[CIS PIDD] [cis-pidd] Adenopathy in patient with Hyper-IgM syndrome

[Routes, John]

Might consider checking for KSHV---wonder if the histological diagnosis of unusual lymphoproliferative disorders might be altered by the absence of certain features due to the PID itself---for example, the absence of germinal centers in Howard's patient. Personally, with really high 18-FDG numbers (teens), progressive disease and no response to conservative measures I would probably treat the lymphoproliferative disease as if a malignancy with combination chemotherapy based on the inflammatory infiltrates

good luck---fascinating cases
Jack


John M. Routes, MD
Chief, Section of Allergy and Clinical Immunology
Professor of Pediatrics, Medicine, Microbiology and Molecular Genetics
Department of Pediatrics
Children's Hospital of Wisconsin
Medical College of Wisconsin
9000 W. Wisconsin Ave.
Milwaukee, WI  53226-4874
Phone: Office 414-266-6840
Fax: 414-456-6487 (Clinical)
Fax: 414-456-6323 (Laboratory)
Email: jroutes at mcw.edu<mailto:jroutes at mcw.edu>

On Aug 22, 2013, at 11:58 AM, Dewton Vasconcelos <dmvascon at usp.br<mailto:dmvascon at usp.br>>
 wrote:

Dear Howard, good afternoon

I have seen a 20 yo female patient with a similar necrotizing adenopathy who was sent to our outpatient unit with a working diagnosis of CVID and Kikuchi syndrome.
She arrived already receiving IVIg replacement (she really had hypogammaglobulinemia - all isotypes) and antibiotics, but due to the Kikuchi diagnosis, she was also treated with high dose corticosteroids.

Despite this she was febrile, losing weight with a clear consumptive disease. Her lymphnodes were really big and they seemed terrifying to me, and I thought initially about the possibility of a high grade lymphoma.
A comprehensive investigation of infectious agents resulted negative and her clinical features were evolving really bad.

A PET-CT demonstrated very high uptake of 18F-FDG in several lymphnode chains (cervical, axillary, supra and infraclaviculary, mediastinal, retroperitoneal), bones (spine and ilium), and also in liver and spleen.

The hypothesis of a lymphoma gained force and he biopsied again in a region with a very high uptake of 18F-FDG. The histopathological features were similar, the immunohistochemistry uncharacteristic (reactional lymphoid hyperplasia of a paracortical pattern with subcapsular aggregates of epithelioid histiocytes and coagulative pattern necrosis. Fungi and AFB negative; CD20+ focal, CD3+ focal, CD30-, CD15-, Ki67+ in 20%, CD68+ in histiocytes, CD10+ in germinal centers, MUM-1+ in scarce cells).

She was biopsied once more in the liver and in bone marrow, without a reasonable diagnosis (similar features) to such a terrible disease.
After approximately two months with us and two weeks as inpatient she developed fulminant hepatic failure (without any evidence of hepatic pathogens) and eventually died.

Discussing with our colleagues here they told me that they had a similar case, extensively investigated but also without final diagnosis.

I think that is interesting that colleagues who have (had) patients with similar features present their data. Could be very interesting to try to study these patients together!

Finally, as your patient present high IgM, I thought about the possibility of a nodal marginal zone lymphoma (??)

Best regards,

Dewton


Dewton de Moraes Vasconcelos, MD, PhD
Primary Immunodeficiencies Outpatient Unit ADEE3003
Lab. of Medical Investigation Unit 56
University of São Paulo School of Medicine

Howard Lederman wrote:
I need help with a patient hyper-IgM patient who has a necrotizing lymphadenitis.

M.K. is a 16 y/o male with hyper-IgM syndrome of undetermined etiology.  He has had persistent bilateral cervical lymphadenopathy since 6/2012.   Lymphadenopathy first was noted on a routine follow-up exam. A fine needle aspirate of a right cervical node during the summer of 2012, found pus and cultures grew Hemophilus and MRSA.  He was treated with clindamycin and Augmentin for 4 weeks, and then Bactrim for an extended course,  but there was only a slight clinical response.  Pathology from the FNA revealed histiocytic necrotizing lymphadenitis with a mixed lymphoid population.
On 8/29/2012, he underwent an excisional biopsy of 2 large lymph nodes in his right neck.  Pathology showed patchy geographic necrosis. There was no significant apoptotic debris or histiocytes in the necrotic areas which had an almost infracted look. There were abundant histiocytes rimming the necrotic areas. There were few, if any, neutrophils.  The architecture of the lymph nodes was distorted by this necrosis and histiocytes. Reed Sternberg cells or variants were not appreciated.  There were no granulomas identified and the paracortical infiltrate did not resemble viral change. PCR for EBV was negative.  There were scattered microcalcifications. CD68  and MPO staining highlighted abundant histiocytes.  Flow cytometry showed no evidence of lymphoma. AFB and GMS stains showed no evidence of microorganisms.  The morphologic features and immune-phenotype of the node raised the possibility of Kikuchi disease, however, lack of histiocytes and apoptotic bodies inside the necrotic areas was not considered to be consistent with Kikuchi disease.
The area of those biopsies never healed.  Other lymph nodes enlarged, there was a thin, yellow discharge.  The overlying skin broke down, and a sinus tract formed.  A PPD and a Quantiferon-Gold test were negative.  He was treated with prednisone (80 mg or approximately 1 mg/kg/day) with no response.  Enbrel was added, again with no significant clinical response.
In 3/2013, the site of the previous biopsies was opened open for debridement.  There was a large amount of “necrotic, fibrinous, cheesy material” with no obvious intact lymph nodes. He needed months of wound packing for the area to heal, and there continues to be some thin, yellow drainage through the incision sites.   Coagulase negative staphylococcus and Hemophilus influenzae were cultured.  He was treated with antibiotics despite the fact that we thought these organisms were contaminants transmitted from skin into the tissue via the sinus tract.   Prednisone was tapered and Enbrel was discontinued with a slow increase in the size of the lymph nodes
In 7/2013, he had an excisional biopsy of a left cervical lymph node.    Pathology was similar to what was seen last year.  No organisms identifiable by stain.  Coagulase negative staphylococci grew from a culture.  The following week, a culture of wound drainage grew enterococcus.  Once again, he was treated with antibiotics without response.
I have had hyper-IgM patients who develop generalized lymphadenopathy with follicular hyperplasia that usually responds to Rituxan.   This patient has a very different picture for which therapy has been ineffective and for which I do not even have a theory about the pathophysiology.  I wonder if anyone has seen this before, and/or if anyone has an idea for further elucidating the problem or an idea for empiric therapy.
I can email photomicrographs to anyone who wants to see them, but don’t think that I am allowed to include an attachment as part of the ListServ distribution.

Howard
Howard M. Lederman, M.D., Ph.D.
Professor of Pediatrics, Medicine and Pathology Division of Pediatric Allergy and Immunology Johns Hopkins Hospital - CMSC 1102 600 N. Wolfe Street Baltimore, MD 21287-3923
Phone: 410-955-5883
Fax: 410-955-0229
Email: Hlederm1 at jhmi.edu<mailto:Hlederm1 at jhmi.edu>

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