[CIS PIDD] ALPS versus CVID patient with progressing lymphoproliferative syndrome

[Sanchez Ramon.Silvia]

Dear colleagues,



we are taking care of a 15-yo boy followed by Digestive Dept. since 2007 for Crohn disease (biopsy not conclusive), and axillary polyadenopathies. Past medical history of atopic dermatitis and chronic migraines, negative for recurrent infections. He was referred in 2011 to us due to splenomegaly, multiple laterocervical adenopathies and hypogammaglobulinemia (IgG: 343 mg/dL; IgA 30 mg/dL and IgM: 28.6 mg/dL). He was clinically well.
At that time he showed lymphopenia B of 3%, with low switched-memory B cells of 3%; very low CD8+ T lymphocytes of 3%. Low baseline Ab titers to TT and pneumococcal Ag (he was on steroids 56 mg po/d for IBD). His WBC have been stable around 2000-2500/uL with moderate neutropenia of 600-700/uL; Lymphos 3,300/μL. The remaining series are normal (Hb: 12.8 g/dL Hematocrit 37.1 %; platelets: 135 10E3/μL ).
Normal expression of ZAP70 on T lymphocytes; normal HLA class I and II; IL-2, IL-7 and  IFNγ receptors expression. Noted to have 6% double negative T cells (CD3+CD4-CD8-) alpha-beta; Gamma-delta cells 3%.  No other features of ALPS. He was given IVIg replacement therapy, with suspicion of CVID (TACI mutation was negative) versus ALPS.

Other investigations
Coeliac disease screening: negative. Other autoantibodies (ANA, ENA, ANCA): negative. Normal complement. Normal TSH, T4L. Direct Coombs negative.
Normal serum biochemistries. Ferritin, vit.B12, folate: all normal.
Extensive viral/bacterial investigations, including: Serologies to CMV, EBV, toxoplasma, HB, HC, HIV1-2, bartonella, parvovirus negative. Repeated negative PCR for CMV and VEB.

In the last months the latero-cervical enlarged lymph nodes with approx 5 cm diameter, and splenomegaly (of 15 cm). Several cervical lymph nodes biopsies have shown lymphoid hyperplasia suggesting unspecific lymphoproliferative disorder, with high proliferative rate (Ki67), without necrosis areas or granulomas, without evidence of malignity and EBV (IHC and ISH) negative. There is a predominance of CD4 T cells, disperse B cells of probable follicular origin (CD20/CD79a/Bcl6+) and TFh (PD1+) cells. No Reed-Sternberg cells or non-haematopoietic neoplastic cells. PCR study: IgH gene: (FR1/JH): polyclonal (FR2/JH): polyclonal (FR3/JH): polyclonal. TCR-gamma (VJ-A) gene: polyclonal (VJ-B): polyclonal.

Bone marrow biopsy: normocellular BM parenchyma (3/5), without madurative changes. Multifocal mature lymphohistiocytic aggregates and interstitial lymphocytosis of predominantly CD4+ T cells (IHC). No blast cell aggregates, parasites, fungi, viral cytopathic inclusions, siderosis, mielofibrosis (except on the lymphohistiocytic nodules), or bone alterations were observed. No non-haematopoietic neoplastic infiltrates were observed.
Cervical ultrasound: bilateral intraparotideal, yugulodigastric and laterocervical adenopathies, more evident at the right side.
 Thoracoabdominal CT: Thoracic and abdominopelvic adenopathies, some of them of 4.5 and 3.2 cm diameter, bilateral lung nodules and hepatosplenomegaly.
PET-scan: multiple bilateral laterocervical, thoracic, abdominopelvic lymphadenopathies, and  multiple bone and bilateral lung nodules compatible with the diagnosis of lymphoproliferative syndrome.

Given the suspected ALP syndrome with multiple lymphadenopathies, therapy with Sirolimus (3.7 mg/24 h po after initial charge dosis) was started in Jan 2012. He showed a significant improvement of adenopathies and recovery of neutropenia, with no secondary effects.
He started with lumbalgia in January 2012. MRI disclosed a vertebral L4 body lesion with extension to intervertebral foramina L3-L4 and L4-L5. Biopsies showed non-caseating granulomas. PCR panfungal: negative. Parasites and mycobacteria: negative. PCR Universal 16S rARN negative. PCR Bartonella sp. neg. PCR Aspergillus sp. neg. PCR Panfungal negative. PCR CMV <100 copies/mL. Hemocultures, coprocultures x3, nasopharyngeal cultures all negatives. Negative quantiferon. At the Oncohematology Unit the patient was then given one cycle of chemotherapy, with COP (ciclophosphamide 400 mg/m2 1 dosis, vincristine 1.5mg/m2 and prednisone 60 mg/m2 X7 days.
Despite of this, a new MRI shows paravertebral and epidural mass with soft-tissue extension and increased signal in T1 and turbo stir. New sacral and lumbar bone lesions. The radiological image suggests progression of the lymphoproliferative disorder versus metastatic lesions.

He’s on prophylactic Bactrim, IVIg and sirolimus, and tapering doses of prednisone. Currently ongoing: study of caspase 8 and 10, and Fas/FasL mutations.

We are concerned about the clinical course of this young patient and on the best management for him, since we still have no definitive diagnosis.

1. What other treatment possibilities? Thoughts on chemotherapy?
2. What other tests or diagnoses would you consider?

Thanks so much in advance for your help.

Best regards,

Dra. Dolores Gurbindo, Section of Immunopediatrics
Dra. Silvia Sánchez-Ramón, Unit of Clinical Immunology

Silvia SÁNCHEZ-RAMÓN, MD, PhD
Unidad de Inmunología Clínica
Departamento de Inmunología
Hospital General Universitario Gregorio Marañón
Calle Doctor Esquerdo, 46
E- 28007 - Madrid, Spain
Tel: +34 914265181
FAX: +34 915868018
E-mail: ssanchez.hgugm at salud.madrid.org

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