Janus kinase-signal transducers and activators of transcription (JAK-STAT) activation in anti-programmed death-1 (PD-1) therapy – associated granuloma annulare: a case series

Interferon gamma (IFN- γ) expressing T-helper lymphocytes have been hypothesized to play a central role in idiopathic granuloma annulare (GA) pathogenesis, leading to constitutive Janus kinase-Signal transducer and activator of transcription (JAK-STAT) pathway activation¹. Here, we report 3 cases of immunotherapy-associated GA that exhibit JAK-STAT activation on immunohistochemistry, suggesting a potential shared mechanism with sporadic GA.

The first case is a 67-year-old female who started nivolumab for stage IV epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma after her disease progressed on erlotinib and cetuximab. She showed complete tumor response to nivolumab, but developed multiple 3–10 cm annular pink plaques on her bilateral lower legs and ankles (Fig.1A). Biopsy results showed histopathologic findings consistent with GA, including a dermal infiltrate with perivascular lymphocytes and interstitial histiocytes (Fig.2A). The lesions responded well to topical clobetasol 0.05% cream.

Figure 1.

(A) Annular pink plaques on the bilateral lower legs and ankles of patient 1.

(B) Numerous generalized pink-brown papules distributed on the arms of patient 2.

(C) Annular pink-brown plaques on the dorsal hand of patient 3.

Figure 2.

(A) Hematoxylin and eosin staining showing focal palisading of histiocytes around areas of altered collagen from case 1, x20. (B) Representative pSTAT1 and (C) pSTAT3 immunohistochemistry staining, x60. Similar findings were seen in all 3 cases.

The second case is a 55-year-old male who started pembrolizumab concurrently with cisplatin and radiation for stage IV squamous cell carcinoma of the soft palate. His oral cancer showed complete response to pembrolizumab with cisplatin and radiation. After 6 months of pembrolizumab therapy, he developed dozens of pink annular papules and plaques on his chest, back, shoulders and arms (Fig.1B). Biopsy results were consistent with GA, showing perivascular lymphocytic infiltrate with well-developed palisades of histiocytes around areas of altered collagen. He was initially treated with augmented betamethasone dipropionate 0.05% cream and minocycline 100 mg twice daily (BID) for 4 weeks without significant improvement. Subsequently, treatment with hydroxychloroquine 200 mg BID resulted in partial improvement after 4 months.

The third case is a 64-year-old female who started pembrolizumab concurrently with carboplatin and pemetrexed for Stage IV lung cancer. Her interval chest scans showed remarkable response to her anti-cancer regimen, with complete resolution of a hilar mass, resolution of some nodular densities, and significant regression of a pleural lesion. She had developed annular pink papules and plaques on the left hand, chest, and forehead for approximately 1 year prior to the diagnosis of lung adenocarcinoma (Fig.1C). Significantly more lesions appeared once she was on pembrolizumab therapy, with lesions becoming increasingly itchy. Biopsy results showed palisading histiocytes and multinucleated giant cells in the dermis, with perivascular lymphocytes and plasma cells, suggestive of GA. Initial treatment of the skin lesions with topical augmented betamethasone dipropionate 0.05% cream BID and doxycycline 100mg BID showed inadequate improvement. Then, treatment with 200 mg hydroxychloroquine BID resulted in complete resolution after 3 months.

In all cases, activated STAT1 and STAT3 staining was observed in both histiocytes and lymphocytes using immunohistochemistry for phosphorylated STAT1 and STAT3 (Fig.2B, 2C).

Recently, GA has been reported as an immune-related dermatologic manifestation of PD-1-inhibitor therapy^2,3. In our study of patients who developed GA in the context of PD-1-inhibitor therapy, the development/progression of GA in all three patients was associated with a favorable response to immunotherapy, with complete tumor response in patients 1 and 2. While patient 3 developed GA prior to treatment with pembrolizumab, it is interesting to note that she had significant worsening of GA during treatment with pembrolizumab. These findings agree with prior literature suggesting a positive prognosis for patients who exhibit granulomatous reactions while on immune checkpoint inhibitors⁴. We also found activated STAT1 and STAT3 expression in all three patients, which suggests that production of JAK-STAT dependent cytokines may be important in the pathogenesis of PD-1 inhibitor-associated GA, as has been previously suggested for sporadic GA⁵.