INTRODUCTION

Histiocytic necrotizing lymphadenitis, also called Kikuchi’s lymphadenitis (KL), is a benign self-limited reactive condition with unknown etiology usually seen in young females causing cervical lymphadenopathy and fever.[1] In rare circumstances, the disease can have unusual presentations, such as axillary lymphadenopathy.[2] Cytological diagnosis is possible with adequate lymph node sampling by fine needle aspiration (FNA) in the proper clinical setting.[3] However, pathologists face some difficulties in making the diagnosis due to the overlapping findings seen in other conditions, such as tuberculosis, lupus lymphadenitis, non-specific reactive conditions, and even malignant lymphoma.[4] The diagnosis by cytopathology has the advantage of using minimally invasive interventions to avoid the unnecessary excision of the lymph node.[3]

CASE REPORT

We present the case of a 21-year-old woman with no known co-morbidities or genetic abnormalities. The patient presented with a 2-week history of right axillary pain and enlarged lymph nodes, with no fever, weight loss, or skin changes. The patient took a course of amoxicillin for 7 days with no relief from her symptoms. She had no family history of connective tissue diseases or malignancies.

A computed tomography scan showed multiple enlarged right axillary lymph nodes, the largest of which measured 2.4 × 1.6 × 2.8 cm with a homogenous texture. An axillary FNA of the right axillary lymph node was performed. Two Papanicolaou stains, one hematoxylin and eosin (H&E), and three air-dried Diff Quick stained smears were examined. The staining results showed a hypercellular yield comprising polymorphous populations of lymphocytes, immunoblasts, and increased numbers of tangible body macrophages – many of which had eccentric crescentic nuclei, acidophilic cells, and extracellular apoptotic bodies/karyorrhexis [Figure 1a and b]. No neutrophils, epithelioid granulomas, multinucleated giant cells, malignant cells, or atypical large lymphoid cells were seen.

Figure 1: (a) Lymph node fine needle aspiration papanicolaou stain showing karyorrhectic debris with crescentic histiocytes (yellow arrow). Scale bar = 50 µm. (b) Lymph node fine needle aspiration hematoxylin and eosin stain (H&E) stain showing acidophilic cells (red arrow) admixed with heterogenous lymphoid cell populations. Scale bar = 50 µm. (c) H&E slides from the excised lymph nodes showing partially effaced nodal architecture with necrosis. Scale bar = 200 µm. (d) Karyorrhectic nuclear debris, with apoptotic cells and multiple immunoblasts (green arrow) noted. Scale bar = 50 µm. (e) Myeloperoxidase immunohistochemistry stain showing positivity within the histiocytes. Scale bar = 100 µm.

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The patient received no treatment after the excision of the lymph node. Upon follow-up, the patient was well. No enlarged lymph nodes were seen in ultrasound imaging.

QUESTIONS

Q1: What is your diagnosis for the above findings?

Lupus lymphadenitis

Tuberculous lymphadenitis

Histiocytic necrotizing lymphadenitis

Malignant lymphoma

The answer is (c).

Necrotizing histiocytic lymphadenitis, also called KL, is a self-limited reactive condition first described in 1972 by Hutchinson and Wang.[1] The condition is usually seen in young adults of Asian descent and manifests as an acute onset of localized cervical lymphadenopathy with fever and leukopenia.[2] KL has also been described to involve other anatomical areas (e.g., the axillary lymph node) in 2–40% of cases.[1] The etiology and pathogenesis of KL are still unknown.[3] Many theories suggest that the condition is caused by an immune response of T cells and histiocytes to an infectious agent such as Yersinia, Toxoplasma, Epstein–Barr virus, human herpes viruses 6 and 8, human T-lymphotropic virus type-1, and parvovirus,[4] but this has not been confirmed.

Further workup of the case

An excisional biopsy was performed, which confirmed the diagnosis of necrotizing histiocytic lymphadenitis. Histological examination of the lymph node showed a partially effaced nodal architecture. There were patchy irregular areas of necrosis consisting of bright eosinophilic fibrinoid deposits with karyorrhectic nuclear debris and apoptotic cells. Multiple immunoblasts were noted adjacent to this area, as highlighted by CD30 immunohistochemistry. The area of necrosis and the karyorrhectic debris showed histiocytes that were positive for myeloperoxidase (MPO) and CD68 (DACO, GA511, Copenhagen, Denmark). CD20 highlighted the native B lymphocytes within the lymphoid follicles. No atypical lymphoid cells were identified [Figure 1c-e].

ADDITIONAL QUIZ QUESTIONS

Q2: What are the cytological features of necrotizing histiocytic lymphadenitis?

Crescentic histiocytes + karyorrhectic debris and acidophilic body

Epithelioid granuloma, neutrophils, and multinucleated giant cells

Necrotic debris + hematoxylin bodies (LE bodies)

Atypical cells + necrotic debris

The answer is (a).

