February 2023 – Hematopathology Case One

A 72-year-old woman presented with progressively worsening right parotid swelling and right neck lymphadenopathy that occurred over a one-month timespan. Computer-tomography demonstrated multiple enlarged right intraparotid and cervical lymph nodes. A FNA of the cervical lymph nodes demonstrated polymorphous lymphocytes and scattered markedly atypical large cells with prominent nuclei. An excisional biopsy of a right neck lymph node, which was noted to be densely adherent to the surrounding soft tissue, was subsequently performed. 

The lymph node architecture was effaced by multifocal collections of large, atypical mononuclear cells (Figure 1). In addition to the stains performed in Figure 1, the large cells were positive for CD163 (weak), cyclin D1, OCT2 (weak in a subset), and showed an increased Ki-67 proliferation index. They were negative for PAX5, CD20, CD3, CD30, CD15, BRAF V600E, EBER, and BCL2. A subset of small residual germinal centers in the background demonstrated the suspicious immunophenotypic findings observed in Figure 2. 

Figure 1
Figure 2

Based on the main finding, what is the most likely diagnosis?

  • Langerhans cell sarcoma.
  • Interdigitating dendritic cell sarcoma.
  • Langerhans cell histiocytosis.
  • Follicular dendritic cell sarcoma.

The correct answer is ...

Langerhans cell sarcoma.

The correct answer is “Langerhans cell sarcoma,” which has also been recognized as malignant histiocytosis with Langerhans phenotype. Morphologically, the neoplasm effaces the lymph node architecture and consists of clusters of large, pleomorphic cells that demonstrate highly irregular nuclear contours, vesicular chromatin, prominent nucleoli, and abundant pale cytoplasm. The immunophenotypic features are those of a histiocytic neoplasm (expressing CD4, CD68, CD163) with a Langerhans cell phenotype, expressing CD1a, Langerin (rare single cells), S100, and ZBTB46 (Figure 1). Many cases of histiocytic and dendritic cell neoplasms show overlapping features due to shared progeny: They are believed to arise from a common myeloid stem cell differentiating towards histiocytic or dendritic cell types. Conversely, many of these neoplasms are associated with a preceding or concurrent lymphoproliferative disorder with which they share immunoglobulin or T-cell receptor rearrangements and chromosomal aberrations, constituting a transdifferentiation event.

In the case presented, the malignant histiocytic component demonstrated a BCL2 rearrangement. Although too minute for definitive FISH analysis, the small residual CD10 and BCL6-positive germinal centers that appear to show aberrant expression of BCL2 (Figure 2) are highly suggestive of in situ follicular neoplasia (ISFN). The suspicion for ISFN coupled with the BCL2 rearrangement (Figure 2) in the histiocytic neoplasm suggests a shared genetic background and that the histiocytic neoplasm is a secondary process resulting from transdifferentiation of a B-cell lymphoma.

Langerhans cell histiocytosis shares immunophenotypic features with our case but would show more bland cytology, including convoluted nuclei with thin nuclear membranes, longitudinal nuclear grooves, and eosinophilic cytoplasm in a background of eosinophils.

Follicular dendritic cell sarcoma cells are derived from mesenchymal stem cells and express CD21, CD23, and CD35 but lack expression of histiocytic and Langerhans cell markers. In addition, they frequently show a spindled cell appearance with interwoven cytoplasmic processes and plump nuclei with prominent nucleoli. Follicular dendritic cell sarcoma has not been shown to be related or consistently associated with other lymphoid neoplasms.

Interdigitating dendritic cell sarcoma is a neoplasm of spindled to ovoid cells with a characteristic phenotype with expression of S100 but lack of CD1a and Langerin. ZBTB46 is a marker that distinguishes dendritic cells from other immune cell lineages, including monocytes, and macrophages. This is especially useful in histiocytic/dendritic neoplasms arising in the context of other hematolymphoid malignancies, which often show ambiguous macrophage/dendritic cell marker expression, and in which ZBTB46 unambiguously establishes dendritic cell lineage.


  1. Medeiros, L.J., Ioachim’s Lymph Node Pathology (Wolters Kluwer Health, 2021) 
  2. Swerdlow et al., WHO classification of tumours of the haematopoietic and lymphoid tissues, IARC, 2017. 
  3. Satpathy AT, Brown RA, Gomulia E, Briseño CG, Mumbach MR, Pan Z, Murphy KM, Natkunam Y, Chang HY, Kim J. Expression of the transcription factor ZBTB46 distinguishes human histiocytic disorders of classical dendritic cell origin. Mod Pathol. 2018 Sep;31(9):1479-1486. doi:10.1038/s41379-018-0052-4. Epub 2018 May 9. PMID: 29743654; PMCID: PMC6138663.

Frido Bruehl, M.D.

Fellow, Hematopathology
Mayo Clinic

Adam Wood, D.O., M.S.

Consultant, Hematopathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

MCL Education

This post was developed by our Education and Technical Publications Team.