Pembrolizumab-associated hemophagocytic lymphohistiocytosis in recurrent metastatic squamous cell carcinoma of the ovary arising in a teratoma

Highlights

• •We report a rare case of pembrolizumab-associated HLH in ovarian SCC arising from a mature teratoma.
• •This case illustrates diagnostic challenges of HLH during immune checkpoint inhibition.
• •We demonstrate successful HLH management with corticosteroids and multidisciplinary collaboration.

Abstract

Background

The expanding use of immune checkpoint inhibitors (ICIs) in gynecologic oncology has been accompanied by an increasing incidence of immune related adverse events (irAEs), requiring rapid recognition and management to prevent significant morbidity and mortality (Conroy and Naidoo, 2022, Liu et al., 2023, Kanji et al., 2022). Hematologic immune related adverse events remain particularly challenging due to their rarity, nonspecific presentation, and diagnostic complexity (Kroll et al., 2022). Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome that is life-threatening if not promptly identified and treated (Henter, 2025).

Case report

We report a case of pembrolizumab associated HLH in a patient with recurrent metastatic squamous cell carcinoma of the ovary arising in a teratoma. The patient presented with persistent fevers, cytopenias, and laboratory abnormalities concerning for immune mediated toxicity following pembrolizumab therapy. Diagnostic evaluation highlighted the challenges of distinguishing HLH from other causes of systemic inflammation and infection in the oncology setting. Both HLH 2024 criteria and the HScore were utilized to support the diagnosis (Naymagon et al., 2025). The patient was successfully treated with steroid monotherapy with clinical and laboratory improvement.

Conclusion

HLH remains a rare but potentially fatal immune related adverse event associated with immune checkpoint inhibitors. We review previously reported cases of HLH in gynecologic malignancies, including two cases in cervical cancer, two in ovarian cancer, and one in endometrial cancer (Wei et al., 2024, Rollet et al., 2024, Nosratian-Baskovic et al., 2016, Li et al., 2022). Increased awareness, early diagnostic consideration, and prompt treatment are essential to improve outcomes in patients receiving immune checkpoint inhibitors.

1. Introduction

The introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the therapeutic landscape of gynecologic oncology, providing new treatment options for several gynecologic malignancies. However, by enhancing immune system activity, ICIs can lead to a spectrum of immune-related adverse events (irAEs) that may affect multiple organ systems and, in some cases, be life-threatening. While a growing body of literature has characterized common irAEs (Conroy and Naidoo, 2022, Liu et al., 2023, Kanji et al., 2022), Hemophagocytic Lymphohistiocytosis (HLH) is an exceedingly rare complication that is not well described in gynecologic oncology literature. HLH is a severe hyperinflammatory syndrome in which impaired down-regulation of the immune response leads to persistent activation of CD8 + T cells and macrophages. This uncontrolled immune activation drives excessive cytokine release, resulting in widespread tissue damage, multiorgan failure, and high risk of mortality (Henter, 2025). Broadly, HLH can be either inherited or acquired, with triggers including infection, malignancy, autoimmune disease, medications, or idiopathic causes. This report describes a case of HLH as a life-threatening irAE following pembrolizumab treatment for recurrent metastatic squamous cell carcinoma of the ovary arising from a mature teratoma.

2. Case report

A 34-year-old woman with past medical history significant only for active tobacco use presented to the emergency department with right lower quadrant pain. Imaging revealed a cyst resembling a dermoid, and she underwent a right oophorectomy with intraoperative cyst rupture. Pathology showed moderately to poorly-differentiated invasive squamous cell carcinoma arising from a mature cystic teratoma. PD-L1 immunostaining was performed showing membranous staining in approximately 70% of the tumor cells. She underwent staging surgery and was classified as stage IC1. She began adjuvant chemotherapy with carboplatin, paclitaxel, and bevacizumab, but local recurrence was detected one month after completing treatment. She was then transitioned to palliative therapy with cyclophosphamide, bevacizumab, and pembrolizumab.

