Honc: Late recurrence of breast CA

Morning Report
August 11, 2011
Nancy Luo
Dr. Hoffman
Please Swipe!!
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MKSAP Question
A 54-year-old postmenopausal woman is
evaluated after she discovered a right axillary
mass. She is otherwise healthy. She has never
smoked cigarettes and drinks alcohol only
socially. Family history is significant for her
mother who developed breast cancer at age 62
years.

MKSAP Question
On physical examination, temperature is
normal, blood pressure is 138/78 mm Hg, pulse
rate is 64/min, and respiration rate is 16/min;
BMI is 19. Thyroid examination is normal. A
mobile, nontender 2-cm axillary lymph node
mass is noted. There is no palpable breast mass
or other lymphadenopathy.

MKSAP Question
An excisional biopsy reveals adenocarcinoma.
Results of mammography and breast MRI are
normal. The complete blood count, metabolic
panel, urinalysis, and chest radiograph are
normal. Immunohistochemical staining results
are positive for CK-7 and are negative for CK-20,
estrogen receptor and progesterone receptor,
and TTF-1 expression.

MKSAP Question
Which of the following is the most appropriate
next step in management?
1. Chest CT scan
2. Panendoscopy of the aerodigestive tract
3. Right mastectomy and axillary lymph node
dissection
4. Thyroid ultrasonography

Please make your selection...
1. Chest CT scan
2. Panendoscopy of the
aerodigestive tract
3. Right mastectomy
and axillary lymph
node dissection
4. Thyroid
ultrasonography
25% 25% 25% 25%
1 2 3 4

MKSAP Question
Although most cases of unilateral axillary
lymphadenopathy in women are benign, when a
malignancy does occur, it is most commonly breast
cancer. Other tumors manifested by axillary lymph node
metastasis include those of the lung, thyroid, head and
neck, skin, and gastrointestinal tract. The primary site
remains unknown in about 30% of patients. Patients
with axillary lymphadenopathy, negative imaging
studies, and positive findings on immunohistochemical
analysis supportive of a diagnosis of occult breast cancer
should receive treatment according to established
guidelines for stage II breast cancer.

