A Malignant Mimicker: Features of Kikuchi-Fujimoto Disease in the Pediatric Population

Abstract

Background

Kikuchi-Fujimoto disease (KFD) is a rare, benign, and self-limited disease that presents with cervical lymphadenopathy and systemic symptoms. Histologic evaluation is often necessary to differentiate KFD from other entities.

Methods

Electronic medical records and diagnostic material were reviewed for 14 children diagnosed with KFD and 6 children diagnosed with infectious mononucleosis (IM) from 2013-2021. Four cases of KFD were further characterized using targeted DNA-based next-generation sequencing.

Results

Systemic symptoms were present in 86% (n = 12/14) of KFD patients, the most common being fever. Laboratory values worrisome for malignancy included cytopenia(s) (n = 9/12), elevated ESR and/or CRP (n = 9/12), elevated ferritin (n = 7/7), and elevated LDH (n = 7/10). Histologically, lymph nodes showed characteristic necrotic foci without neutrophils surrounded by MPO+ “crescentic” histiocytes. Immunoblasts and CD123+ plasmacytoid dendritic cells (pDCs) were also increased surrounding the necrosis. IM lymph nodes showed similar features when necrosis was present but increases in pDCs were patchy and rare neutrophils were seen in the necrotic foci. Molecular analysis of 4 KFD cases did not identify pathogenic variants.

Conclusion

While the signs/symptoms of KFD are worrisome, there are pathologic features that help differentiate it from potential mimics. We did not identify characteristic molecular features to aid in the work-up of these cases.

Keywords

crescentic histiocytes histiocytic necrotizing lymphadenitis Kikuchi-Fujimoto disease lymph node plasmacytoid dendritic cells

Introduction

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, was first described in 1972 in two independent but simultaneous reports from Japan by Kikuchi¹ and Fujimoto.² To date, the etiology of this uncommon disease still remains to be elucidated. While this diagnosis is more prevalent in Asian women in their third decade of life,^3-5 cases from other ethnicities and age groups have been reported, including pediatric patients. Clinically, KFD is benign and typically self-limited, often regressing without treatment.⁶ The predominant clinical feature is usually acute to subacute cervical lymphadenopathy with bulky and painful lymph nodes,^4-11 which are more likely to be unilateral than bilateral.^7,8,10,12,13 However, some patients present with more concerning systemic symptoms and abnormal laboratory tests that mimic the clinical presentation of a malignancy, such as lymphoma.^{6-9,11,12,14-18}

Histologically lymph nodes involved by KFD demonstrate necrotizing lymphadenitis with karyorrhexis, increased histiocytes, and a notable lack of neutrophils. Many of these histiocytes have peripherally-placed crescentic nuclei, coined “crescentic histiocytes,”¹⁹ and prominent engulfment of karyorrhectic and other debris. The lymph node paracortex is often expanded by populations of enlarged lymphocytes, immunoblasts, plasmacytoid dendritic cells (pDCs) and/or foamy histiocytes, which may surround the areas of necrosis. Three histologic types of KFD have previously been described and include: a) proliferative (early) phase, b) necrotizing (intermediate) phase, and c) xanthomatous (late) phase.^5,12 The proliferative phase is characterized by increased histiocytes, lymphocytes, pDCs, and karyorrhectic debris, while the intermediate, or necrotizing phase shows coagulative necrosis; overlap of both the proliferative and necrotizing phase may also be observed. Cases are typically classified as being in the xanthomatous phase if increased foamy histiocytes are present, regardless of the presence or absence of necrosis. Both the proliferative and necrotizing phases often contain increased large lymphocytes and immunoblasts, which may give the histologic appearance of large cell lymphoma or be confused with the immunoblastic proliferations associated with EBV infection.

Notably, many of the patients eventually diagnosed with KFD initially presented to our hematology/oncology service due to their worrisome systemic symptoms and abnormal laboratory results. In this study, we review our institution’s pediatric experience with KFD, including patients’ systemic symptoms and laboratory values, and strategies for distinguishing KFD from other clinical and pathologic mimics.

