4th National Haemato-Oncology Course Dr Bhupinder Sharma, Dr Sunil Iyengar, Dr Claire Dearden, Dr Dima El-Sharkawi, Dr Ayoma Attygalle, Dr Matthew Cross, Dr Joel Cunningham  79 year old retired Consultant radiologist  Presented to GP in May 2018 with bilateral tender neck nodes  PMHx: Multiple resected BCC and SCC  Clinical examination: Multiple up to 1.5cm nodes bilaterally in the neck, bilateral groin nodes of 1cm, palpable liver edge 4cm and spleen tip palpable  Mild sweats, no weight loss, no fevers  Dry cough but no SOB  Normal FBC and biochemistry  Excision lymph node biopsy performed at an external centre – subsequently referred to RMH

CD79a CD20

CD138 EBER k l CD3 PD-1

CD10  PCR for Immunoglobulin gene rearrangements: Clonal IGH/IGK rearrangements detected.

 PCR for T-cell receptor gene rearrangements: Clonal (weak) TRB/TRG rearrangements detected with multiple, weakly clonal rearrangements present in the TRG reaction (indicates presence of multiple small clonal T cell proliferations, but no dominant T cell clone). Initial impression: Appears Symptom progression to EBV driven proliferation  By August 2018 – but concern for an un- increasing fatigue and diagnosed malignancy breathlessness, ongoing dry cough Additional results:  Increasing size of  EBV IgG +ve lymphadenopathy, very  EBV IgM +ve at referring tender nodes hospital but –ve at RMH  Fevers/rigors and a rash –  EBV PCR 8000 maculopapular across copies(IU/ml) July 2018 thorax  Repeat PET and excision biopsy arranged  Excision biopsy of left sided level 5 LN mid August  Post operatively – fevers/rigors/rash – unclear if infective or disease related

CD3 CD20 CD20 PD-1 CD10 CD10 CD10 ICOS CXCL13

CXCL13 CD21 EBER  PCR for Immunoglobulin gene rearrangements: Clonal (weak) IGH/IGK rearrangements detected, however the amplification is lower than seen in the previous sample and the pattern of clonal (weak) rearrangements is not identical to the previous clone in previous lymph node biopsy

 PCR for T-cell receptor gene rearrangements: Clonal TRB/TRG rearrangements detected.  Involved by angioimmunoblastic T-cell lymphoma

 PCR for clonality analysis -Clonal (weak) TRB/TRG rearrangements detected, with a pattern consistent with the one seen in the Lymph node sample

-Ig gene rearrangements: restricted repertoire, likely to be due to low number of polyclonal B-cell present

 Initial Prednisolone 30mg OD – improvement in fevers and rash  Commenced CHOP 05/09/18

 Relatively rapid onset widespread adenopathy and hepatosplenomegaly  Initial histology suspicious for EBV reactivation  Subsequent development of fevers, rigors and rash  Repeat PET showed progression and excision biopsy confirmed angioimmunoblastic T-cell lymphoma  Currently responding to CHOP and to consider autologous SCT depending on response.  42 year old gentleman  Initial presentation in August 2017 with fluctuant fevers, LUQ discomfort with splenomegaly and transient thrombocytopenia that spontaneously resolved. BM biopsy showed a lymphoid infiltrate of uncertain aetiology. Nodal biopsy recommended  September 2017 recurrence of fevers and thrombocytopenia, ongoing splenomegaly, lymphadenopathy.  Ferritin >7500

