Pediatric Hemato-Oncology

Interhospital Conference

Pallapa BunjerdlukDivision of Hemato-Oncology,

Department of Pediatrics, Faculty of Medicine,

Prince of Songkla University

19-Dec-2017

Patient profile

• เดกชายไทย อาย 14 ป• ภมล าเนา จ.พทลง

• Chief complaint: มแผลเจบทปากเปนมา 2 เดอน

Present illness

2 เดอนกอนมารพ.มแผลในปาก เจบ มเลอดออกซมๆ แผลเปนเองโดยไมไดมอบตเหตใดๆ แผลเปนปนสขาว ทกระพงแกม ลน ทานอาหารไดลดลง ไมมตมน าทผวหนงสวนอน รสกมไขต าๆ ตาแดงเลกนอยมขตาไมมาก

รพช.ใหการวนจฉยวา oropharyngeal stomatitis ไดยา Acyclovir(200) 1x5 เปนเวลา 5 วน อาการดขน แผลยงไมหายสนทแตเจบดขน แพทยจงใหกลบบาน

1 เดอนกอนมารพ. แผลในปากยงมเทาๆ เดม และเรมมแผลทรมฝปากเพมขน รพช.สงตอรพ.จงหวดใหการวนจฉยวา herpetic gingivostomatitis with secondary bacterial infection ใหการรกษาดวย augmentin 500 mg IV q 12 hr 7 วน หลงจากนนอาการแผลดขนแตกไมไดหายสนท แพทยจงใหกลบบาน

1 สปดาหกอนมารพ.แผลทปากเปนมากขน มอาการตาแดงเพมขน ตามตวมตมน าขนและแตก ทางรพ.จงหวดจงสงตวมารพ.มอ.

ซกประวตเพมเตม

• Birth history: บตรคนท 3/3, C/S due to post-term, Birth weight 3,500 gm, no complication

• ไมมโรคประจ าตวแขงแรงดมาตลอด• ไมมแพยาอาหาร• มน าหนกลด 7 กโลกรมใน 2 เดอน • อาศยอยบานคณปาทมสขภาพด

ประวตเพมเตม

Physical examination

GA: active childV/S: BT 36.9OC, PR 111/min, RR 24/min, BP 110/65 mmHgMeasurement: BW 38.4 kg[P10-25], Ht 162.5 cm[P50-75]HEENT:

-not pale, no icteric sclera, bilateral mild injected bulbar conjunctiva -oral painful erosions with hemorrhagic crusting and gray dirty patch at buccal mucosa, tongue and lips

Heart: normal S1S2, no murmurLungs: mild suprasternal retraction, normal chest contour, clear breath sound both lungs

Abdomen: soft, no palpable mass, liver and spleen can’t be palpatedGenitalia: normal size testes, no mass, no lesionLymph node: no significant all groups Ext: no lesionNeurological examination: grossly intactSkin: generalized, painful, erythematous papule, vesicle, bullae, erosive and target lesions at forehead and trunk

Problem list

Problem list

• Painful erosion in oral cavity and lips• Bilateral injected conjunctiva • Generalized vesiculobullous at chest wall and back• Significant weight loss• Suprasternal retraction

Differential diagnosis

1…

Ans

Differential diagnosis

• Autoimmune disorder:pemphigus vulgaris, rheumatoid arthritis, myasthenia gravis

• Infectious disease: virus(Herpes virus: HHV-8, acute herpetic stomatitis ), bacteria(impetigo, SSSS), fungus(candidiasis), TB

• Paraneoplastic pemphigus: Occult Non-Hodgkin lymphoma, Castleman’s disease

• Drug reaction: SJS, TEN, EM

Investigations

A B C D E F

Df

G IH J K M

Ans

Pathologic diagnosis

• Skin at chest wall• Eosinophilic spongiosis• Suprabasal separation with acantholytic cells, eosinophils and

lymphohistiocytes.• Slight infiltration of lymphohistiocytes, neutrophils and eosinophils in the

dermis• No malignant cell involvement, Tdt negative• Immunofluorescence study:

