case #1 unforced error - ucsf cme · •case control study of uc patient with refractory disease...
TRANSCRIPT
5/26/2017
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Pitfalls in Gastrointestinal and Hepatic Pathology
Laura W. Lamps M.D.Godfrey D. Stobbe Professor of Gastrointestinal Pathology
University of Michigan Department of Pathology
Patient Safety Officer, Michigan MedicineAnn Arbor, MI
• Unforced error (LWL)– A player makes an error that is not the result of an action by his/her opponent– The player has full control of his/her actions, but still makes a mistake
• Forced error (LWL plus clinician)– The opponent hits a difficult shot and causes the player to miss– Succumbing to an impossible ball that can’t be returned
• Errors from the stands– Errors that I did not actually commit, but watched happen, and had good seats
Case #1Unforced Error
50 year old woman s/p renal transplant, with diarrhea
Duodenal biopsy
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Next day………….
• Clinician called and asked for CMV immunostain because he was sure patient had CMV (of note, this was on the requisition, but it’s on 98% of his requisitions, so I ignored it)
• CMV immunostain grudgingly ordered
CMV immunostain
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Mistakes Made• Looked at cases too quickly
• Violated own rules of when to order special stains
Mistakes Made• Looked at cases too quickly
• Violated own rules of when to order special stains
• Allowed irritability to cloud judgment• Corollary: Just because the person asking drives you nuts,
doesn‘t mean what they are asking for is crazy
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Essentially Normal Bx in Immunocompromised Patient
Increased apoptotic
epithelial cells
CMVAdenovirus
Don’t overlook spirochetosis, coccidians, or
Giardia!
Are they severely immunocompromised?Is there another reason
to worry?
No
Done!
Yes
Get history, consider GMS,
CMV
Big unexplained ulcer
? Elderly Patient
Yes
CMV
No
Get history, tailor workup to that
Immunocompromised Patient
Yes
CMV?HSVGMS?AFB
Utility of Special Stains in Evaluation of Biopsies for GI Infections
• Monkemuller et al, AJCP 2000• HIV patients• 28 months• Sensitivity and specificity for CMV diagnosis on H&E were 97%
and 100%• AFB/GMS stains did not identify previously diagnoses infection in
any patient• Long-term follow-up revealed no missed infections on H&E• Stains doubled cost
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Utility of CMV Stains in Evaluation of Biopsies from UC Flares
• Kambham et al, AJSP 2004• Case control study of UC patient with refractory disease• 25% of patients with refractory UC had CMV inclusions on immunostain
• 60% of these had been missed on H&E• Recommend using CMV IHC in evaluation of biopsies in these patients
CMV-poorly formed inclusions
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Lessons Learned• Slow down
• Don’t break own your own rules; you made them for a reason
• Don’t allow irritability to cloud judgment/good patient care
Whatever it was, I didn’t do
it.
Case #2Unforced Error
56 year old woman with abdominal pain, gastritis
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Partial gastrectomy
Pseudo-Signet Ring Cells•Benign cells with signet ring morphology
• Degenerative change associated with:• Ulceration/reactive gastropathy• Ischemia• C. difficile-associated pseudomembranous colitis
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Autoimmune gastritis
Pseudo signet ring cells in C. difficile infection-courtesy Dr. Wendy Frankel
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Real signet ring cells
Mistakes Made
• Didn’t put enough weight on the fact that all the atypical cells were detached
• Didn’t put enough weight on the fact that the largest nuclei were not that much larger than normal nuclei
• Correlation with macroscopic appearance (doesn’t always help with gastric cancer, though)
Can Stains Help?• Cytokeratin
• Both benign and malignant signet ring cells will be positive• Exception: muciphages
• Mucin• Helpful if negative, not so if positive
• Reticulin• Maybe
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Muciphages
Can Stains Help?• Proliferation markers
• Maybe• Reactive processes can also be very proliferative
• E-cadherin• Maybe• E-cadherin often decreased in signet ring cell carcinomas
From Hughes, Greywoode, and Chetty: Virchows Arch 2011;459:347-9
Reticulin stain highlights basement membrane of glands
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E-cadherin
Pseudomembranous colitis Signet ring cell carcinoma
Courtesy Dr. Wendy Frankel
E-cadherin-signet ring cell carcinoma
Ki-67Pseudomembranous colitis Chemical gastropathy
Courtesy Dr. Wendy Frankel
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Lessons Learned• Location of signet ring cells of paramount importance
• Lamina propria vs. discohesive, detached
• Four fine pathologists can all be wrong
• Proliferation markers, reticulin, E-cadherin might have helped but not necessarily
Is that a real signet ring cell or a fake one?
