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I Cannot Diagnose a Diseasethat is Unknown to Me

V{tÜÄxá WA fàâÜz|á? `AWAAssociate Professor & Staff Cytopathologist

A Memoir of Personal Pathological Frustrations with Admitted Ignoranceand Candid Self-Deprecation

Disclosures:

Consultant for Ventana (PDL-1 in NSCLC) 2015-2016Consultant for Philips (Pivotal Study, Digital Microscopy) 2015-2016

History for Index Case:

The patient was a 66 year-old, never-smoker, married, Caucasian male with an eight year remote history of pTXpN2pM0 moderately differentiated squamous carcinoma of the pharyngeal tonsil.

Remote tonsillectomy with modified neck dissection and adjuvant chemotherapy / radiotherapy.

Followed up with physical examination and imaging studies on an annual basis.

Surveillance positron emission tomography (PET) scan detected a cluster of intensely avid soft tissue nodules (likely lymph nodes) in the splenic hilum with no other evidence of disease.

The patient then underwent endoscopic ultrasound (EUS) guided fine needle aspiration of the splenic hilar adenopathy.

Rapid On Site Evaluation in Endoscopy

Malignant cells present.

Asked for additional passes for cell block.

Collection of sample into RPMI for possible flow cytometric immunophenotypic studies

deferred.

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3

IHC Performed onCell Block

Positive

CD30 (focal)CK AE1/3 (focal)

EMA (focal)

NegativeCK5/6P40CK7

CK20CDX-2CD45CD20CD3

CD15PLAP

OCT3/4SALL4

Hemiscrotal fullness and low level hemiscrotal pet avidity were clinically diagnosed as

epididymitis and treatedwith antibiotics.

NOT seminoma (despite my “genius”

contributions and fitting morphology withtigroid background)…

It’s gotta be a seminoma, and don’t I just look,

well, brilliant,studly & amazing

“Reed Sternberg Fixation of Sturgis”A new DSM – 5 category

Included in DSM – 5 American Psychiatric Association’s (APA)

Classification and Diagnostic ToolPublished May, 2013

“Reed Sternberg” cells were everywhere at that time…In the air around me and in my dreams…

Sadly, that cytomorphology is about as specific for a disease entity as was my sanity at that time.

Classical Hodgkin Lymphoma –Neck FNA Smear

Nodular Lymphocyte Predominant Hodgkin Lymphoma – Touch Prep

Diffuse Large B Cell Lymphoma –Body Fluid ThinPrep

Monomorphic Post Transplant Lymphprolif Dis – Brain Touch Prep

Metastatic Ocular Melanoma –Scalp FNA Smear

Anaplastic Large Cell Lymphoma –Neck FNA Smear

Reed-Sternbergcells of classical

Hodgkin’s Lymphoma

27M, FNA direct smear, Papanicolaou 59F, FNA direct smear, Modified Giemsa

21M, Touch Preparation, Modified Giemsa 38F, FNA, ThinPrep, Papanicolaou

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40M, Neck Mass, Touch PreparationClassical HL, Mixed Cellularity Type

CD3 CD45 CD15 CD30

21M, CHL, Nodular Sclerosis Type 59F, CHL, Lymphocyte Rich Type

CD15

CD30

PAX5

MUM1

OCT2

CD45

26 FPleural Effusion

ThinPrep Papanicolaou Stain

Known History of Classical

Hodgkin Lymphoma

CD30 MUM1

Nodular Lymphocyte Predominant Hodgkin’s

Lymphoma 60F FNA Parotid Area

Arch Pathol Lab Med2010

CD45+ CD20+ PAX5+

CD3- CD15- CD30- ALK1-

OCT2+ BOB1+

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74M, Porta Hepatis 4.6 cm Enlarged Lymph NodeEUS FNA with Cell Block and Core Biopsy

ALCL ALK+

Ki-67

CD30

ALK1

28% of ALCLspositive for PanCK

PanCK

69M Multiple bone lesionswith soft tissue mass at L1

Bone marrow later diagnosed as

“Plasmablastic Myeloma”

FNA L1

Core L1

CD138

Cyclin D1

MUM1

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Yo, Fellow Cytotrons

Learn from my ignorance…

Don’t suffer from thesame deficits in knowledge

as your illustrious speaker…

Charles “D” Sturgis, M.D.

I called it: “Malignant cells present”… Duh,I wrote a comment that was more than a full page long.

A splenic hilar lymph node was then excised.