Methods and Materials

With Institutional Review Board approval and waiver of consent, the Seattle Children’s Hospital pathology database was queried for cases diagnosed as histiocytic necrotizing lymphadenitis or KFD from January 2013 through December 2021. The diagnosis was independently confirmed by two board-certified hematopathologists (KMC and SDB) who reviewed the original hematoxylin and eosin (H&E) stained slides and any available immunohistochemical studies, including CD123. The phase of KFD was also recorded. Additionally, 6 lymph nodes previously diagnosed as infectious mononucleosis were retrieved and immunohistochemically stained with CD123 and MPO for comparison.

Clinical charts were reviewed and the following clinical information was recorded (if available): 1) patient demographics (age, sex, race), 2) presenting symptoms, 3) clinic/location of initial care, 4) sites of adenopathy (including radiographic size), 5) treating physicians’ differential diagnoses, and 6) duration and evolution of signs/symptoms. Additional laboratory and pathology findings, including size and histologic features of the excised lymph node(s) were also noted. The recorded laboratory values included white blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), hemoglobin, mean corpuscular volume (MCV), platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, aspartate transaminase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), ferritin, lactate dehydrogenase (LDH), antinuclear antibody (ANA) presence and titers, and presence/absence of anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibody.

Four specimens demonstrating either proliferative or necrotizing phases of KFD (cases 5, 7, 9, and 11) were subjected to UW OncoPlex version 6 (OPXv6), a 340-gene DNA-based next generation sequencing (NGS) panel designed to detect single nucleotide variant (SNVs), insertion/deletions (indels), copy number alterations, and select structural rearrangements; OPXv6 is also validated for the detection of microsatellite instability and tumor mutational burden (TMB).²⁰ In brief, DNA was extracted from formalin-fixed paraffin embedded (FFPE) tissue using the Qiagen GeneRead DNA FFPE Kit (Qiagen, Valencia, CA) prior to shearing and library preparation using KAPA HyperPrep reagents (Roche, Wilmington, MA). Prepared libraries were subsequently hybridized to OPXv6 (IDT, Coralville IA) prior to sequencing on an Illumina NextSeq500 (Illumina, San Diego, CA) and processing through an automated, custom-designed bioinformatics pipeline developed by the University of Washington NGS Analytics Laboratory. The data was then analyzed for the presence of clinically significant alterations by two board-certified molecular pathologists (VP, KT).

Results

Kikuchi-Fujimoto Disease: Clinical Characterization

Over this 9-year time-period, 14 cases of KFD were confirmed at Seattle Children’s Hospital, with a male to female ratio of 6:8 and a median age of 15.7 years (range: 9.6-18.6 years). These patients included: 8 Asian, 2 Caucasian, 2 Hispanic, and 1 African American; race was not available for 1 patient. Figure 1 depicts the most common presenting symptoms among our patients, including fever (n = 10), fatigue (n = 10), weight loss (n = 7), loss of appetite (n = 5), night sweats (n = 5), and headache (n = 5). Six of the 14 patients either presented to the hematology/oncology clinic, were admitted to the hematology/oncology team through the emergency room, or were admitted to the general ward from the emergency room with hematology/oncology team consultation.

Lymphadenopathy was present in all 14 patients. Twelve patients had cervical adenopathy (noted to be unilateral in 7 patients and bilateral in 5 patients); 1 patient had left posterior triangle lymphadenopathy, and the remaining patient had bilateral axillary lymphadenopathy. By imaging, the median size of the largest lymph node dimension was 2.5 cm (range: 1.3 to 3.5 cm). Of the 7 patients with radiologic imaging of anatomic areas outside the neck, only 2 demonstrated other sites of lymphadenopathy: 1 with mildly enlarged periportal lymph node(s) of up to 1.3 cm, and 1 with multiple conspicuous nonenlarged but enhancing lymph nodes scattered throughout the chest, abdomen, and pelvis (thought to be reflective of systemic inflammatory response or infection). The differential diagnoses included malignancy (leukemia or lymphoma) for the majority of patients (70%), with malignancy considered most likely in 40%. Other differential diagnostic considerations included viral lymphadenitis, rheumatologic disorders (including systemic lupus erythematosus, SLE), juvenile idiopathic arthritis, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis. The duration of symptoms prior to diagnosis ranged from 10 days to 4 months (median duration: 1.5 months).