Case #3Unforced Error
65 year old man with poorly defined gastric mass
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Diagnosis: Plasmacytoid Neoplasm• Very poorly defined (or so I’m told)
• Gross description describes tiny bits
• I worked in one of the largest myeloma centers in the world
• CD138 +++++++++++++++++++++• Kappa and Lambda have high background staining, not useful
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Two months later……..• Attend CME conference where John Goldblum speaks about new GIST variants
• Describes a strikingly plasmacytoid variant of GIST
• Uh-oh. !@#$%!!
Mistakes Made• Should have known the literature better
• Did not know all the vagaries of immunostainsemployed
• Allowed context of where I worked to influence differential
Plasmacytoid (pleomorphic) GIST•Majority of GISTs are monomorphic•Small subset are pleomorphic
• Myxoid/hyalinized stroma• Variant of epithelioid GIST• Some have very distinctive plasmacytoid features
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Immunostains will get you into trouble• CD117
• Plasma cells• GIST• Melanoma• Neuroendocrine
tumors• Thymic and other
carcinomas• Kaposi’s sarcoma• PEComa
DOG-1Molecular studies
Immunostains will get you into trouble
• DOG-1 positivity• Non-mesenchymal
• Gastric adenocarcinoma• Acinic cell carcinoma of
salivary gland• Melanoma
• Rare mesenchymal• Synovial sarcoma• MPNST
Hemminger and Iwenofu. Histopathology 2012;61;170-77.
Immunostains will get you into trouble• CD138
• Plasma cells• Plasmacytoid urothelial
carcinoma• Papillary thyroid
carcinoma• Other plasmacytoid
carcinomas and mesenchymal tumors
• Endometrium
Lessons Learned• Remove oneself from context before making final diagnosis
• Keep up with literature
• Understand your immunostains
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Zoe and Alys contemplate the pitfalls of immunohistochemistry.
Case #4Forced Error
Solitary liver mass in young woman with “renal cell carcinoma”
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Frozen Section Conversation• LWL: What kind of renal cell carcinoma did she have?
• Surgeon: The regular kind.• LWL: Clear cell?• Surgeon: Yeah.
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Mistakes Made• Should have worked harder to find out history on our own
• Should have more strongly considered all the options in the differential diagnosis of “renal cell carcinoma”
• Noncirrhotic liver……
• LWL (looking at frozens of multiple spindled nodules on serosa of bowel and stomach): This looks like a neurofibroma.
• Surgeon: No way!!
SILENCE…………
• Surgeon: Huh. Maybe that explains the bumps all over him and his family.
In my defense……..
• KC (looking at frozen of weird metastatic liver lesion): It says here that the patient had cancer in the tail of the pancreas. Do you know what kind of cancer it was?
• Surgeon: The kind that is in the tail of the pancreas.
Nodules in Cirrhotic vs. Noncirrhotic Livers
• CIRRHOTIC LIVER• Regenerative nodule• HGDN• Hepatocellular
carcinoma
• NONCIRRHOTIC LIVER• Focal nodular
hyperplasia• Adenoma• Nodular regenerative
hyperplasia• Hepatocellular
carcinoma• Mets
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HCC, well differentiated
Normal
HCC
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Quiz: RCC vs. HCC
Quiz: RCC vs. HCC Quiz: RCC vs. HCC
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Quiz: RCC vs. HCC Helpful hint: put in more sections
Helpful hint: HCC, clear cell variant, Hepatocyte Antigen
Feature HCC RCC ACC
Clear Cells Yes Yes Yes
Prominent vessels Common Common +/-
EMA - + -
Hepatocyte Antigen, Arginase-1, etc.
+ - -
Inhibin, SF1 Negative Negative Positive
PAX2 and PAX8 - + -
Differentiation Between HCC and Other Trabecular Neoplasms
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A few last minute IHC warnings• CD10 can stain HCC• PEComa can lose reticulin (but will be HMB45 positive)• Hepatocyte antigen can stain carcinoids, and neuroendocrine
markers can stain HCC• HCC can stain with CK7 and CK20 and CK19• Some adenocarcinomas can stain with HSA, but it’s still better than
AFP
Pulmonary adenocarcinoma: HSA+
Lessons Learned• Always leave yourself a little wiggle room on difficult
cases• Most people have metastases rather than a new weird
primary
• Always treat unproven verbal information relayed by surgeon with healthy degree of skepticism
• Morphologic pitfalls are even harder to deal with on frozen section
What do you mean that’s a watering
can? It’s not a renal cell carcinoma? I
am shocked!