Ten days after her fifth cycle, the patient presented to the emergency department with high fevers to 39.8 °C and headache. The patient was hemodynamically and clinically stable without signs of sepsis apart from fevers. The initial laboratory evaluation revealed anemia (Hemoglobin 10.4 g/dL), thrombocytopenia (Platelet 40 × 10³/µL), transaminitis (Aspartate Aminotransferase 75 U/L, Alanine Aminotransferase 45 U/L), and hyperbilirubinemia (total bilirubin 1.4 mg/dL). Imaging was notable for multiple splenic lesions on computed tomography but without overt splenomegaly. An extensive infectious disease evaluation was performed with Infectious Disease consultation, and the patient was empirically treated with broad-spectrum antibiotics. Epstein–Barr virus PCR was positive at low levels and was not felt to be clinically significant. Given persistent fevers, worsening pancytopenia and unrevealing infectious work-up, hematology was consulted. With the available information at the initial time of evaluation, HScore was 225, driven by high-grade fever (Tmax 39.8 °C), three-lineage cytopenia (hemoglobin 8.2 g/dL, platelets 18 × 10³/µL, WBC 3.3 × 10³/µL), markedly elevated ferritin (>15,000 ng/mL), hypertriglyceridemia (1.72 mmol/L), hypofibrinogenemia (2.47 g/L) and underlying immunosuppression, corresponding to a 96% probability of HLH (Table 1). Additionally, 3 of 7 HLH-2024 (revised HLH-2004) criteria were met (fever, cytopenia affecting ≥ 2 lineages, and ferritin > 500 ng/mL) (Table 2). Bone marrow biopsy demonstrated occasional hemophagocytic histiocytes, which satisfies the HLH-2024 criterion requiring only the presence, not the abundance, of hemophagocytosis, and IL-2 receptor levels returned elevated (6,969p/mL). Had these results been available at the time of diagnosis, the patient would have met 5 of 7 HLH-2024 criteria and had an updated HScore of 244 (99% probability of HLH) (Table 1 and Table 2).

Table 1.

Hscore Criteria used to calculate the probability of HLH.

Hscore					HScore	Probability of HLH, %
Feature	Cut-Off Value	Score	Case Report		90	<1
					100	1
Fever	<38.4 38.4–39.4 >39.4	0 +33 +49	+49 Tmax = 39.8		110	3
					120	5
					130	9
					140	16
Organomegaly	Absent Hepatomegaly alone Splenomegaly alone Hepatosplenomegaly	0 +23 +23 +38	0*		150	25
					160	40
					170	54
					180	70
Cytopenia	1 lineage 2 lineages 3 lineages	0 +24 +34	+34 3 lineages		190	80
					200	88
					210	93
					220	96
Hgb ≤ 92 g/L Plt ≤ 110,000/mm3 WBC < 5,000/mm3			Hgb = 82 g/L Plt = 18,000/mm3 WBC = 3,300/mm3		230	98
					240	99
					250	>99
Ferritin	<2,000 ng/mL 2,000–6,000 ng/mL >6,000 ng/mL	0 +35 +50	+50 >15,000 ng/mL
Triglyceride	<1.5 mmoles/L 1.5–4 mmoles/L >4 mmoles/L	0 +44 +64	+44 1.72 mmol/L
Fibrinogen	>2.5 gm/L ≤2.5 gm/L	0 +30	+30 2.47 gm/L
Hemophagocytosis on bone marrow aspirate	Absent Present	0 +19	+19 Present
Known underlying Immunosuppression	Absent Present	0 +18	+18 Present**

HScore criteria, assigned point values, and calculated probability of HLH for the present case. The table summarizes each HScore variable, corresponding diagnostic cutoffs, and point contributions, alongside the patient’s measured values and cumulative score. The patient’s total HScore of 244 corresponds to an estimated 99% probability of HLH based on validated HScore probability estimates. Table adapted from Fardet et al¹⁴.

*Splenomegaly was radiographically present but attributed to multifocal infarcts versus metastatic involvement and therefore was not considered diagnostic splenomegaly in the context of HLH criteria.

**Patient was receiving systemic chemotherapy at the time of presentation

Table 2.