Kikuchi-Fujimoto Disease: Laboratory and Pathology Evaluation

Laboratory values were available for 12 of the patients prior to their diagnosis and included many abnormalities suspicious for malignancy. Figure 2 summarizes the main laboratory findings (due to the different reference ranges for these assays, the values were expressed as multiples of the upper and lower normal limits). All laboratory values and normal reference ranges are listed in Table 1. Common peripheral blood findings included leukopenia (n = 9, median: 3.0 K/μL), neutropenia (n = 7, median: 1207/μL), anemia (n = 7, hemoglobin median: 12.1 g/dL), and thrombocytopenia (n = 4, median: 166 K/μL). Unilineage cytopenia was present in 2 patients, bilineage cytopenias in 5 patients, and trilineage cytopenias in 2 patients. Lymphopenia was also noted in 6 patients (median: 1039/μL), while all patients had normal absolute monocyte counts (median: 240/μL). The inflammatory markers ESR and CRP were elevated in 9 of 12 patients (median: 24.5 mm/hr) and 5 of 10 patients (median: .9 mg/dL), respectively. Albumin was decreased in 2 of 6 patients (median: 4.0 g/dL). Liver enzymes including AST, ALT, and GGT were elevated in 7 of 10 patients tested, though most with only mild elevations (medians of 48 IU/L, 45.5 IU/L, and 34 IU/L, respectively). Ferritin was elevated in all 7 of 7 patients (median: 528 ng/mL), while LDH was elevated in 7 of 10 tested patients (median: 1026 IU/L). ANA was negative in 5/9 patients. Positive titers in 4 patients included: 1:40 in one patient, 1:80 in another patient, and greater than or equal to 1:640 but less than <1:5120 in two patients; all four patients had negative anti-dsDNA.

Table 1.

Laboratory values in patients with Kikuchi-Fujimoto disease.

