PDL1 Expression and Outcomes in Histiocytic Neoplasms

Abstract

Introduction

Histiocytic sarcoma (HS) and interdigitating dendritic cell sarcoma (IDCS) are both extremely rare and aggressive histiocytic neoplasms that are most often treated with lymphoma-based chemotherapy; however, there is growing use of immune checkpoint inhibitors (ICI) in the second- or further-line settings as prognosis is typically poor in these neoplasms.

Case Presentations

We describe two cases: first, HS in a 60-year-old man with primary tumor in the right anterior lower limb, and second, IDCS in an 82-year-old man in the right para-parotid region after initial wide local excision of a right postauricular mass suggestive of a pleomorphic undifferentiated sarcoma. Systemic imaging showed retroperitoneal, inguinal, and pelvic adenopathy in the first case and no distant metastases in the second case. Both were diagnosed via biopsy with extensive immunohistochemistry and were also found to be strongly positive on PDL1 testing. Treatment was initiated with ICIs in both patients, which was paired with palliative radiotherapy for the HS patient. Both cases exhibited a durable response to treatment upon repeated systemic imaging.

Conclusion

To our knowledge, these are the first-reported cases of the use of ICIs in the first-line setting in these histiocytic neoplasms and highlight their efficacy. The significant elevation in PDL1 expression seen in both cases may serve as a potential biomarker of excellent response in these neoplasms.

Introduction

Histiocytic sarcoma (HS) is a rare and aggressive malignant neoplasm of the histiocytic lineage, with peak incidence from ages 50 through 69 [1, 2]. HS is diagnosed by histological features of mature tissue histiocytes and a characteristic immunophenotypic signature (presence of CD68, lysozyme, CD163, PU.1 vs. absence of B cells, T cells, dendritic cells, epithelioid cells, and myeloid markers) that differentiates it from other similar neoplasms [1–3].

Interdigitating dendritic cell sarcoma (IDCS) is another histiocytic neoplasm that shares similar characteristics. Diagnosis is heavily reliant on immunohistochemistry, with the main expressed markers being S100 and vimentin, although histiocytic markers such as CD68, CD163, and HLA-DR may also be positive [4].

Due to the rarity of these conditions and the paucity of clinical trials, including HS and IDCS, there are no established standards of care. Lymphoma-based chemotherapy protocols including cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) or ifosfamide, carboplatin, and etoposide phosphate (ICE) with or without radiotherapy are most often recommended. Surgical resection is recommended for local diseases. Both typically present at an advanced stage and have limited response to chemotherapy. HS typically has an overall survival (OS) of 6 months [1, 2], and IDCS has a reported median OS of 12 months and median progression-free survival of 6 months [5]. In the past decade, there have been several reports of immune checkpoint inhibitors (ICI) used as second- or further-line therapies for HS with varying levels of PD-L1 expression, usually after progression of disease on chemotherapy. To our knowledge, this report describes the first documented cases of ICI combined with radiotherapy first-line therapy in treating both HS and IDCS.

Case 1

A 60-year-old man initially identified a red lesion on his right anterior lower limb in February 2023, which was initially thought to be an infectious entity and was treated with antibiotics. The lesion progressed and developed central necrosis. Simultaneously, the patient developed right inguinal adenopathy and was referred to oncology locally for evaluation. Biopsies of both the tibial and inguinal lesions and extensive testing revealed a neoplasm characterized by atypical histiocytoid cells and immunostains positive for PU.1, CD68, CD163, CD45, with patchy CD4 staining and very wispy equivocal staining for EMA. Immunostains were negative for keratin AE1/AE3, CD1a, S100, CD34, CD20, CD15, CD21, muramidase, BRAF, CD123, and ALK. The combination of positive PU.1, CD68, and variable CD163 and negative CD1a, S100, CD34, CD20, and CD15 was used to confirm diagnosis of HS. A pathologic ARAF mutation (S214F) was also found to be the only and most likely pathogenic point mutation. Further immunohistochemistry for PD-L1 determined a high positive expression of 95% (shown in Fig. 1).

Fig. 1.

