An autopsy series of an oft-missed ante-mortem diagnosis: hemophagocytic lymphohistiocytosis

Majumder, Anusree; Sen, Debraj

doi:10.4322/acr.2021.243

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Autopsy Case Report • Autops. Case Rep. 11 • 2021 • https://doi.org/10.4322/acr.2021.243 copy

An autopsy series of an oft-missed ante-mortem diagnosis: hemophagocytic lymphohistiocytosis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome resulting from a hyperactivated immune system. Diverse patient profiles and clinical presentations often result in misdiagnosis. This article describes the varied clinical presentations and autopsy findings in three patients with this entity. The etiopathogenesis of HLH, its disparate and confounding clinical features, the diagnostic criteria, and management principles are also briefly reviewed.

Keywords
Autopsy; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Ferritins; Hypertriglyceridemia

	Case 1	Case 2	Case 3	Normal range
Diagnosis	CMML in blast crisis	Adult-onset Still’s disease	Septic shock, acute respiratory illness (? Viral)
Hb (g/dl)	6.5	10.2	6.8	12-17 g/dl
TLC (/mm³)	200	26,000	1,900	4000-11,000
DLC	PMN 20%, Ly 80%	PMN-90%(Bands-30%), Ly-10%	PMN-32%, Ly-60%, Mo-08%
Platelets (/mm³)	2,000	8,0000	10,000	1.5-4.5 x 10⁵
INR	3.25	3.75	5.25
ESR (mm/hr)	46	120	68	<20
CRP (mg/L)	160	89	78	<0.3
bilirubin (mg/dL)	2.3	1.8	3.4	0.2-1.2
AST (IU/L)	389	470	850	5-40
ALT (IU/L)	288	397	679	7-56
Ferritin (mcg/L)	6900	18500	11980	20-250
Triglycerides (mg/dL)	270	494	342	<150
LDH (IU/L)	895	4482	3376	140-280
Fibrinogen (g/L)	-	1.8	1.0	2-4

	Case 1	Case 2	Case 3
Gross findings	Heavy, boggy lungs Ascites; sero-sanguineous pleural effusion; hepatosplenomegaly; multiple paratracheal; para-aortic peripancreatic lymph nodes.	Heavy, boggy lungs; Sero-sanguineous pleural effusion; cardiomegaly; multiple thoracic, abdominal lymph nodes; hepatosplenomegaly.	Heavy, boggy lungs; sero-sanguineous pleural effusion; nutmeg liver; multiple enlarged paratracheal; peribronchial lymph nodes; congestive splenomegaly; left gangliocapsular hematoma.
Heart blood/CSF/ Ascitic/ Pleural culture	Klebsiella pneumonia	No growth	No growth
Post-mortem tracheal & nasopharyngeal aspirate	-	-	Pandemic A (H1N1)
Microscopy	Hemophagocytosis in bone-marrow, spleen & lymph nodes; diffuse alveolar damage lungs; steatosis with spotty necrosis & periportal inflammation in liver, acute tubular necrosis in kidneys	Hemophagocytosis in bone marrow, spleen & lymph nodes; lymphocytic myocarditis; diffuse alveolar damage lungs; steatosis with periportal inflammation & spotty liver necrosis; acute tubular necrosis in kidneys	Hemophagocytosis in bone marrow, spleen & lymph nodes; diffuse alveolar damage lungs; acute passive congestion in liver, acute tubular necrosis in kidneys; left gangliocapsular hematoma with liquefactive necrosis of brain parenchyma

Based on HLH 2004			2016 classification criteria for MAS complicating sJIA (Ravelli et al.⁸8 Ravelli A, Minoia F, Davi S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016;68(3):566-76. http://dx.doi.org/10.1002/art.39332. PMid:26314788. http://dx.doi.org/10.1002/art.39332... )
1. Molecular diagnosis (Confirmed HLH associated genetic mutation)			A known or suspected patient of sJIA with fever is classified as having MAS if the following criteria are met:
Or			· Ferritin >684ng/ml and
2. Fulfilment of 5 out of the following 8 criteria:			· Two of the following:
(a) Fever			o Platelet count ≤ 181x10⁹/l
(b) Splenomegaly			o AST> 48U/l
(c) Cytopenias in peripheral blood (affecting at least 2 hematopoietic cell lineages):			o Triglycerides >156 mg/dl
- Hemoglobin < 90 gm/L			o Fibrinogen≤360mg/dl
(<100gm/L in infants < 4 weeks of age)
-Platelets < 10x10⁹ /L
-Neutrophils <10x10⁹/L
(d) Hypertriglyceridemia and/or hypofibrinogenemia:
-Fasting triglycerides ≥3.0 mmol/L (ie, ≥265 mg/dL)
-Fibrinogen ≤1.5 g/L
e) Hemophagocytosis in the bone marrow, spleen, or lymph nodes
f) Low or absent natural killer cell activity
g) Ferritin ≥500 ng/mL
h) Soluble CD25 (ie, soluble interleukin-2 receptor) ≥2,400 U/mL
Based on the ‘H’ Score
Parameter	N^o of points	H score	Probability of Hemophagocytic syndrome
Known underlying immunosuppression	0 (no) or 18 (yes)	90	<1
Temperature (⁰C)	0(<38.4),	100	1
Temperature (⁰C)	33 (38.4-39.4) 49(>39)	110	3
Organomegaly	0(No)	120	5
	23(Hepatomegaly or splenomegaly)	130	9
	38(Hepatomegaly and splenomegaly	140	16
No of cytopenias	0(1 lineage)	150	25
	24(2 lineages)	160	40
	34 (3 lineages)	170	54
Ferritin (ng/ml)	0(<2000)	180	70
	35(2000-6000)	190	80
	50(>6000)	200	88
Triglyceride (mmol/L)	0(<1.5)	210	93
	44(1.5-4)	220	96
	64(>4)	230	98
Fibrinogen (g/L)	0(>2.5)	240	99
Fibrinogen (g/L)	30(≤2.5)	250	>99
Serum glutamic oxaloacetic transaminase (IU/L)	0 (<30)
Serum glutamic oxaloacetic transaminase (IU/L)	19(≥30)
Hemophagocytosis features on bone marrow aspirate	0 (No)
Hemophagocytosis features on bone marrow aspirate	35(Yes)
Hb ≤ 9.2gm/dl; Leukocyte count ≤5000/mm³; Platelet count ≤1,10,000/mm³
HIV positive/On long term immunosuppressive therapy (Glucocorticoids/Cyclosporine/Azathioprine)
Best cut-off for H score - 169

	H score	Probability of HLH
Case 1	287	>99
Case 2	327	>99
Case 3	299	>99

Hospital Universitário da Universidade de São Paulo Hospital Universitário da Universidade de São Paulo, Av. Prof. Lineu Prestes, 2565 - Cidade Universitária, 05508-000 - São Paulo - SP - Brasil, (16) 3307-2068, (16) 3307-2068 - São Paulo - SP - Brazil
E-mail: autopsy.hu@gmail.com

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[1] Authors’ contributions: Anusree Majumder was responsible for study concept and design, literature search and manuscript preparation. Debraj Sen was responsible for literature search and manuscript preparation. Both authors have approved the final version of the manuscript and shall be responsible for each part of the collaborative work in its final version.