HLH-2024 diagnostic criteria (Revised HLH-2004) and patient findings.

HLH-2024 diagnostic criteria (Revised HLH-2004 diagnostic criteria)
Feature	Cut-Off Value	Case Report
Fever	≥38.5 °C	39.8 °C
Splenomegaly	≥2 cm below costal margin	“Splenomegaly with new solid-appearing splenic lesions, concerning for metastatic disease in this context.”*
Cytopenia	≥2 cell lines
Hemoglobin Platelets Neutrophils	<90 g/L <100 x 109/L <109/L	Hgb = 82 g/L Plt = 18 × 109/L Neutrophils = 2 × 109/L
Hypofibrinogenemia or hypertriglyceridemia	Fibrinogen ≤ 1.5 g/L or Triglyceride level ≥ 3.0 mmol/L	Fibrinogen = 2.47 g/L Triglyceride = 1.72 mmol/L
Hyperferritinemia	≥500 mg/L	>15,000 mg/L
Hemophagocytosis	Presence on Bone Marrow biopsy	“Occasional histiocytes with hemophagocytosis are seen”
Elevated Soluble CD25 (Interleukin-2 receptor)	≥2400 U/mL	6,969 pg/mL**

The table summarizes the HLH 2024 diagnostic criteria (revised HLH-2004) and the values or findings of each criterion present in the patient described in this case. Diagnosis requires fulfillment of at least five of seven criteria; the patient met five of seven criteria. Table adapted from Henter (2025).

*Splenomegaly was radiographically present but attributed to multifocal infarcts versus metastatic involvement and therefore was not considered diagnostic splenomegaly in the context of HLH criteria.

**Reported in pg/mL per institutional assay (ARUP Laboratories). Units differ from HLH-2024 criteria; elevation interpreted using laboratory reference standards.

In consultation with the infectious disease team, steroid treatment for HLH was delayed until extensive workup for rare but potentially dangerous bacterial, fungal, and parasitic infectious etiologies was completed. On the eighth hospital day, after infectious studies returned negative, antibiotics were discontinued, and steroid treatment was initiated with intravenous dexamethasone 10 mg/m² daily. The patient’s fevers resolved immediately following steroid administration. Laboratory abnormalities improved, notably ferritin decreased to 5,380 ng/mL on the day of discharge, with subsequent continued improvement and normalization to 99.6 ng/mL approximately 4 weeks after discharge. The patient was discharged after ten days hospitalized. The steroid taper was over the course of 8 weeks without dose reduction. The patient has not been rechallenged with pembrolizumab and has had no recurrence of HLH. At her 8-month follow-up (time of manuscript submission), her disease remained stable on cyclophosphamide and bevacizumab.

3. Discussion

3.1. Hematologic immune-related adverse events (irAEs)

Immune checkpoint inhibitors have increasingly become a part of the treatment for gynecological malignancies in both the frontline and recurrent settings. While generally well tolerated, they can cause a spectrum of irEAs affecting almost any organ system (Conroy and Naidoo, 2022, Kanji et al., 2022). Hematologic irAEs are rare, accounting for < 1% of reported toxicities, and include autoimmune hemolytic anemia, immune thrombocytopenia, aplastic anemia, and, in extremely rare cases, HLH (Liu et al., 2023, Kroll et al., 2022). HLH is a life-threatening hyperinflammatory syndrome characterized by uncontrolled immune activation and cytokine storm, which can result in multiorgan failure if not promptly recognized and treated (Henter, 2025). In the context of ICIs, HLH onset can vary in its presentation ranging from days to many months after initiation; in the present case, symptoms developed after five cycles of pembrolizumab. Potential predisposing factors include underlying autoimmune disease and concurrent triggers such as Epstein–Barr Virus infection, although these were not evident here (Zhai et al., 2024). Notably, malignancy itself, most often lymphoma or leukemia can precipitate HLH, and rare reports link solid tumors, including ovarian germ cell tumors, to paraneoplastic HLH (Zhai et al., 2024, Wang et al., 2023, Walmsley et al., 2025). Therefore, while temporal association strongly supports pembrolizumab as the primary trigger in this case, the contribution of the underlying malignancy cannot be excluded.

