribute substantially to the size of
the tumor masses. By suppressing this inflammatory reaction, corticosteroids
often shrink lymphomas considerably, making them more amenable to surgical
removal or chemotherapy, as well as reducing their impact on the function of the
horse’s organs, including the gastrointestinal (GI) tract. Pressure on the GI tract
by the lymphoma masses in the abdomen was likely the cause of the colic signs
experienced by Lost In The Fog initially.
The splenic biopsy samples, which were pale yellow in color and of firm
consistency, were submitted to the VMTH’s Pathology Service for evaluation. In
addition to standard cytologic, histopathologic (microscopic) examination, the
samples
were
evaluated
using
two
state-of-the-art
procedures,
immunohistopathologic examination on fresh frozen samples and clonality
testing, that were developed at UC Davis by pathologist, Dr. Peter Moore, and
his research group. Standard histopathologic examination involves fixing biopsy
samples in formalin, embedding them in paraffin blocks, slicing them into ultrathin slices, staining them with stains that are taken up by different cell types and
cellular organs to different degrees, and then examining them under a high
magnification microscope. This type of testing allows pathologists to determine
whether the architecture of the organ in question is normal or abnormal and gives
them an overall impression of the types of cells that may be invading the organ.
In Lost In The Fog’s case, the architecture of the spleen was clearly abnormal
and areas were invaded by islands of similar-looking abnormal cells resembling
lymphocytes. These histopathology results, which were available within 48 hours,
were highly suggestive of lymphoma but, because of the unique cellular
response that horses show in tissues invaded by lymphoma cells, it was not
possible to confirm the diagnosis of lymphoma with 100% certainty, or to
determine the specific type of cell involved, without the use of more sophisticated
laboratory methods.
Tumors form when mutations (mistakes) happen during the normal process of
division and multiplication of cells within the body. Normally, these mutated
offspring do not cause a problem because they are quickly detected and
destroyed by the body’s immune surveillance system. If the body does not
recognize these mutated cells, however, they tend to multiply rapidly, unhindered
by the body’s normal regulation mechanisms, and a tumor is formed. In benign
types of cancer, the tumor grows slowly in the organ in which it forms, whereas in
more malignant types, the tumor grows rapidly and spreads via the bloodstream
or via lymphatics to invade organs elsewhere in the body. In the case of
lymphoma, the progenitor (parent) cells are lymphocytes. Lymphocytes are
important components of the body’s immune system and circulate in the
bloodstream as members of the family of white blood cells. They also populate
lymph nodes and lymphoid centers in the spleen and other organs. Because
lymphocytes are normal constituents of blood, lymphoma in most species,
including humans and dogs, typically causes lymphoid leukemia, an increase in
the number of lymphocytes in the circulation. Under these circumstances
definitive diagnosis can often be achieved by examination of blood samples. This
is rarely the case in the horse, however; therefore, it is necessary to examine
biopsies collected from abnormal tissue masses.
Complicating matters further is the fact that not all lymphocytes in the body are
the same. This is important to recognize because it has an important impact on
the choice of drugs and dosage protocols that could potentially be used in
chemotherapy and on the likely outcome of such chemotherapy. Whereas all
lymphocytes are descendents of a common lymphoid stem cell, they differentiate
into two main families (B-cells and T-cells) during development. Descendents of
these progenitor B-cells and T-cells then differentiate further to generate many
families of lymphocyte subtypes that each play a specific role in the body’s
coordinated immune response to infectious agents and other challenges. Each
family and subfamily of lymphocytes expresses unique identifying markers on
their surface. Many years of painstaking research performed by Drs. Peter
Moore, Jeff Stott, and their colleagues in the School of Veterinary Medicine at
UCD, has very recently resulted in the production of antibodies that allow
pathologists at UCD to examine biopsy samples and to not only identify that a
suspected tumor is of lymphocyte origin, but also to precisely define the
subfamily of lymphocytes involved. In Lost In The Fog’s case, standard
immunohistochemical staining methods using commercially available reagents
on the formalin-fixed biopsy sample failed to provide the needed information.
Fortunately, Dr. Moore was able to reach an accurate definitive diagnosis by
applying the unique reagents he has developed in his laboratory to a tiny sample
of Lost In The Fog’s splenic biopsy that had been stored fresh frozen. The
certainty of diagnosis was further verified by results of clonality tests developed
in Dr. Moore’s laboratory, the only laboratory in the world that can perform this
testing. Results of the tests performed by Dr. Moore confirmed the splenic mass
to be a lymphoma of B-cell origin. The following is a quote from the report
prepared by Dr. Moore and his colleagues, Drs. Robert Higgins and Jenny Luff,
specialists in pathology: “the sections examined were histologically consistent
with a large cell lymphoma. The diagnosis of B cell lymphoma was based upon
the positive immunoreactivity with CD11a (leukocyte marker), CD21 (B cell
marker), and CD79a (B cell marker) on sections of frozen tissue and the results
of clonality (clonal rearrangement of IGH - immunoglobulin heavy chain gene).
The sample was negative for T cell markers on frozen sections (CD3, CD4, and
CD8).” Dr Moore, working with fellow pathologists, Drs. Jim MacLachlan and
Patricia Gaffney, applied the same testing procedures to the biopsy sample
collected from mass at the base of the cecum during the laparoscopic procedure
and confirmed that it was a B-cell lymphoma identical to that found in the splenic
mass.
Despite the need to apply many intricate and sophisticated tests, accurate
characterization of Lost In The Fog’s primary cancer and metastatic masses was
achieved within 10 days of his presentation to the VMTH, a timeframe that is
rarely achieved in human medical centers. Drs. Magdesian and Galuppo will visit
Lost In The Fog at Golden Gate Fields on August 31st and, working with Mr.
Gilchrist and Dr. Smith, will perform another detailed physical examination,
bloodwork, and abdominal ultrasound examination to evaluate shrinkage of the
lymphoma mass in the spleen. In addition, they will examine the abdomen per
rectum to determine whether the mass at the base of the cecum has changed in
size. If it is determined that the masses have shrunk considerably, the possibility
of surgical removal will be revisited and discussed with Mr. Gilchrist and Mr.
Aleo. If the masses remain inoperable, complete cure is likely unattainable. In
that case, the prospect of inducing remission of the cancer with chemotherapy
will be revisited and discussed in detail.
Dr. Alain Theon has in recent years performed a substantial amount of
pioneering research on equine tumors and has made tremendous progress in
establishing safe protocols for high dose systemic chemotherapy in horses. He
has now developed a standard protocol of combination chemotherapy that
includes doxorubicin and has used this protocol to treat a substantial number of
horses with tumors. The aggressive drug doses included in this protocol could
potentially induce remission of Lost In The Fog’s tumors, although it is unlikely
that a complete cure could be accomplished. If chemotherapy is pursued, Lost In
The Fog would be monitored very closely for potential side effects, many of
which are the same as those seen in human chemotherapy patients. Allergic
reactions, bone marrow suppression, gastrointestinal upsets, adverse impacts on
fertility, and adverse effects on the heart, are all potential complications that
might need to be addressed. On a positive note, Dr. Theon’s work to date
indicates that horses tolerate high dose chemotherapy much better than do many
species, including humans and dogs. Despite the many advances Dr. Theon and
his colleagues have made in the treatment of tumors in horses in recent years,
Lost in the Fog's condition highlights the tremendous need for further research
and funding in this important area.