• Positive 2+ of IgG, C3 at intercellular space• Negative of IgA, IgM and C1q

Pic

Skin pathology

L

Skin pathology

IgG

Skin pathology

C3

Infectious work up

• PPD test: 0 mm• Anti HIV screening test: non reactive• Tzanck smear vesicle: negative multinucleated giant cell• HHV type 1-6 by PCR: not detected• Hemoculture: no growth• Sputum: negative for TB by PCR• Tissue culture for TB, Fungus- negative

L

Autoimmune disease work up

• CH50: 85% [ref 90-94]• ANA by IFA:

• positive mix pattern(homogeneous, speckle, nucleolar) titer 1:320 [ref: negative titer <1:80]

• Anti ds-DNA by IFA: negative• Rheumatoid factor: negative <20 IU/mL• Anti Sm (ELISA): negative

L

Dermatoimmunology

• Indirect immunofluorescence(IIF)• Negative for rat bladder substrate• Negative for circulating IgG anti-intercellular antibody using human

skin substrate• Anti-desmoglein 1 antibody, ELISA: 74.30 U/mL (0-20): positive• Anti-desmoglein 3 antibody, ELISA: 37.80 U/mL (0-20): positive

Imp: positive anti-Dsg 1 and 3 by ELISAL

Complete blood count

• WBC 8,330 /µL, PMN 50%, Lymph 46%, Eo 4%• Hb 14 g/dL, Hct 42%, RBC 5.15x106/µL, MCV 81.4 fL, MCH 27.2 pg,

MCHC 33.4 g/dL, RDW 12.8%• Plt 330,000/µL• Retic 1.32%

L

Blood chemistry

• BUN 9.9 mg%, Cr 0.72 mg%• Na 137.5 mmol/L, K 4.26 mmol/L, Cl 96.9 mmol/L, HCO3 25 mmol/L• Ca 9.5 mg%, Phos 4.0 mg%• Uric 3.3 mg%• DB 0.25 mg%, TB 0.64 mg%, SGOT 28 U/L, SGPT 21 U/L, ALP 203 U/L,

TP 8.6 g%, Alb 4.0 g%, GLOB 4.6 g%

L

Pathologic diagnosis

• Anterior mediastinal mass, needle biopsy• Positive for CD3, CD4, CD8, CD10, Tdt, CD99• Negative for CD20, EMA, AE1/AE3, CK19, P63, CD15, CD30• No granulomatous formation

Imp: T lymphoblastic leukemia/lymphoma

L

Pathologic diagnosis

• Clotted marrow:• 40% cellularity• Presence of all three lineages with maturation• No clusters of blasts(CD34+ rare, Tdt+ few)• Negative for malignancy

Imp: Normal bone marrow study

L

Tumor marker

• LDH 295 U/L• AFP 0.74 ng/mL• B-HCG < 1.00 mIU/ml

L

Chest X-ray

2

L

CT-chest• A well-defined heterogeneous intense enhancing mass involving

ant.and middle mediastinum size 8.9x6.4x7.4 cm• Mass compression trachea, left shifting of trachea and posterior

displacement of rt. main bronchus• Mediastinal node size 1.2 cm• No pulmonary mass, nodule or infiltration• No bony destruction

Imp: Anterior and middle mediastinum mass L

CT-abdomen

• No significant intraabdominal lymphadenopathy• Prominent sized liver without focal mass• Spleen, pancreas, both kidneys and urinary bladder are unremarkable

Imp: Normal study

L

Paraneoplastic pemphigus(PNP)T lymphoblastic lymphoma stage III

Vesiculobullous lesion

Inherited disorder

1.Bullous ichthyosiformerythroderma2.Incontinentia pigmentti3. EpidermolysisBullosa