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Case #5Errors from the Stands
60 year old man with “refractory sprue”
Duodenal biopsy
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“Refractory Sprue”•Meanwhile…..
• Patient continued to do poorly• ANA positive, TTG negative• Eventually, anti-enterocyte and anti-goblet cell
antibodies came back positive• Patient started on azathioprine, did much better
Mistakes Made• Persistent belief in diagnosis even though patient
has never responded to therapy and labs don’t match up with diagnosis
• Multiple doctors in different systems that don’t communicate
• Persistence of false history in medical record• ”Chart virus”
Autoimmune Enterocolitis• Well recognized in children; probably markedly under-recognized in
adults• Associated with many extraintestinal autoimmune illnesses
• Diabetes mellitus• Membranous glomerulonephropathy• Thyroid disease• Thymomas• Autoimmune hemolytic anemia• Autoimmune polyendocrine syndrome
Autoimmune EnterocolitisClinical Presentation
• Profound diarrhea and weight loss• No response to gluten free diet
• Patients often initially diagnosed as celiac disease• Antibodies against enterocytes and/or goblet cells• May also have positive ANA, AMA, anti-SM, etc.
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Celiac Disease vs. Autoimmune Enteropathy
Celiac disease• Villous blunting• Intraepithelial lymphocytes
• Usually more than AIE• Neutrophilic inflammation• Numerous lamina propria
plasma cells• Crypt hyperplasia
Autoimmune enteropathy• Villous blunting• Intraepithelial lymphocytes• Neutrophilic inflammation
• Often more than celiac disease• Numerous lamina propria plasma
cells• Apoptotic epithelial cells• Lack of goblet cells• May affect entire gut
Autoimmune Enteritis vs. Celiac Disease
Autoimmune enteropathy Celiac disease
Celiac disease
Celiac Disease vs. Autoimmune EnteritisCeliac disease Autoimmune enteritis
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Colon with plasmacytic infiltrate, cryptitis, no goblet cells, apoptosis
Normal Villi Variable Defect Severe Defect
Immuno-deficiency* X X X
Amyloid* X
Mastocytosis* X X
Celiac Disease X X X
Infection* X X X
Drug Injury X X X
Crohn’s X X
Autoimmune enteritis X X
Peptic duodenitis X X
Chemo/radiation* X X
Eosinophilic enteritis* X X
Protein injury X X
Stasis X X
*may have more specific or diagnostic histologic features
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Common Variable Immunodeficiency• Small bowel
• Celiac disease-like lesion• GVHD-like lesion• Decreased plasma cells, goblet cells• Granulomatous enteropathy• Nodular lymphoid hyperplasia• Crohn’s like enteritis• Lymphoma• Infection
Common Variable ImmunodeficiencySprue-like Lesion
• Often associated with severe malabsorption
• May require parenteral nutrition• May be indistinguishable from celiac
disease• Most patients do not respond to gluten-
free diet
CVID: sprue-like pattern
Idiopathic Eosinophilic Gastroenteritis
• Infiltration of one or more segments of GI tract by eosinophils, including pancreas and biliary tree
• Villous blunting, increased IELs overlap with celiac disease in mucosal-predominant IEG
• Excess of eosinophils favors IEG• 75% of patients have peripheral eosinophilia• Negative TTG, no response to gluten free diet
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Olmesartan Toxicity• Common angiotensin II receptor antagonist
(antihypertensive)• Severe chronic diarrhea and weight loss, often
requiring hospitalization• Morphologic changes may resemble celiac disease,
collagenous sprue, and/or microscopic colitis
Courtesy Dr. Dora Lam-Himlin
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Features on Biopsy Helpful Features
Eosinophilicenteritis
Increased eos Peripheral countH/o atopy
Autoimmune enteritis Too many polysAbsent goblet cells
Apoptotic epithelial cells
Anti-enterocyte/ anti-goblet cell labsMore than small bowel involved
CVID Decreased/absent plasma cellsApoptotic epithelial cells
Immunodeficiency w/uMore than small bowel involved
Olmesartan +/- marked villous blunting, crypt hyperplasia, IELs, eosinophils
Medication history
“Scalloping” is nonspecific Lessons Learned• Most patients with negative celiac disease serologies and
no response to gluten free diet do not have celiac disease
• There are many mimics of celiac disease,common and uncommon
• When many things don’t fit, keep looking, and encourage our colleagues to do so as well
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Summary• Everyone makes mistakes• Most mistakes are not because of incredibly complex
cases, but because we do (or fail to do) something simple• If someone can help you mess up, they will