CD138 Lambda

EMA

CD79a

MUM1VS38c

Ki-67

ALK-1

Negatives

AE1/AE3, CAM5.2

CD3, CD4, CD20, CD21, CD30, CD34, CD35, CD56,CD68, EBER, HHV8, PAX-5

Desmin, HMB-45, S-100

ALK+ LBCL

Expression of ALK protein. (A) Staining for the intracellular portion of ALK protein (antibody ALK1) is granular cytoplasmic staining associated with a dot-like reaction in the Golgi area. (B) The same antibody gives a diffuse cytoplasmic and nuclear labeling of a classical ALCL expressing the chimeric NPM-ALK protein. (C) Staining with an antibody (ALK-EC) against the extracellular portion of the ALK molecule shows a membrane associated labeling pattern. (D) A classical ALCL case expressing NPM-ALK is negative with this antibody.

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ALK Diffusely Positive CD138 Diffusely Positive CD20 Negative

MUM1 Diffusely Positive IgA Diffusely Positive EMA Variably Positive

2015

Letter to the Editor

81%M, Age range 9 to 85 years, Median 35 years51% extranodal

96% of expressed CD138 and 99% expressed EMA

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ALK-1 ALK-D5F3

Retrospective Studies from Cell Block

ALK-positive diffuse large B-cell lymphoma (ALK + DLBCL) is a rare and poorly characterized subtype of lymphoma. Reports suggest that this type of tumor responds poorly to standard regimens for non-Hodgkin’s lymphoma, with rituximab playing no therapeutic role due to the absence of CD20 expression. In view of the expression of ALK in this disease, it is plausible that the ALK inhibitor crizotinib may be an effective treatment. We report a case of a 21-year-old male ALK + DLBCL patient. He initially received five cycles of CHOP-21 (vincristine, pirarubicin, cyclophosphamide and prednisone) and achieved a partial remission (PR) but soon deteriorated. He was subsequently treated with five courses of the salvage chemotherapy regimen ICE (ifosfamide, carboplatin and etoposide) and achieved PR again. He refused to accept an autologous stem-cell transplantation, after which the disease progressed rapidly. We administered two courses of an alternative salvage chemotherapy regimen containing GEMOX and dexamethasone with the addition of the ALK inhibitor crizotinib. His symptoms alleviated for a short time but soon worsened and the patient died of massive progressive disease.

ALK + DLBCL was first reported by Delsol et al in 1997 based on a series of seven cases and was officially defined as a new subtype of lymphoma by the WHO in 2008

Int J Clin Exp Med 2015;8(5):6977-6985

Kansai Rosai Hospital, Amagasaki, Hyogo, JapanDiagnostic Cytopathology, Vol 42, No 1

2013May 2013; MSKCC, NY, NY

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ALK+ LBCL66M

An explanation for my “tigroid” background

PAS

DPAS

2008 WHO Classification emphasizes combination of:

MorphologyImmunophenotyping

CytogeneticsMolecular Profiling

Cancer Cytopathology July 2015

CHL NLPHL DLBL ALK+ LBCL ALCL PB Lymphoma PB Myeloma Melanoma Seminoma Carcinoma

ALK Neg Neg Neg Pos Var Neg Neg ALK1

BCL2 Var Var BCL2

BCL6 Var Pos Var BCL6

BOB1 Var Pos Pos BOB1

CD1a   CD1a

CD3 Neg Neg Neg Neg Var       CD3

CD5 CD5

CD10 Var Var CD10

CD15 Pos Neg Neg Neg CD15

CD20 Var Pos Pos Neg Neg Var Var CD20

CD21 CD21

CD30 Pos Neg Var Neg Pos Var Var Neg CD30

CD38 Neg Pos Pos Pos CD38

CD43 Neg Neg Var Var CD43

CD45 Neg Pos Pos Var Var Var Var Neg Neg Neg CD45

CD68 CD68

CD79a Var Pos Pos Neg Neg Var Pos CD79a

CD138 Neg Pos Pos Pos Var CD138

CK Var Var Neg Var Pos CK

Clusterin Pos Neg Pos Clusterin

Cytop Ig Neg Var Var Pos Neg Var Pos Cytop Ig

D2‐40 Pos D2‐40

EBER Var Neg Neg Neg Var EBER

EMA Neg Var Var Pos Var Var Pos Pos EMA

Fascin Pos Neg Pos Fascin

HMB45 Pos HMB45

LMP1 Var Neg Var Neg Neg Var LMP1

MART‐1 Pos MART‐1

MUM1 Pos Var Var Var Pos Pos MUM1

0CT2 Var Pos Pos 0CT2

0CT4 Pos 0CT4

PAX5 Pos Pos Pos Neg Neg Var Neg Neg Neg PAX5

PLAP   Pos PLAP

SALL4 Pos SALL4

S100 Pos S100

CHL HLPHL DLBL ALK+ LBCL ALCL PB Lymphoma PB Myeloma Melanoma Seminoma Carcinoma