Unique cytologic features of thyroiditis caused by immune checkpoint inhibitor therapy for malignant melanoma

Abstract

Blockade of immune checkpoint molecules to reverse cancer-induced immune suppression can improve anti-tumor immune responses in cancer patients. Monoclonal antibodies targeting two such molecules, Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) have shown clinical benefit in the treatment of advanced malignancies, including metastatic melanoma. Adverse effects of these immune checkpoint inhibitors include immune-related adverse events (irAE), of which one of the most common is autoimmune thyroiditis. Though thyroiditis is increasingly recognized, there are no reports of the pathological findings that occur in immunotherapy-induced thyroiditis. We present a case of immunotherapy-induced thyroiditis demonstrating its unique cytopathologic features. A 51-year-old woman with metastatic melanoma was found to have a suppressed TSH and elevated free thyroxine concentration 14 days after starting treatment with nivolumab (PD-1 antagonist) plus ipilimumab (CTLA-4 antagonist) therapy. A thyroid biopsy was performed based on ultrasound findings and cytopathology revealed unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes. This case reports cytopathologic features found in immune checkpoint inhibitor related thyroiditis. These appear to be unique findings and may help inform future research regarding the pathophysiology and mechanisms of this condition.

Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review

“…Immunohistochemistry showed that PD-L1 overexpression was present especially in areas of follicular destruction. Angell et al reported a case of ICI-induced thyroiditis with unique cytopathologic features, including abundant clusters of necrotic cells, lymphocytes, and CD163-positive histiocytes ( 66 ).…”

<p>Thyroid Dysfunctions Due to Immune Checkpoint Inhibitors: A Review</p>

“…Unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes were described. 21 …”

“… 12 Adrenal insufficiency should be ruled out before the start of hormonal replacement to avoid adrenal crisis that could be lifethreatening 12 Hormonal replacement with levothyroxine at a dose of 1–1.6mcg/kg/day (depending on the age and comorbidities) is the mainstay of the treatment. 21 When the TSH below 10 mU/L, the decision on hormonal replacement should be evaluated on an individual basis (depending on the presence of symptoms or antibodies). 12 Some experts recommend measuring anti-TPO in the setting of a high TSH between 5 and 10 mU/L to guide the decision for treatment.…”

Schilddrüsenfunktionsstörungen unter Immuncheckpoint-Inhibitor-Therapie

“…Die zytologische Analyse einer Schilddrüsenbiopsie einer Patientin mit Ipilimumab-Nivolumab-Kombinationstherapie-assoziierter Thyreoiditis ergab einzigartige Eigenheiten, inkl. Cluster an nekrotischen Zellen, Lymphozyten und CD163-positiven Histiozyten [7]. Der Mechanismus der Schilddrüsendestruktion scheint aber unabhängig von Schilddrüsenantikörpern [3,8] trathyreoidalen Lymphozyten bedingt sein könnte [8,9].…”

“…Sonographisch kann sich die Schilddrüse initial transient hyperechogen und hypertrophiert präsentieren mit gelegentlich verstärkter Vaskularisation, um da-nacheine hypoechogene Erscheinung anzunehmen [7,11]. Eine Schilddrüsen-Szintigraphie sollte nur in unklaren Fällen erfolgen, wobei sich bei der destruktiven Thyreoiditis ein reduzierter Uptake zeigen würde.…”