HPI
69 year old female who presents to Urgent Care
with nausea
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HPI Summary
• Nausea and associated retching for a month
• Improves with food intake, then worsens couple hours
after
• Regurgitation of mucus or partially digested food
• No burning pain
• Loss of appetite, early satiety, weight loss 5#, fatigue
• LUQ constant dull pain
• States this happened in 2009
• Baseline diarrhea (up to 3 loose BM a day) unchanged
and does not make nausea better
• Denies fever/chills, melena/BRBPR, headache, chest
pain, shortness of breath. Worsening dry cough recently.
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PMH Medications
• Type 2 diabetes 12 years
• Chronic depression/fatigue
• GERD
• H/o mild dysphagia x2yrs
• Subclinical CAD
• HTN
• Hyperlipidemia
• Breast cancer in remission, s/p
mastectomy 2000
• R arm lymphedema since
2000
• Stress urinary incontinence
• Chronic venous insufficiency,
L>R leg
• DJD of cervical spine
• Obesity
• Prevacid 60mg daily
• Prozac 20mg daily
• Lantus 17 units daily
• Glipizide 10mg BID
• Ascarbose 25mg TID
• Pioglitazone 30mg daily
• Metformin 1000mg BID
• Lipitor 20mg daily
• Avalide 300/25mg daily
• Amlodipine 10mg daily
• Oxybutynin 5m BID
• Imodium AD 2 mg prn
• Aspirin 81mg
• Vitamin E and D
next
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Oncologic History
The patient had a screening mammogram in 05/2000 which revealed
a 4.3 cm mass which was found behind the right nipple. In 09/2008,
underwent right radical mastectomy with lymph node dissection.
Pathology revealed invasive ductal adenocarcinoma, SDR grade 2 of
3. Surgical resection margins were clean and 1 of 25 lymph nodes
were positive. ER is immunochemically very positive. PR is
moderately positive and HER-2 was also positive. She underwent 4
cycles of Adriamycin and Cytoxan without Taxol, as well as 6 weeks of
XRT all completed in 2000. CT of the chest and bone scan 01/2002
revealed no definite evidence of metastatic disease. Subsequent yearly
diagnostic mammograms revealed no recurrence of cancer. She
completed 5 years of antiestrogen therapy. Patient does not follow
with oncologist.
back
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Past Surgical History Social History
• Right mastectomy 2000
• ORIF L ankle 9/2008
• Cholecystectomy 1980
Allergies
Adenosine, Phenobarbital,
Venlafaxine, Tamoxifen,
Anastrozole, Sucralfate
• Married to a statistician at U of
C
• Used to distribute Cephalon
cookware, now retired.
• Denies alcohol
• 30 pack year remote smoking
history
• Denies illicit drugs
Procedural history
EGD 2009: Normal esophagus. Bilious
fluid found in cardia and in gastric
body. Localized mildly erythematous
mucosa found in gastric antrum.
Otherwise normal stomach.
-bilious gastric fluid may have been
secondary to delayed gastric emtying
or bile reflux
-recommended upper GI series and
gastric emptying study (not complete)
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Physical Exam
• BP 100/52 Pulse 88 Ht 5’5” Wt 238 lb
• GEN: Pleasant, obese, somewhat anxious in no acute distress
• HEENT: Sclerae clear, MMM
• NECK: Supple. No supraclavicular or axillary adenopathy
• CHEST: Lungs clear to auscultation and percussion
• HEART: Regular rate rhythm. No murmurs/rubs/gallops.
• ABDOMEN: Soft, minimally tender in epigastric region
without mass or organomegaly
• EXTREMITIES: Non-pitting leg edema. R arm edematous.
• MUSCULOSKELETAL: Gait is narrow-based and steady.
• NEURO: Non focal, A&O x3
• PSYCH: Mood is dysthymic. Patient is articulate, but worried
in a nonspecific manner
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Differential diagnosis?
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Differential
Nausea/Vomiting
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Plan of action?
• Labs
• Empiric Rx
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Labs
13.7
9.2 261
38.9
HbA1C 7.5
132 94
4.1 26
17
1.1
264
9.9
7.8
0.5
4.3
18 19
131
Onc hx
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Clinic course
• Patient diagnosed with dyspepsia versus delayed
gastric emptying
• Given omeprazole BID with improvement
• Over 2-3 urgent care visits…
• H pylori checked
• Sent for gastric emptying study
• Sent for small bowel follow through
• Prescribed ondansetron with improvement in
symptoms
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Mechanism of Nausea and Emesis
• Coordination between CNS, PNS, GI tract
• Brainstem:
▫ “vomiting center” or central pattern generator
Indistinct collection of nuclei in medulla
Coordinates efferent respiratory, GI, autonomic activity associated with
n/v
Final effector pathway through which a variety of afferent stimuli can
activate emesis
▫ Area Postrema aka “chemoreceptor trigger zone”
Circumventricular, caudal end of 4 th ventricle
Outside BBB, accessible to emetic stimuli borne in blood or CSF
Important source of afferent input to vomiting center
Muscarinic, dopamine, serotonin, nerukinin-1, histamine receptors
• Higher brainstem/Cortex
• Vagus and Splanchnic nerves – carry input from GI tract
(terminates in brainstem in nucleus tractus solitarius)
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Neurotransmitters of clinical
significance
• Dopamine
▫ D-2 antagonists
▫ Metoclopramide, Prochlorperazine (Compazine)
• Serotonin (5-HT)
▫ Selective antagonists 5-HT3 receptor
▫ Ondansetron (Zofran), palonosetron (Aloxi)
▫ Side effect: constipation, mild HA,
• Substance P
▫ Neurokinin-1-receptor antagonists
▫ Aprepitant (Emend)
• Endocannabinoids
▫ Dronabinol and nabilone
▫ Side effects: postural hypotension, dysphoria
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6 weeks later, returns to PCP…
• Nausea persists
• No emesis for 4 weeks
• Unable to walk more than half a block
• Weight loss and loss of appetite
• H Pylori Ab 0.34
• Gastric emptying: normal
• UGI series: enlarged fundus of the stomach and
delayed gastric emptying
Onc hx
24

Next steps?
• Refer
• Endoscopy
• Imaging
25

Indications for referral
26

Referral to GI
• Repeat Endoscopy: Tortuous esophagus. Gastric
mucosal abnormality characterized by erythema.
Pathology normal.
27

CT Abd/Pelv
• Metastatic disease. Bilateral adrenal lesions and
right iliac bone metastasis. Primary
adrenocortical carcinoma (left adrenal gland
lesion) with metastatic disease is a primary
consideration although certainly other
metastatic neoplasms (such as lung cancer) can
present similarly.
• Onc Hx
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Admission
• States she is wheelchair bound
• More history?
• Workup?
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MRI Head
• Multiple lesions in the brain stem and right
parietal and frontal lobes are suspicious for
metastatic disease given the patient’s clinical
history. Although metastases is the most likely
diagnosis a non-neoplastic diagnosis cannot be
entirely excluded.
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Bone Scan
• Right iliac crest lesion
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CT Chest
• RUL pulmonary nodule highly suspicious for
malignancy. Differential diagnosis for this
includes primary lung cancer or metastatic
disease. Bilateral adrenal gland masses also
highly suspicious for malignancy.
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Laboratory testing
• Aldosterone

Brain metastasis
• Any cancer can metastasize to brain (up to 25%
of patients dying of cancer)
• Lung, breast, and melanoma most common
• 90% supratentorial: most commonly gray/white
matter junction, and in watershed areas of brain
• Focal or generalized symptoms, but subtle
• 50% have headaches, may also may present with
acute seizures, symptoms of increased ICP
• MRI is most sensitive and specific
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Increased intracranial pressure : an
oncologic emergency
• Resulting from brain edema and tumor expansion
• Nausea specifically by edema or mass at/near area postrema of the medulla
• Triggered emesis by change in body position
• Headache, depressed consciousness, CN VI palsies, papilledema,
spontaneous periorbital bruising, focal symptoms of herniation
▫ Cushing’s triad (bradycardia, respiratory depression, hypertension)
• Treat symptoms
• Dexamethasone (most lipid soluble)
▫ 4-16mg daily in divided doses (up to 24mg IV initially if very symptomatic)
• Antiepileptics
▫ Prophylaxis not necessary
• Hyperventilation/IV Mannitol/invasive ICP monitoring as indicated
• Surgery
▫ Solitary metastasis, oligometastases (