Patient	Sex	Age (years)	WBC(K/µL) (normal range)	ANC (/µL) (normal range)	ALC (/µL) (normal range)	AMC (/µL) (normal range)	Hgb(g/dL) (normal range)	MCV (fL) (normal range)	Platelet (K/µL) (normal range)	ESR (mm/hr) (normal range)	CRP(mg/dL) (normal range)	Albumin (g/dL) (normal range)	AST(IU/L) (normal range)	ALT(IU/L) (normal range)	GGT(IU/L) (normal range)	Ferritin (ng/mL) (normal range)	LDH(IU/L) (normal range)	ANA (normal range)
1	M	17.6	2.8 (L)	1072 (L)	1380	325	12.3 (L)	85.2	169	6	n/a	n/a	n/a	72 (H)	n/a	n/a	557	Negative
			(4.5-11.0)	(1500-7200)	(1100-4500)	(0-900)	(13.0-16.0)	(78.0-98.0)	(150-450)	(0-15)				(10-50)			(313-618)	(Negative)
2	F	15.8	3.5 (L)	2555	805 (L)	140	10.0 (L)	87.8	202	29 (H)	<0.8	4.2	42 (H)	44 (H)	15	528 (H)	1850 (H)	≥1:640, <1:5120^a
			(4.5-11.0)	(1500-7200)	(1100-4500)	(0-900)	(12.0-16.0)	(78.0-98.0)	(150-450)	(0-20)	(≤0.8)	(3.8-5.4)	(5-41)	(6-40)	(5-55)	(10-70)	(370-645)	(Negative)
3	M	14.0	3.9 (L)	1537	2071	250	12.1 (L)	86.4	256	23 (H)	<0.8	n/a	n/a	n/a	n/a	n/a	n/a	n/a
			(4.5-11.0)	(1500-7200)	(1100-4500)	(0-900)	(13.0-16.0)	(78.0-98.0)	(150-450)	(0-15)	(≤0.8)
4	M	18.5	4.0	2800	800 (L)	300	14.4	86	195	57 (H)	10.66 (H)	4.4	34	47	n/a	967 (H)	292 (H)	Negative
			(3.5-11.0)	(2000-8500)	(1000-4500)	(100-900)	(13.4-17.0)	(80-100)	(150-400)	(0-14)	(≤0.79)	(3.5-5.0)	(10-40)	(<55)		(22-275)	(125-243)	(Negative)
5	M	17.3	1.3 (L)	1144 (L)	143 (L)	13	5.9 (L)	94.8	66 (L)	26 (H)	1.8 (H)	2.8 (L)	409 (H)	452 (H)	76 (H)	4280 (H)	3751 (H)	1:80^a
			(4.5-11.0)	(1500-7200)	(1100-4500)	(0-900)	(13.0-16.0)	(78.0-98.0)	(150-450)	(0-15)	(≤0.8)	(3.8-5.4)	(5-41)	(10-50)	(15-85)	(10-300)	(313-618)	(Negative)
6	F	13.0	1.3 (L)	702 (L)	559 (L)	39	10.2 (L)	87.0	117 (L)	29 (H)	<0.8	3.8	60 (H)	34	n/a	1320 (H)	2720 (H)	1:40^b
			(5.0-11.0)	(1500-7200)	(1100-4500)	(0-900)	(12.0-16.0)	(78.0-98.0)	(150-450)	(0-20)	(≤0.8)	(3.8-5.4)	(5-41)	(6-40)		(10-70)	(370-785)	(Negative)
7	M	16.8	2.6 (L)	1102 (L)	1214	231	13.7	85.7	145 (L)	23 (H)	n/a	n/a	54 (H)	82 (H)	n/a	417 (H)	1608 (H)	Negative
			(4.5-11.0)	(1500-7000)	(1100-4500)	(0-900)	(13.0-16.0)	(78.0-98.0)	(150-450)	(0-15)			(5-41)	(10-50)		(10-300)	(313-618)	(Negative)
8	F	9.6	3.2 (L)	1270 (L)	1590	330	12.1	85.8	149 (L)	21 (H)	1.6 (H)	n/a	30	15	n/a	n/a	1110 (H)	n/a
			(4.5-13.5)	(1800-7000)	(1500-5000)	(0-900)	(11.5-15.5)	(77.0-95.0)	(200-450)	(0-10)	(≤0.8)		(5-41)	(5-31)			(370-840)
9	F	16.8	1.9 (L)	939 (L)	864 (L)	76	10.3 (L)	98.1 (H)	170	55 (H)	1.0 (H)	3.4 (L)	41	41 (H)	14	147 (H)	942 (H)	≥1:640, <1:5120^a
			(4.5-11.0)	(1500-7200)	(1100-4500)	(0-900)	(12.0-16.0)	(78.0-98.0)	(150-450)	(0-20)	(≤0.8)	(3.8-5.4)	(5-41)	(6-40)	(5-55)	(10-70)	(313-618)	(Negative)
10	F	15.7	5.4	2446	2328	421	14.4	89.3	254	5	<0.8	n/a	n/a	27	n/a	n/a	374	Negative
			(4.5-11.0)	(1500-7200)	(1100-4500)	(0-900)	(12.0-16.0)	(78.0-98.0)	(150-450)	(0-20)	(≤0.8)			(6-40)			(370-645)	(Negative)
11	F	11.3	2.0 (L)	1060 (L)	780 (L)	120	10.1 (L)	80.7	219	74 (H)	1.5 (H)	4.2	79 (H)	71 (H)	53	375 (H)	654	Negative
			(5.0-11.0)	(1500-7200)	(1100-4500)	(0-900)	(11.5-15.5)	(77.0-95.0)	(200-450)	(0-10)	(≤0.8)	(3.8-5.4)	(5-41)	(5-31)	(5-55)	(10-70)	(370-840)	(Negative)
12	F	15.0	4	1700	1600	400	13.6	83.5	162	5	<0.02	n/a	n/a	n/a	n/a	n/a	n/a	n/a
			(4.0-11.0)	(1400-6600)	(1100-4800)	(0-1000)	(11.1-15.7)	(75.0-89.0)	(150-400)	(0-20)	(<0.9)
13	F	17.4	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a

14	M	9.8	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a	n/a

^aHomogenenous pattern; anti dsDNA normal (≤120)

^bSpeckled pattern; anti dsDNA normal (≤120); follow-up ANA was negative

ALC, absolute lymphocyte count; ALT, alanine aminotransferase; AMC, absolute monocyte count; ANA, antinuclear antibody; ANC, absolute neutrophil count; AST, aspartate transaminase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamyl transferase; Hgb, hemoglobin; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; n/a, not available; Plt, platelets; WBC, white blood cell count.