CD20 CD3 Granzyme B POSITIVE NEGATIVE

 CD4  CD2  CD30  CD5  TIA1  CD7  Perforin  CD8  CD10  PD1  ICOS  EBER-ISH  Involvement by peripheral T-cell lymphoma  Peripheral T-cell Lymphoma  Haemophagocytic lymphohistiocytosis (HLH aka Haemophagocytic syndrome) based on fulfilling 5/8 criteria . Fever . Splenomegaly . Bi-lineage cytopenia, . Hypertriglyceridaemia and hypofibrinogenaemia . Ferritin >500  Received 1 cycle of CHOP and then in view of HLH 2 cycles of R-CHOEP  Patient seen at RMH December 2017 post 1 x CHOP and 2 x CHOEP.  Worsening lymphadenopathy, recurrence of fevers.  Deranged LFTs – ALP 1200, ALT 120, Bilirubin 120, Albumin 24  Coagulopathy – APTT 41.5 (23-33), Fibrinogen 0.37 (1.9-4.0), PT did not clot.  EBV PCR –ve. Hep B, C, HIV all -ve  ESHAP commenced January 2018 with dose reduction due to deranged LFTs (50% Cytarabine dose)  Improvement in adenopathy, splenomegaly and fevers  Referred for autologous SCT if remission achieved  Recurrence of fever mid January – initial suspicion of bacterial endocarditis but ruled out on TOE/multiple cultures.  Repeat CT showed re-enlargement of the spleen  Treated briefly with high dose Methylprednisolone before giving IVE however developed Ifosfamide neurotoxicity.  Short lived response to treatment and then recurrence of fevers, raised lactate felt to be due to splenic necrosis  Decision for splenectomy and cholecystectomy – performed February 2018

Bone marrow trephine – 3rd Jan 2018 CD3 CD3 Splenectomy–15th Feb 2018

CD3 Station 11 lymph node biopsy –15th Feb 2018 CD3  Splenectomy complicated by bleeding from splenic bed  Post op developed multi-organ failure  Patient required inotropic support, haemofiltration, intubation and ventilation but sadly passed away.  Peripheral T cell lymphoma  Haemophagocytic lymphohistiocytosis  Poorly responsive/refractory to all lines of therapy

 53 year old lady  PMHx: Thyroidectomy age 20 for multiple benign nodules.  Initially noted a small nodule to right arm in mid 2012.  This gradually enlarged and she developed other nodules on both arms and her back over a few months.  Initially felt to be Dercum’s disease – a disease characterized by multiple painful subcutaneous growths consisting of lipomas.  3-4 months after developing first skin nodule she developed . Fevers, night sweats, fatigue, decreased appetite and mild weight loss.  These symptoms progressed over 2 months and prompted a biopsy and referral to RMH  FBC normal except for lymphopaenia (L 0.4)  HIV, Hepatitis B and C all –ve. CMV and EBV PCRs –ve  LDH 446 (over 2 x ULN)  Deranged LFTs ALT 233, ALP 424, GGT 395, Bili 16  Hyponatraemia with SIADH picture – urinary sodium 45

CD3 CD8 TCR- beta  Enrolled in the Chemo-T trial and randomised to receive Gem-P  Received 4 cycles Gem-P  End of treatment imaging showed excellent PR with only small volume residual subcutaneous soft tissue with low grade metabolic activity.  Consolidated with LEAM conditioned autologous SCT June 2013  PET 3 months post SCT showed metabolic CR  Development of multiple subcutaneous nodules over 6 months followed by B symptoms  PET showed stage 4 disease with multiple PDG- avid skin lesions  Diagnosis of Subcutaneous panniculitis-like T- cell lymphoma  Treated to excellent PR with Gem-P x 4 on the CHEMO-T trial and consolidated with a LEAM auto SCT  Remains in CR 5 years from treatment  43 year old female . 2004 - BRCA2 mutation carrier, prophylactic bilateral mastectomy with implants

. November 2012 – exchange of implants and bilateral capsulectomy

. 2013 – recurrent left breast seroma; further capsulectomy and implant exchange

. May 2015 – persistent seroma, requiring repeat capsulectomy and removal of left breast implant 5.2.15

1.7.15

10.7.15

CD30  Bone marrow aspirate & trephine: no disease

 PET: no evidence of distant disease Implant associated anaplastic large cell lymphoma (ALCL), ALK negative

 Removal of both mastectomy flaps, removal of right-sided implant, bilateral capsulectomy - total capsulectomies on both sides 22.02.16

28.10.15 18.05.17 • 31 year old female

• April 2012 – bilateral breast augmentation

• July 2015 – right breast lump, no B symptoms

USS breast + biopsy: 24.7.15

CD30 CD2

CD4 CD3 • Anaplastic large cell lymphoma, CD30 positive, ALK negative. • Minimal implant-related seroma/no obvious connection to implant.