Acquired disorder

Infection Autoimmune disease

Drug reaction

Virus:HSV

Bacteria,TB

Candidiasis

Bullous pemphigoid

Paraneoplastic pemphigusEM: Erythema multiforme

SJS-TEN

EM

Indian J Pediatr 2015 ;82:805-8Indian J Paediatr Dermatol 2015;16:9-16

Pemphigus vulgris/ foliaceus

Bullous scabies

Paraneoplastic pemphigus

• First described in 1990• Paraneoplastic autoimmune multiorgan syndrome or PAMS• Rare, life-threatening immune-mediated bullous condition• Characterized by the presence of

• Intractable painful stomatitis • Cutaneous include palms,soles and nails: flaccid cutaneous bullae,

erosion• Ocular: irritation, pain, redness, worsening of vision and mucus

dischargeClin Dermatol 2016;34:205-13.

J Am Acad Dermatol 2017;77:795-806.

Diagnostic criteria: revised by Camisa and Helm, 1993Major criteria:1.Polymorphic mucocutaneous eruption 2.Concurrent internal neoplasia 3.Specific serum immunoprecipitation pattern Minor criteria:1.Histologic evidence of acantholysis in biopsy specimen at least one site2.DIF showing intercellular and basement membrane staining3.IIF staining with rat bladder epithelium

Three major OR Two major and two minor criteria Oral Oncol 2004;40:553-62

Paraneoplastic pemphigus

Pathogenesis:- NOT Fully known!- Tumor(eg. B-cell lymphoma) produce autoantibodies directed against:

desmosomal and hemidesmosomal antigens(periplakins and envoplakins)- Antitumor immune response cross-reacts with normal epithelial proteins- Epitope spreading: chronic inflammation leads to exposure of new self-antigen,

triggering a humoral response - Failing of the antineoplastic immune surveillance caused by

immunosuppressive therapy for pemphigusPediatrics 2004;114:e513-6

Int J Dermatol 2001 ;40:367-72Clin Dermatol 2013 ;31:382-390

Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick's Dermatology in General Medicine, 8e; 2012

Approach to patient with paraneoplastic pemphigus

Paraneoplastic pemphigus

Children:-Castleman’s disease-Sarcoma

Acta Haematol 2014;132:73-74Br J Dermatol 2015;173:1447-52

Adult-lymphoma-89% B cell phenotype-11% T cell phenotype

Pediatr Dermatol 1997;14:264-72.

- 23 immunobullous-children in a referral population base of 4 million people over a 16-year period.- PNP: only one case - Castleman’s disease

• The largest pediatric case series: 14 children with PNP• Severe oral mucositis and cutaneous lichenoid lesions• Occult Castleman’s disease • Diagnostic marker: Serum autoantibodies against plakin proteins• High mortality: pulmonary injury(bronchiolitis obliterans pneumonia)

Br J Dermatol 2002;147:725-32.

• The first report of PNP in a child, only one report• A 7-yr-old boy with a T-cell lymphoblastic lymphoma stage IV • Severe persistent erosive and crusting mucocutaneous eruption• DIF: deposition of C3 in a linear pattern along the dermo-epidermal junction• IIF staining with rat bladder epithelium • Slow resolution of skin disease over a period of 4 weeks• 11 months after initiation of CMT, he was in complete remission but continued

to develop occasional isolated small oral erosionsBr J Dermatol 1993 ;128:418-22.

Prognosis

• Very poor prognosis and high mortality rate• Unfavorable: Non-Hodgkin lymphoma• Favorable: Castleman disease and thymoma• Overall survival rates: 49%, 41% and 38% at 1, 2 and 5-year

• Cause of death: bronchiolitis obliterans and infection.• Poor factor:

• erythema multiforme-like skin lesions (High serum level of TNF, Fas ligand)• Histologic keratinocyte necrosis

• Treatment of the underlying neoplasm: may improve PNP

Br J Dermatol 2003;149:1143-51Arch Dermatol 2012;148:1165-72

Progression note

• After complete induction phase • Improve skin lesion• Persistent post inflammatory

hyperpigmentation• Persistent oral painful erosions• Decreased size of anterior

mediastinum mass

2 weeks after start induction

2 weeks after start induction

After HR-augmented consolidation phase II week 5

Thank you