Surgical specimens submitted for histologic evaluation consisted of lymph node excisions or excisional biopsies, with the largest lymph node dimension ranging from .6 to 2.2 cm (median: 1.4 cm). Morphologic examination revealed features indicative of KFD, with 2 cases classified in proliferative phase, 6 in necrotizing phase (some early), and 6 in xanthomatous phase. No increase in plasma cells was observed in any of the cases, nor were hematoxylin bodies or other features of SLE identified. The lymph nodes were relatively enlarged with foci of necrosis lacking neutrophilic inflammation (necrotic phase, Figure 3). Within and adjacent to the necrosis were many CD163-or CD68-positive histiocytes with crescentic nuclei (Figure 3(d)). Aberrant myeloperoxidase (MPO) staining was also identified in these histiocytes by immunohistochemistry (Figure 3(e)). As illustrated in Figure 4, enlarged lymphocytes/immunoblasts with prominent nucleoli often surrounded the necrotic foci; such features can be mistaken for a malignancy. However, in KFD, the lymphocyte proliferation contains a mixture of CD4⁺ T cells and CD8⁺ T cells, the latter often more prominent (Figure 4(d)). Additionally, CD123+ pDCs were increased in all 14 cases of KFD (Figure 5).

Flow cytometry was performed on a limited number (n = 3) of the lymph nodes. In general, there were no abnormal B or T cell populations identified and no downregulation of pan-T cell antigens. However, the T to B cell ratios were elevated in all three lymph nodes (2.0:1, 4.0:1, and 4.7:1) compared to reported normal lymph node ranges (1.6-1.8:1^21,22). Additionally, the CD4:CD8 ratios were reduced at 1.6:1 and .9:1 in the two cases in which these antigens were evaluated (normal range 3.5-4.5:1^21,22). Plasmacytoid dendritic cells were enumerated at 1.8% in the one lymph node with CD123 antigen employed by flow, which is elevated compared to normal lymph nodes (.45 ± .05%²³).

As part of the work-up for systemic symptoms and cytopenias, three patients underwent bone marrow aspiration and core biopsies (patients 5, 6, and 11). Of these three, all had hypocellular bone marrows for age (20-40% cellularity) but with trilineage hematopoiesis and full-spectrum maturation. Lymphocytes were not increased and there were no lymphoid aggregates detected on core biopsies. Crescentic histiocytes were not identified. Flow cytometry was performed on one of these marrows and did not identify abnormal populations; the T:B cell ratio was normal at 4.3:1 (normal range 4-5:1²⁴). However, and most interestingly, all three cases demonstrated hemophagocytosis, including histiocytes engulfing myeloid precursors.

Infectious Mononucleosis: Histologic Mimicker

Anecdotally, we have identified foci of necrosis and increased pDCs in cases of infectious mononucleosis. In order to further explore the possible overlapping histology, 6 lymph node cases diagnosed with infectious mononucleosis (all positive for EBV by EBER in situ hybridization) were retrieved from our archives and stained with CD123 and MPO. By H&E, 3 of the 6 cases contained foci of necrosis. Most of these necrotic foci also contained identifiable crescentic histiocytes (Figure 6). The presence of scattered neutrophils within at least some of the areas of necrosis helped distinguish infectious mononucleosis from KFD. Interestingly, MPO staining also highlighted mononuclear cells in these 3 cases of infectious mononucleosis, similar to what we observed in cases of KFD. All cases of infectious mononucleosis additionally demonstrated patchily increased pDCs, which were especially prominent surrounding the areas of necrosis, although not to the degree observed in KFD. In areas outside the necrotic foci, pDCs were scattered and not significantly increased.

Kikuchi-Fujimoto Disease: Molecular Characterization

In order to help identify potential pathogenic somatic or germline predisposition variants, a targeted DNA-based NGS assay was performed on 4 KFD specimens. No copy number alterations, fusions, or definitively pathogenic or likely pathogenic variants (somatic or potentially germline) were identified. PCR-based T cell clonality was performed in one of the 14 cases as part of the clinical work-up and was negative for a clonal (or oligoclonal) TCR gamma or beta gene rearrangement.

Discussion

In this study, the majority of our patients diagnosed with KFD demonstrated clinical symptoms that were worrisome for malignancy, including fever and fatigue, weight loss, and night sweats. Fever is common in KFD (reportedly seen in 35-94% of patients^4,6,9,11,18) and is more frequent in children than in adults.^9,13,18 Worrisome symptoms similar to those observed in our cases have been reported in the literature including weight loss/loss of appetite, gastrointestinal complaints, fatigue, headaches, arthralgias, myalgias, rash, and night sweats.^9,12,15 In a pediatric series of KFD, 42% of 86 cases showed more than 2 systemic symptoms other than fever, again emphasizing the systemic hallmarks of this disorder, and the possible symptomatic overlap with malignancy, particularly in children.⁹ The frequent referral to hematology/oncology among our patients further supports the worrisome clinical presentations commonly encountered in KFD cases.