Treatment: • Commenced CHOP chemotherapy at local hospital • Initial response but rapid progression prior to 4th cycle

• November 2015: 7.10.15

2.11.15

30.10.15 Disease progression on CHOP

 Brentuximab 21.01.16

10.12.15

10.12.15 Residual PET update after #4 (no other sites)

 Bilateral implant removal with bilateral total capsulectomy and mastopexies 19.10.16  42 year old female . 2001 – bilateral breast implants inserted

. March 2017 – swelling over left breast noted

. Surgical review: intracapsular rupture, implant noted to have irregular surface

. USS-guided biopsy undertaken…

CD30 16.5.17 16.5.17  Surgical excision: . 40mm x 35mm mass . Consistent with the diagnosis of breast implant associated anaplastic large cell lymphoma, ALK negative

 Concern regarding local control: . Mastectomy advised by MDT . 3 cycles of CHOP post mastectomy due to extent of original lesion  What is appropriate management for a implant-associated ALCL? . Reported by the FDA 2011, included in WHO lymphoid neoplasms in 2016 revision . By September 30th 2017, 414 FDA reports of BIA- ALCL with the death of 9 deaths . More common in implants with textured surfaces . Largely present as stage 1 disease 1. Confined to fibrous capsule = lower relapse rate 2. Breast mass = higher relapse rate and mortality Management: 1. Local therapy; capsulectomy/implant removal or radiotherapy 2. +/- Systemic chemotherapy

Improved EFS and OS when total capsulectomy with implant removal

No prospective studies performed Event-free Overall survival survival

Clemens, MW et al. 2016. Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma. Journal of Clinical Oncology. 34:160-168.  BIA ALCL . Clemens, MW et al. 2016. Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma. Journal of Clinical Oncology. 34:160-168. . Miranda, RN et al. 2014. Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow- Up of 60 Patients. Journal of Clinical Oncology. 32:114- 120.  58 year old male

. 2012: T-cell Prolymphocytic Leukaemia diagnosed; initially managed on watch & wait

. September 2016: weight loss and abdominal symptoms . GI endoscopy and biopsy carried out . CT + PET imaging undertaken

CD3 CD4 3.9.16

3.9.16 28.9.16 28.9.16 TPLL with disease progression

 Alemtuzumab (12 weeks) 5.12.16 21.12.16 21.12.16  Bone marrow: . No definite evidence of TPLL

 Restaging gastroscopy: . Ongoing T cell infiltration

 Liver biopsy:

Diagnosis: Diffuse large B-cell lymphoma

CD20

Ki 67 Diffuse large B-cell lymphoma (germinal centre phenotype)

CD10 BCL6

MUM-1 EBER-ISH Liver biopsy: Diffuse Large B Cell Lymphoma (GCB subtype, EBV PCR -ve)

6 cycles of R-CHOP to very good response

End of treatment PET: 23.5.17

31.1.17 11.3.17 23.5.17  Flu-LEAM-Alemtuzumab MUD Allograft (July 2017)  Initial a diagnosis of T-PLL with relatively long asymptomatic phase  Symptoms from GI infiltration prompting need for treatment  Treatment with Campath with good response except for focus in liver with biopsy proven DLBCL  DLBCL treated to CR with R-CHOP x6  Consolidated with F-LEAM Campath Allogeneic stem cell transplant