PD-L1 immunohistochemistry in histiocytic/dendritic cell sarcoma. Tumor in a presented in deep somatic soft tissue and is composed of cells with brightly eosinophilic cytoplasm, demonstrates significant pleomorphism, and is disposed in a vaguely storiform pattern. Morphology and S-100-positivity/SOX10-negativity raised the possibility of a histiocytic/dendritic cell neoplasm. That impression was further supported by expression of CD68, lysozyme, PU.1, and CD4 (not shown). Tumor in c presented in the skin and demonstrates a dense dermal infiltrate of epithelioid cells with granular, pale cytoplasm, frequently reniform nuclei, and moderate nuclear atypia. Demonstration of an ARAF mutation supported the diagnosis of HS. b, d In both cases, PD-L1 immunohistochemistry shows diffuse, strong tumor cell staining – so strong that it obscures visualization in any tumor-associated immune cells. All images ×100 magnification.

The patient was referred to our institution for further HS treatment in June 2023. A computed tomography (CT) of the chest, abdomen, and pelvis (CAP) revealed progressive hypermetabolic retroperitoneal, inguinal, and pelvic adenopathy (shown in Fig. 2). A pre-treatment positron emission tomography (PET) scan showed a Deauville score of 5 with an SUV maximum of 33.1. Due to elevated PD-L1 expression, pembrolizumab was recommended. Given the patient’s significant pain and drainage/bleeding from the lesion, palliative radiation to the inguinal and right tibial masses was initiated. The patient presented after three cycles of pembrolizumab with right tibial, right hip, and lower back pain. CT CAP demonstrated a significant reduction of both radiated disease of right inguinal lymph nodes, and nonirradiated disease of left inguinal lymph nodes, right pelvic lymph nodes, and retroperitoneal adenopathy. The patient was subsequently found to have a septic joint infection and was treated appropriately with orthopedic management and antibiotic administration. Pembrolizumab was continued. After five cycles, the patient underwent resection of primary leg ulceration due to pain which revealed no evidence of malignancy. The patient has had over 14 months of treatment with no evidence of disease (shown in Fig. 2). PET/CT was not repeated as the patient demonstrated complete radiographic response on CT imaging. The patient tolerated pembrolizumab well with no adverse drug reactions.

Fig. 2.

a CT CAP from June 13, 2023, prior to initiation of pembrolizumab, showing largest right inguinal mass (white arrow). b Most recent CT CAP from August 12, 2024, showing durable response to treatment.

Case 2

An 82-year-old man with a history of basal and squamous cell cancer status post-excision developed swelling behind his right ear in December 2022. Fine needle aspiration was indeterminant. Wide local excision of the right postauricular mass was performed and pathology was suggestive of a high-grade undifferentiated pleomorphic sarcoma. The patient was scheduled to undergo adjuvant radiation to the postoperative bed, but he reported a new swelling at the angle of his right jaw. MRI and CT demonstrated a 2 cm heterogeneous cystic solid mass within the inferior aspect of the right parotid gland, most consistent with a metastatic intra-parotid or peri-parotid lymph node (shown in Fig. 3). A PET/CT CAP showed no other distant metastatic disease.

Fig. 3.

a CT of neck from March 9, 2023, prior to initiation of pembrolizumab, showing right para-parotid mass (white arrow). b Most recent CT neck from September 10, 2024, showing durable response to treatment.

The patient was referred to our institution for further treatment in April 2023. Immunohistochemistry showed weak positivity for SOX10 and S100, as well as multifocal positivity for PU.1, CD4, CD68, and muramidase. Melan-A, HMB-45, MITF, BRAF IHC, keratin AE1/AE3, desmin, CD21, CD23, and CD1a were negative. Overall, the findings best fit with IDCS, along with 100% positivity for PD-L1 and pembrolizumab was initiated (shown in Fig. 1). Radiotherapy was not indicated in this patient as there was no significant debility from the tumor. CT scan at 3 months showed a significant decrease in size of the para-parotid metastatic lymph nodes. CT scan at 9 months showed further significant decrease. Pembrolizumab was continued 200 mg every 3 weeks indefinitely. The patient has had over 17 months of treatment without disease recurrence (shown in Fig. 3). The patient tolerated pembrolizumab well with no adverse drug reactions.