Similarly, patients in this series had abnormal laboratory tests that raised concern for malignancy. These included leukopenia (specifically neutropenia), anemia, thrombocytopenia, elevated LDH, increased ESR and C-reactive protein, elevated ferritin, and abnormal liver function tests; these findings have also been reported in the literature.^4,6,11-13,15 However, in some of the largest KFD series, abnormal lab findings (other than elevated ESR and leukopenia) are only present in a minority of cases (<10%).^4,19 While showing increased symptomatic patients compared to adult case series, our case series displays similar/mildly increased percentages of pediatric patients with abnormal peripheral blood counts (75% with leukopenia, 66.7% with neutropenia, 50% with anemia, and 33% with thrombocytopenia) compared to three other pediatric series.^9,11,13 Interestingly, Lin et al¹¹ showed that 63.6% of their patients had peripheral monocytosis, a finding that was absent in our patients. The increased ESR, CRP, and LDH identified in this study is also in line with prior pediatric series.^11,13

Given potentially confounding clinical findings in KFD, the diagnosis relies heavily on the histologic findings within an involved lymph node; hence, pathologists must be familiar with all histologic subtypes of this disease and any potential morphologic or immunohistochemical mimics. While many cases of KFD have partial retention of the lymph node architecture with residual germinal centers, some cases may simulate a Hodgkin lymphoma or a non-Hodgkin lymphoma with increased immunoblasts and large atypical lymphocytes, sometimes forming sheets. In fact, in some studies, more than 30% of KFD cases were originally diagnosed as lymphoma, and only upon consultation was the correct diagnosis reached.^8,17,25

KFD also shares multiple histologic similarities with infectious mononucleosis, including paracortical lymphocytic expansions, increased immunoblasts, foci of necrosis, and residual germinal centers. In this study, our examination of infectious mononucleosis lymph nodes identified crescentic histiocytes and MPO+ histiocytes in foci of necrosis (if present), as well as increased pDCs especially in foci surrounding coagulative necrosis; these findings further expand the spectrum of overlapping features between KFD and EBV. Therefore, EBER in situ hybridization staining should be considered upon identifying such morphology, particularly if neutrophils are not identified within the areas of necrosis. Additionally, we found the increase in pDCs to be patchy and proportionally lower than the increased pDCs typical of KFD, findings supported by prior studies.^26-31 For example, Rollins-Raval et al²⁸ reported fewer pDCs in viral infections (including CMV, HIV, Hepatitis C and a case of chronic HIV and EBV) compared to KFD and other causes of granulomatous inflammation. pDCs are known to migrate from the bone marrow to T-cell rich areas of lymph nodes.^32,33 Increased T cells are well-described in KFD and in the paracortical regions in infectious mononucleosis; therefore, the identification of increased pDCs is not surprising. pDCs play an important immunomodulatory role, secrete cytokines in response to apoptotic cells, and are known to internalize apoptotic particles,^34-37 which explains their localization to areas of necrosis and karyorrhexis in KFD and our cases of infectious mononucleosis.

While KFD is classically known to have crescentic histiocytes, MPO+ histiocytes, and increased plasmacytoid dendritic cells, our study exemplified some more novel associations with KFD. Firstly, hemophagocytosis was identified in all three of the bone marrows that were performed as part of a malignancy work-up. While hemophagocytosis has been reported in cases of KFD, it is also associated with infections, autoimmune diseases, and malignant entities including lymphoma.^4,6,38 Additionally, while only a few of the KFD lymph nodes in our series had flow cytometry performed, the findings included increased T:B cell ratios and decreased CD4:CD8 ratios compared to published normal ratios.^21,22 Though these findings are notable, they are non-specific as increased T:B cell ratios can be seen in T-cell lymphomas, Hodgkin lymphomas, some B-cell lymphomas, and reactive conditions. In addition, CD4:CD8 ratios can be decreased in some lymphomas and other reactive conditions including infectious mononucleosis.³⁹ Future prospective work may help determine whether these findings are consistently seen among cases of KFD.