KL has distinct cytological features that help to reach a diagnosis. These features comprise crescentic histiocytes (with eccentrically placed crescentic nuclei and ingested nuclear debris in the cytoplasm), karyorrhectic debris, and acidophilic bodies, which are considered sensitive but not specific markers for KL.[5] All of these features were seen in our case. The answer (b) describes the microscopic features seen in other infectious cause, because KL has no infectious causes, including Mycobacterium tuberculosis, where epithelioid granulomas, neutrophils, and multinucleated giant cells are noted. In such cases, usually, the immunoblasts are less prominent than what is seen in KL. Cat scratch disease is another infectious mimicker, where the patient usually presents with a cutaneous lesion in addition to lymphadenitis and fever. Microscopically, cat scratch disease shows palisading, geographic microabscesses,[6] and neutrophils, which are not present in KL cases. Our patient’s serology, PCR, and culture were negative for Mycobacterium tuberculosis and Bartonella henselae. The answer (d) describes features usually seen in cases of lymphomas. Such cases usually show hypercellular smears with a monotonous population of atypical lymphoid cells, occasionally admixed with necrotic debris, which includes neutrophils with no crescentic histiocytes or acidophilic bodies. As the immunoblasts in KL may mimic atypical lymphoid cells in lymphoma cases, a comprehensive interpretation of all the findings in the smear is crucial to distinguish between the two differential diagnoses.

Q3: Can we distinguish between necrotizing histiocytic lymphadenitis and lupus lymphadenitis in cytology?

Yes.

No

The answer is (b).

The cytological distinction between lupus lymphadenitis and KL is extremely difficult and should not be attempted in the absence of clinical information and laboratory tests that aid in the diagnosis.[7] Smears with lupus lymphadenitis reveal features of necrotic debris comprising cellular debris with hematoxylin lupus erythematosus (LE) bodies, which are intensely stained, PAS-positive necrotic materials. The hematoxylin bodies (LE bodies) are pathognomonic for the diagnosis of systemic lupus erythematosus (SLE). Other cytological features include immunoblasts, plasma cells, lymphocytes, and macrophages. The immunoblasts have large, irregular nuclei that resemble Reed–Sternberg cells; therefore, Hodgkin lymphoma must be excluded in such cases.[7] In our case, the patient had no clinical symptoms suggestive of SLE, and her serological and immunological laboratory studies came back negative for antinuclear antibody, rheumatoid factor, and anti-double stranded DNA.

Q4: What are the histological features of necrotizing histiocytic lymphadenitis?

Atypical lymphoid cells + necrosis + eosinophils

Epithelioid granuloma, neutrophils, and multinucleated giant cells

Necrotic debris + hematoxylin bodies (LE bodies)

Effaced nodal architecture by necrosis + karyorrhectic debris + histiocytes with eccentric crescentic nuclei + no neutrophils

The answer is (d).

Histologically, the involved lymph node shows a partially effaced nodal architecture by paracortical expansion of well-defined foci of necrosis, with abundant karyorrhectic debris and histiocytes. Some of the histiocytes show eccentric crescentic nuclei with cytoplasmic nuclear debris. In some cases, many immunoblasts with necrotic debris and tangible body macrophages are seen adjacent to the necrotic area. No neutrophils or eosinophils are usually seen.[3]

There are three evolving phases identified histologically: proliferative, necrotizing, and xanthomatous. Diagnosis is usually based on the morphological findings; however, immunohistochemistry markers are used to exclude malignant lymphoma. The histiocytes in KL are positive for the immunohistochemical markers MPO, CD4, and CD68.[1] In our case, the crescentic histiocytes were positive for MPO.

Answer (a) describes the features usually seen in lymphoma, especially Hodgkin lymphoma. Hodgkin lymphoma is recognized in H&E staining by the presence of RS cells, which are large, atypical lymphoid cells with prominent macronucleoli. RS cells are usually negative for the B cell markers and positive for CD30 and CD15. In contrast, immunoblasts that are seen in cases of KL are intermediate in size, show a single prominent nucleolus that is usually smaller than the one seen in R-S cells, and stain positively for B-cell markers, including CD20, PAX5, and CD79a. The nodal architecture is usually totally effaced in cases of Hodgkin lymphoma, whereas it is preserved in cases of KL.

Answer (b) demonstrates the characteristic features seen in cases of tuberculous lymphadenitis. In this case, applying the special stain ZN can help to highlight the bacterial bacilli. Answer (c) reveals the morphological features of lupus lymphadenitis, which require clinical and serological correlation.

SUMMARY

Histiocytic necrotizing lymphadenitis is a benign, rare, reactive condition that must be distinguished from other differential diagnoses, including tuberculous lymphadenitis, SLE, malignant lymphoma, or even metastatic carcinoma. Cytological diagnosis in such cases can help to avoid invasive surgical intervention, which is possible with the proper clinical scenario and adequate, well-preserved samples.

AVAILABILITY OF DATA AND MATERIALS

All the cytology materials are available as smear slides. The lymph node material is available as slide and tissue paraffin blocks. The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

ABBREVIATIONS

EBV: Epstein–Barr virus

FNA: Fine needle aspiration

H&E: Hematoxylin and eosin stain

KL: Kikuchi’s lymphadenitis

MPO: Myeloperoxidase

PAP: Papanicolaou stain

AUTHOR CONTRIBUTIONS

ASA: Data collection, manuscript writing, and refining; BSA: Supervision, review, and editing. All authors read and approved of the final manuscript. All authors meet ICMJE authorship requirements.