3.2. HLH mimics, diagnostic tools and challenges

The clinical triad of persistent fever, cytopenia, and hepatosplenomegaly has a wide differential diagnosis, and HLH is only one exceedingly rare possibility. Chemotherapy toxicities, other drug-related adverse events, infection, or tumor flare can all present with overlapping signs and laboratory abnormalities, such as hyperferritinemia, liver enzyme elevation, coagulopathy, and elevated inflammatory markers. ICI induced hyperinflammation is an increasingly recognized phenomenon, but presentation can be difficult to distinguish from HLH triggered by malignancy progression or infection.

To assist in diagnosis, clinicians often rely on structured tools such as the HScore and the HLH-2024 (revised HLH-2004) diagnostic criteria as detailed in Table 1 and Table 2 (Henter, 2025, Fardet et al., 2014). The HScore uses a weighted combination of clinical, laboratory, and histologic findings to estimate the probability of HLH, while the HLH-2004 criteria provide a binary framework for diagnosis. In 2024, the Histiocyte Society revised the HLH-2004 criteria, most notably removing Natural Killer cell activity from the diagnostic requirements due to its limited availability, inconsistent turnaround times, and variable sensitivity. Under the updated framework, a diagnosis requires at least 5 of 7 criteria to be met as detailed in Table 2 (Henter, 2025).

One of the most significant challenges in this case was the need to rule out atypical infections that could be exacerbated by immunosuppressive therapy, particularly corticosteroids, which are a mainstay of HLH treatment. Infectious disease consultants were especially concerned about rare opportunistic pathogens which often require specialized testing and prolonged turnaround times, creating a diagnostic bottleneck and delayed time to treatment. This delay poses a critical dilemma as waiting for results risks progression of HLH and potential organ failure, while initiating immunosuppression prematurely could precipitate severe infection-related complications. The challenge is compounded by the fact that infection itself is a common trigger for HLH, meaning that both processes may coexist and amplify each other (Henter, 2025).

In practice, early initiation of HLH-directed therapy often hinges on clinical judgment, integrating the likelihood of HLH against competing diagnoses and the risks of delayed treatment. This case underscores the importance of multidisciplinary collaboration between oncology, infectious disease, and hematology teams to balance the urgency of HLH treatment with the prudence required in the face of possible infection.

3.3. HLH treatment and rechallenge considerations

The life-threatening nature of HLH often necessitates prompt treatment before all diagnostic criteria are confirmed. In adults with high clinical suspicion, initiating corticosteroids is supported even if confirmatory tests (e.g., bone marrow biopsy, IL-2) are pending, as early recognition and treatment can be lifesaving (Liu et al., 2023, Wang et al., 2023). Treatment of HLH has previously involved regimens that include corticosteroids in conjunction with other immunomodulators such as tocilizumab (IL-6 inhibition), etoposide or cyclosporine (Naymagon et al., 2025, Wang et al., 2023, Wu et al., 2024). A recent review of 51 ICI‑HLH cases found that steroids alone are effective in many cases (Walmsley et al., 2025). In this review, patients treated with steroids alone had a mortality rate which was comparable to those who received steroids plus etoposide and tocilizumab (Walmsley et al., 2025). Per the established HLH‑94 protocol, etoposide should be reserved for refractory or severe cases, noting the lack of prospective data and potential harm (Naymagon et al., 2025, Wu et al., 2024).

ICI rechallenge after ICI-associated HLH should be individualized and is generally reserved for patients with compelling oncologic need after full clinical resolution of HLH off corticosteroids. Data remains sparse, but limited reports suggest it can be done safely in select cases. One review noted three rechallenges without ICI recurrence of HLH, while another noted four ICI rechallenges with one case of HLH recurrence (Zhai et al., 2024, Walmsley et al., 2025). While there are no specific guidelines for ICI rechallenge for HLH, practical considerations include completion of steroid taper, close early monitoring (fever curve, complete blood counts, ferritin), and rapid access to rescue immunosuppression (Henter, 2025, Rollet et al., 2024). Overall, rechallenge should be considered inadvisable unless treatment alternatives are limited, especially in cases where HLH did not respond to corticosteroid therapy alone (Walmsley et al., 2025).