DNA-based NGS using OPXv6 was performed in four of the cases in our series.²⁰ While KFD is not thought to be a neoplastic process, given the identification of molecular alterations in a variety of non-neoplastic entities, such as RAS family gene mutations in Ras-associated autoimmune leukoproliferative disease (RALD),⁴⁰ variants in the IL7R gene in sarcoid,⁴¹ and mutations and polymorphisms in JAK and STAT genes in inflammatory and autoimmune diseases⁴², we sought to further molecularly characterize a subset of our KFD cohort. However, we did not identify any clinically significant somatic copy number alterations, fusions, SNVs or indels, nor did we identify potential germline predisposition polymorphisms in any of these 4 cases. The lack of variants in neoplasia-associated genes also favors a non-neoplastic process over a lymphoma. Of note, several low frequency population polymorphisms, which have been classified as variants of uncertain significance, were identified (Supplemental Table 1). Many of these variants were found at highest frequencies in East Asian and Latino populations (gnomAD), consistent with the ethnicities of the four patients tested.

Prior studies have identified some molecular alterations in KFD patients; however, many of the identified alterations were in genes that were not present on OPXv6. Of note, OPXv6 does not utilize RNA testing. Tanaka et al⁴³ performed HLA typing in cases of KFD, identifying HLA class II alleles DPA1*01 and DPB1*0202 to be higher in KFD compared to controls. Ishimura et al⁴⁴ used microarray analysis and identified IFI44L, CXCL10, GBP1, EPSTI1, and IFI27 to be up-regulated in KFD. More recently, Anuntakarun et al performed whole exome DNA sequencing on 4 KFD cases and identified 14 single nucleotide polymorphisms (SNPs) in different genes that could predispose to KFD (including seven associated with human cancers)⁴⁵; however, none of the genes they identified were included on our cancer gene panel. This same group also used RNA Seq from one patient to look at transcriptome data and identified multiple upregulated and down-regulated genes, including genes involved in apoptosis, innate immunity, and chromatin structuring.⁴⁵ Interestingly, another recent study utilized NGS testing to evaluate T and B cell immune repertoire in three KFD patients with African American ancestry, and identified a shared complementarity determining region (CDR3).³¹ Further studies are warranted to help determine if any of these SNPs, regions, and/or protein signatures predispose to KFD and/or if they are specific to certain ancestries.

Unfortunately, and despite numerous investigations, the etiology of KFD still remains unclear. Viral studies, including EBV, human herpesvirus 8, parvovirus, and human herpesvirus 6, have been investigated but to no avail.^31,46-49 Mycobacterial, bacterial, and parasite studies have also failed to identify an etiology.^49-51 Notably, viral studies were performed in 9 of the 14 cases in this study without positive results. Additionally, screening for Bartonella, Coxiella, Toxoplasma, Rocky Mountain Spotted Fever, Bordetella, Brucella, Tularemia, and mycobacteria were undertaken in some patients in this study and were found to be negative. Some literature suggests that KFD is an SLE-like autoimmune disorder elicited by transformed lymphocytes due to viruses or other infectious causes^52-54; however, most cases of KFD lack antinuclear antibodies (ANA) and triggers have yet to be identified.

In conclusion, this is a single pediatric hospital experience of lymph node biopsy-proven KFD illustrating clinical and laboratory findings that can mimic lymphoma and with some morphologic overlap with EBV+ infectious mononucleosis. While this study is limited by the relatively small number of cases compared to larger review series and the incomplete medical records for some patients, our findings may aid pathologists in generating an appropriate differential diagnosis when evaluating lymph node samples from patients with concerning clinical presentations.

Supplemental Material

Supplemental Material - A Malignant Mimicker: Features of Kikuchi-Fujimoto Disease in the Pediatric Population

Supplemental Material for A Malignant Mimicker: Features of Kikuchi-Fujimoto Disease in the Pediatric Population by Karen M. Chisholm, MD, PhD, Sandra D. Bohling, MD, Karen D. Tsuchiya MD, and Vera A. Paulson, MD, PhD in Pediatric and Developmental Pathology

Footnotes

Acknowledgments

We thank the University of Washington NGS Analytics Laboratory and the UW Genetics and solid tumors laboratory staff.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: KMC is supported by Seattle Children’s Mark Alan Bomgardner Endowment.

ORCID iD

Karen D. Tsuchiya

Supplemental Material

Supplemental material for this article is available online.

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