Discussion

ICI seems to hold some promise in the treatment of HS and IDCS and it is possible that tumor PD-L1 expression may serve as a predictive biomarker for response. Tumor mutation burden and microsatellite instability are also potential indications and biomarkers for ICI therapy, but they were not being used at our institution when these patients were treated. In other cases where PDL1 expression is low or not present, testing for tumor mutation burden and microsatellite instability may be useful. A growing body of literature on the treatment of HS with ICI appears to be restricted to case reports currently. One clinical trial (NCT03316573) evaluating pembrolizumab in histiocyte/dendritic cell neoplasms was suspended due to low accrual (18 patients in 7 years).

One report described a patient with metastatic HS who had mixed response after four lines of combination CHOP, ICE, trametinib, and imatinib [6, 7]. Immunohistochemistry showed that PD-L1 was expressed in 15–20% of the initial diagnostic tissue sample. Disease progression after three cycles of nivolumab prompted discontinuation. Another report described a patient with a left mandibular mass who underwent several rounds of surgical resection and chemotherapy (cladribine and high-dose cytarabine), after which PET/CT showed metastasis to the left cervical lymph nodes, right lower abdomen, and multiple bones [8]. Tumor cell expressions of PD-L1 40% prompted initiation of pembrolizumab. Treatment resulted in disappearance of bony metastases and a decrease in primary tumor size, but also new metastases to the brain and left foot.

Several recent cases of metastatic HS with high PD-L1 expression (75–95%, including our case) showed significant improvement when treated with ICI, with progression-free survival of 9 months to over 3 years [9–11]. Case reports to date suggest that higher PD-L1 expression, especially >75%, may serve as a predictive biomarker for better prognosis in the treatment of metastatic HS with ICI. With the exception of our patient with HS, reports of better outcomes described one or more lines of cytotoxic chemotherapy that demonstrated limited response before discontinuation and initiation of ICI. While limited in number, cases reported to date seem to indicate that lower levels of PD-L1 appear less likely to respond to ICI treatment. It is also possible that a lymphodepleting chemotherapy regimen may eliminate antitumor lymphocytes, inhibiting the effectiveness of ICI. This raises the question: does cytotoxic chemotherapy, which is profoundly immunosuppressive and causes lymphopenia, result in inhibited antitumoral immune response in neoplasia?

In another report, a patient with metastatic HS that showed 70% PD-L1 expression initially, then 95% PD-L1 expression upon further testing, was treated with concurrent CHOP chemotherapy and pembrolizumab [12]. Due to insurance issues, her pembrolizumab was held for cycles 2–4, then restarted at cycle 5. While PET/CT showed near complete response to treatment after cycle 3, follow-up PET/CT after cycle 6 showed progression of disease to the abdomen and right femur. She was then transitioned to ICE chemotherapy and pembrolizumab for two cycles, after which PET/CT again showed concern for disease progression.

The literature on IDCS has shown worse prognosis for patients with diffuse disease that cannot be surgically resected [5]. Despite poor survival outcomes with adjuvant radiotherapy and chemotherapy, these treatments are still recommended [4, 13]. There are no recommendations on the use of ICI in the treatment of these tumors, but our patient with IDCS illustrates successful response to pembrolizumab.

In conclusion, the testing of PD-L1 expression in the treatment of metastatic HS and IDCS may be indicated as a potential predictive biomarker of ICI therapy success and prognosis. Patients with PDL1 expression >75% should warrant consideration for first-line ICI instead of chemotherapy; however, further research is needed, and this does not preclude the use of ICI in cases with lower levels of PD-L1 expression due to the limited nature of treatment options in these rare neoplasms. This report documents a good response to pembrolizumab with radiotherapy in the first-line setting for the treatment of HS, as well as pembrolizumab following surgical resection in treating IDCS.

The CARE Checklist has been completed by the authors for this report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546447).

Statement of Ethics

The IRB at the University of Iowa does not require formal IRB review in a case series of two as it does not meet the regulatory definition of human subject research, and as such institutional approval was not necessary for publishing the details of these cases. The authors of this report obtained written informed consent directly from the patients described in this report to have the details of their cases and accompanying images used in publication.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Matthew Moon, Mohammed Milhem, and John Rieth contributed to the acquisition, analysis, drafting, revision of intellectual content, and final approval of the version to be published.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.