Sir William Richard Gowers
(20 March 1845 – 4 May 1915)
“Cerebral vomiting may be, and often is, unattended by
nausea, but this is not an invariable characteristic. In some
cases nausea is distressing… the coexistence of persistent
pain in the head, with frequent vomiting, should always
raise a suspicion of cerebral disease… Patients who vomit
without other indications of gastro-intestinal disturbance
should be carefully watched.”
- Gowers. A manual of diseases of the nervous system. 1888
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Neurological symptoms mistaken for
gastrointestinal disease: review
• Report from 1998, 25 patients neurologic symptoms mistaken for GI
disease over previous 23 years at USC/LA County (55,000/year)
▫ Most had nausea, some dysphagia/abd pain
▫ Most common diagnosis: gastritis/gastroenteritis, gastric outlet
obstruction, duodenal ulcer, dysphagia
▫ Many had contrast radiography, 6 had endoscopy (2 had unnecessary
operations)
▫ 13/25 had a diagnosis delay of 5.5 months
▫ On admission to a neurology service
neurological symptoms elicited in 20/25: headache, vertigo/dizziness,
ataxia, diplopia, hoarseness, tinnitis, visual loss, stiff neck
neurological signs elicited 23/25: nystagmus, pupillary abnormalities,
papilledema, bulbar weakness, ataxia/tremor, limb numbness
▫ Nausea was most common and most ambiguous symptoms
▫ Vomiting out of proportion to dizziness was confusing
▫ Abdominal pain- can occasionally be a symptoms of spinal disease, or
caused by repeated vomiting
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Patient course
• Started on oral decadron with symptom
improvement over 48 hours
• Whole brain radiation for 2 weeks
• Interventional radiology performed a CT guided
biopsy of the R iliac lesion
▫ Pathology: metastatic carcinoma morphologically
consistent with breast primary
▫ Strong ER positive 90% cells, PR expressed 5-10%
cells, HER2 negative, TTF-1 negative
38

Breast cancer and cancer dormancy
• Cancer dormancy
▫ An unusually long time between removal of the
primary tumor and subsequent relapse in a
patient who has been clinically disease-free
▫ Analogous to chronic disease model
• Breast cancer, 20% clinically disease-free patient
relapse 7-25 years after mastectomy
▫ From 10 to 20 years, rate of relapse is relatively
steady at about 1-1.5% per year
39

Primary Tumor
CTCs
Bone Marrow
Expansion to steady state
Dormancy
Loss of steady state
(relapse)
Growing metastasis
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Circulating tumor cells
• Circulating tumor cells have been found in patients
in long remission (clinically cured) at rates higher
than reported risk of recurrence
• Usually have short half life in blood
• Must have a source of replicating cells
(micrometastasis or bone marrow)
• Balance between replication and cell death, though
mechanism of control unknown
• Statistically NOT all of these patients found will
develop clinical recurrence, though increased risk is
unknown
• Treatment?
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Brain metastasis in HER2+ breast
cancer treated with Herceptin
• HER2-positive breast cancer patients may have
significantly higher incidence of CNS metastasis
after treatment with trastuzumab (Herceptin)
• HER2+ tends for more aggressive phenotype
• Trastuzumab overcame adverse prognostic
significant of HER2 positivity
• Large monoclonal antibody that does not cross the
BBB
• Improvement in systemic control and survival may
led to “unmasking” of CNS disease recurrence
• Brain may act as “sanctuary site”
42

Follow up
• After completion of palliative whole brain
radiation…
▫ Strength has improved remarkably
▫ Able to climb 27 stairs
▫ No nausea or headaches
• Started on aromatase inhibitor
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References
• Keane JR. Neurologic symptoms mistaken for gastrointestinal disease.
Neurology 1998;50:1189-1190.
• Squires RH. Intracranial tumors: vomiting as a presenting sign. Clin
Pediatrics 1989;28:351-354.
• Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med
1008;358:2482-94.
• Halfdanarson TR, Hogan WJ, Moynihan TJ. Oncologic emergencies:
diagnosis and treatment. Mayo Clin Proc. 2006;81 (6):835-848.
• Uhr JW, Pantel K. Controversies in clinical cancer dormancy. PNAS
2011;108:12396-12400
• Meng SD, et al. Circulating tumor cells in patients with breast cancer
domrancy. Clin Cancer Research 2004;10:8152-8162
• Musolino A, et al. Multifactorial central nervous system recurrence
susceptibility in patients with HER2-positive breast cancer. Cancer
2011;117:1837-1846
• Scorza K, et al. Evaluation of nausea and vomiting. AM FP 2007;76:76-84.
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