Clinicopathological case conference week 1 Case of the week 3rd February 2017 Video linked Southend , Basildon and Chelmsford University hospitals NHS foundation Trust (ESR). East of England, United Kingdom. Dr Amin Islam MB, MRCP UK, FRCPath UK Consultant Haematologist

57 years old lady Referred by her GP on discharge from a tertiary hospital Had a fall during inpatient stay CT head was abnormal Underwent evaluation of pancreatic duct stricture and pseudo cyst Advised to refer to haematology locally

What do you see? Pepper pot skull Lytic lesion Vascular markings Widespread metastatic deposits Brown tumour

PMH Recurrent pancreatitis : idiopathic Type 2 diabetes Hypertension Raised cholesterol Does not drink alcohol, works for a blood charity Medication: Amitriptyline Omeprazole Paracetamol Family history: NIL

Haematology reviewed urgently She does not have any unusual bony aches and pains. There is no history of recurrent infections or inflammation. On examination looked well. no palpable adenoptahy or hepatosplenomegaly.

What test would you do in clinic?

The blood test Hb 109, WCC 6, platelets 168, neutrophils 3.0, lymphocytes 2.5, creatinine 48, LFT normal, calcium normal. Protein electrophoresis did not reveal any abnormal paraprotein. CRP is less than 1. Immunoglobulin normal, LDH normal. Uric acid : Normal Kappa and Lambda light chains are: normal K/L ratio :Normal Urine : BJP : Negative

Skeletal survey

What next test would you do ?

Bone marrow test project on microscopy Aspirate: Haemodiluted but no plasma cells are seen Trephine: >90% infiltration with Plasma cells?

Bone marrow liquid aspirate Multipara metre flow cytometry Haemodiluted but no clonal plasma cells detected Cytogenetic : Not done

What next steps would you do on trephine ?

Immunophenotying By immunohistochemistry

What staining you ask for myeloma?

CD 38 CD 138 CD 56 positive in 60-70 PCM (useful for detecting residual PCM, particularly in morphologically equivocal cases in which light chain restriction cannot be demonstrated, and may serve as a potential response criterion) CD 20 Kappa and lambda

Project the slides on microscope

What is the diagnosis

Non –secretory plasma cell myeloma Non secretary myeloma 57 YRS old lady MDT agreed 6 course of VTD (Valcade/thalidomide/dexamethasone) Consolidate with Autologous stem cell transplantations in 1st CR Response assessment by marrow test after 2-3 cycles of VTD agreed

Marrow after 3 VTD Worse infiltrations on trephine Almost 90-100% Suspicious of non- haematopoietic cells infiltrations Aspirate : normal with no excess of plasma cells noted Flow : No clonal plasma cells noted

Patient reviewed urgently by haematologist and stopped VTD Involved Medical oncologist Clinical oncologist as CUP ( cancer of unknown primary) Patient reviewed and counselled Examination : Unremarkable with no palpable mass and patient asymptomatic PET CT arranged as urgent

What next staining to do: Haemato-histopathologist reviewed the trephine Agreed : metastatic cancer infiltrations of unknown primary

Specialised Immunohistochemical stain to project on microscope Cytokeratin 7: strongly positive Pankeratin : strongly positive CAM5.2 : strongly positive MNF116: strongly positive CD 138 strongly positive CD 38 strongly positive ER : positive ? Kappa and lambda : Negative

CUP review on going Examination : NAD CT CNAP : NAD Breast : NAD PET: left SCF : lymph node 2.5 cm

Lymph node biopsy LT SCF

Treatment Letrozole started Bisphosphonate Asymptomatic Back to her work in London Care transferred to a tertiary hospital Close to her work

Learning points CD 38 and CD 138 are not specific for myeloma Other GI and neuroendocrine tumour can express this marker Clonality study essential Myeloma cells are cytoplasmic kapa/lambda restricted plasma cells

Non secretory myeloma Only 1-4% of all myeloma Good prognosis? t (11:14) many harbour Do not secrete immunoglobulin or its component parts into either the blood or urine widely used serum free light chain assay, have reduced the number of patients with truly non-secretory

Some hypothesis In addition to the state of nonproduction, several mechanisms are proposed to account for the absence of an M protein in NSMM cases. Decrease in M protein synthesis secondary to increased cytoplasmic immunoglobulins Accelerated degradation of abnormal intracellular immunoglobulins,

continued Impaired intracellular transport of immunoglobulins Intermittent excretion of M protein Altered secretion ability of plasma cell, Reduced plasma cell membrane permeability, and Rapid degradation of abnormal immunoglobulin following its secretion

Questions