Interestingly, there is some evidence to suggest an association between HLH onset and favorable tumor responses. In one case series, among patients who recovered from ICI‑HLH, 80% exhibited sustained tumor control even after discontinuation of immunotherapy (Zhai et al., 2024). While intriguing, these observations remain anecdotal and are too limited to draw robust conclusions.

3.4. HLH in Gynecology oncology

To date, reports of HLH in gynecologic oncology remain exceedingly rare, with only a limited number of published cases linking this syndrome to gynecologic malignancies or immunotherapy use. Two published case reports describe patients with cervical cancer who developed HLH in the setting of PD-1 inhibitor–based therapy (Wei et al., 2024, Zhai et al., 2024). The first describes a patient treated with pembrolizumab in combination with bevacizumab who developed HLH within seven days of the initial cycle. Workup confirmed the diagnosis and pembrolizumab was considered the primary trigger with bevacizumab as a possible contributor (Zhai et al., 2024). The second report details a patient receiving toripalimab (PD-1 Inhibitor) with concurrent chemoradiotherapy who developed HLH during treatment (Wei et al., 2024). In both cases, patients fulfilled HLH-2004 diagnostic criteria and improved with corticosteroid therapy alone, without the need for escalation to second-line HLH treatment. Tumor outcomes were favorable with durable disease control in both. Notably, there was no report of either patient undergoing immunotherapy rechallenge following HLH resolution.

There is one case report of HLH associated with endometrial cancer treated with a single dose of dostarlimab (PD-1 inhibitor) (Rollet et al., 2024). The patient exhibited clinical and laboratory features fulfilling secondary HLH criteria. She was treated with corticosteroids and ruxolitinib (JAK inhibitor), resulting in clinical improvement. Notably, oncologic treatment was resumed with chemotherapy alone following HLH resolution. Despite discontinuation of dostarlimab, the patient exhibited partial tumor response in the primary site and a complete response in the metastatic sites (Rollet et al., 2024).

There are also two published case reports describing HLH in patients with ovarian cancer, neither of whom had received immunotherapy prior to HLH onset (Nosratian-Baskovic et al., 2016, Li et al., 2022). The first involved a patient with ovarian dysgerminoma who presented with fever, cytopenia, and splenomegaly; HLH was attributed to a paraneoplastic mechanism, and symptoms resolved following tumor resection (Nosratian-Baskovic et al., 2016). The second described a patient with bilateral ovarian adenocarcinoma who developed HLH. The condition was presumed to be malignancy-associated, and despite glucocorticoid therapy, the patient did not improve and died within two months (Li et al., 2022). There are no other published case reports describing immune therapy related HLH in the context of ovarian malignancy to date.

HLH can present with nonspecific signs such as fever, cytopenia, and liver dysfunction. These are easily attributed to infection, chemotherapy effects, or tumor progression, leading to delayed recognition and treatment. Given the high morbidity and mortality associated with delayed intervention, gynecologic oncologists must maintain a high index of suspicion. This case adds to the growing literature on immune-related HLH and underscores the need for heightened vigilance, prompt multidisciplinary evaluation, and thoughtful consideration of future treatment options.

Consent statement

Written informed consent was obtained from the patient for publication of this case report.

Disclosure of artificial intelligence

Artificial intelligence tools were used to assist with language editing and clarity of this report. The authors reviewed, edited, and approved all content and take full responsibility for the accuracy, integrity, and originality of the work. No artificial intelligence tools were used for content creation, figure generation, or interpretation of test results.

CRediT authorship contribution statement

Jenna S. Powers: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Olivia W. Foley: Writing – review & editing, Supervision, Conceptualization. Connor C. Wang: Writing – review & editing. Jenna Marcus: Writing – review & editing. Emily Hinchcliff: Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.