Johnson ED

Background: Immunotherapy with checkpoint inhibition represents a significant development in the management of advanced malignancies. Toxicity associated with this therapy, or immune-related adverse events (irAEs), is most frequently seen in the form of colitis, dermatitis, pneumonitis, or hepatitis. Prompt initiation of high-dose corticosteroids in severe cases is essential. Refractory toxicity can be seen and requires a multimodality approach.

Case Report: A 68 year old male with a history of stage IVB squamous cell carcinoma (SCC) and an illdefined left renal mass (4.8 × 4.1 cm2, presumed urothelial carcinoma) was successfully maintained on nivolumab monotherapy for nearly two years. However, after 45 cycles he presented to the emergency department with acute hypoxic respiratory failure. He was admitted and found to have multifocal pulmonary consolidations refractory to empiric antibiotics. Ultimately his symptoms were attributed to nivolumab-induced pneumonitis. He improved on corticosteroids and was discharged with a prednisone taper. One month later he returned with severe lower extremity weakness, an elevated creatinine kinase, grade IV hepatitis, and hematuria. Notwithstanding immediate escalation to intravenous methylprednisolone (2 mg/kg) and a trial of IVIG, his myositis and liver dysfunction worsened. Mycophenolate mofetil was added (1000 mg BID) and successfully reversed his creatinine kinase (from 3633 U/L); however, his hepatitis continued to progress (total bilirubin to 16.4 mg/dL). After further discussion with gastroenterology, tacrolimus was also started (2 mg BID) and caused gradual improvement in his transaminases. Once stabilized, he underwent a left nephrectomy for persistent hematuria; pathology results revealed an unusual focus of metastatic SCC. Unfortunately, he developed post-operative bleeding complications and CMV viremia. He elected to pursue comfort measures and passed 2 weeks later.

Conclusion: Checkpoint inhibitor toxicities can demonstrate delayed presentations despite numerous cycles of successful therapy. In cases where aggressive corticosteroid therapy is unsuccessful, additional immunomodulatory agents are required to curb progression of organ-specific damage. Close surveillance for opportunistic infections must be maintained. Additional studies are needed to assess whether earlier discontinuation of checkpoint inhibition is feasible in patients with sustained responses to minimize late irAEs.

Background: Immunotherapy with checkpoint inhibition represents a significant development in the management of advanced malignancies. Toxicity associated with this therapy, or immune-related adverse events (irAEs), is most frequently seen in the form of colitis, dermatitis, pneumonitis, or hepatitis. Prompt initiation of high-dose corticosteroids in severe cases is essential. Refractory toxicity can be seen and requires a multimodality approach.

Case Report: A 68 year old male with a history of stage IVB squamous cell carcinoma (SCC) and an illdefined left renal mass (4.8 × 4.1 cm2, presumed urothelial carcinoma) was successfully maintained on nivolumab monotherapy for nearly two years. However, after 45 cycles he presented to the emergency department with acute hypoxic respiratory failure. He was admitted and found to have multifocal pulmonary consolidations refractory to empiric antibiotics. Ultimately his symptoms were attributed to nivolumab-induced pneumonitis. He improved on corticosteroids and was discharged with a prednisone taper. One month later he returned with severe lower extremity weakness, an elevated creatinine kinase, grade IV hepatitis, and hematuria. Notwithstanding immediate escalation to intravenous methylprednisolone (2 mg/kg) and a trial of IVIG, his myositis and liver dysfunction worsened. Mycophenolate mofetil was added (1000 mg BID) and successfully reversed his creatinine kinase (from 3633 U/L); however, his hepatitis continued to progress (total bilirubin to 16.4 mg/dL). After further discussion with gastroenterology, tacrolimus was also started (2 mg BID) and caused gradual improvement in his transaminases. Once stabilized, he underwent a left nephrectomy for persistent hematuria; pathology results revealed an unusual focus of metastatic SCC. Unfortunately, he developed post-operative bleeding complications and CMV viremia. He elected to pursue comfort measures and passed 2 weeks later.

Conclusion: Checkpoint inhibitor toxicities can demonstrate delayed presentations despite numerous cycles of successful therapy. In cases where aggressive corticosteroid therapy is unsuccessful, additional immunomodulatory agents are required to curb progression of organ-specific damage. Close surveillance for opportunistic infections must be maintained. Additional studies are needed to assess whether earlier discontinuation of checkpoint inhibition is feasible in patients with sustained responses to minimize late irAEs.

Background: Immunotherapy with checkpoint inhibition represents a significant development in the management of advanced malignancies. Toxicity associated with this therapy, or immune-related adverse events (irAEs), is most frequently seen in the form of colitis, dermatitis, pneumonitis, or hepatitis. Prompt initiation of high-dose corticosteroids in severe cases is essential. Refractory toxicity can be seen and requires a multimodality approach.

Case Report: A 68 year old male with a history of stage IVB squamous cell carcinoma (SCC) and an illdefined left renal mass (4.8 × 4.1 cm2, presumed urothelial carcinoma) was successfully maintained on nivolumab monotherapy for nearly two years. However, after 45 cycles he presented to the emergency department with acute hypoxic respiratory failure. He was admitted and found to have multifocal pulmonary consolidations refractory to empiric antibiotics. Ultimately his symptoms were attributed to nivolumab-induced pneumonitis. He improved on corticosteroids and was discharged with a prednisone taper. One month later he returned with severe lower extremity weakness, an elevated creatinine kinase, grade IV hepatitis, and hematuria. Notwithstanding immediate escalation to intravenous methylprednisolone (2 mg/kg) and a trial of IVIG, his myositis and liver dysfunction worsened. Mycophenolate mofetil was added (1000 mg BID) and successfully reversed his creatinine kinase (from 3633 U/L); however, his hepatitis continued to progress (total bilirubin to 16.4 mg/dL). After further discussion with gastroenterology, tacrolimus was also started (2 mg BID) and caused gradual improvement in his transaminases. Once stabilized, he underwent a left nephrectomy for persistent hematuria; pathology results revealed an unusual focus of metastatic SCC. Unfortunately, he developed post-operative bleeding complications and CMV viremia. He elected to pursue comfort measures and passed 2 weeks later.

Conclusion: Checkpoint inhibitor toxicities can demonstrate delayed presentations despite numerous cycles of successful therapy. In cases where aggressive corticosteroid therapy is unsuccessful, additional immunomodulatory agents are required to curb progression of organ-specific damage. Close surveillance for opportunistic infections must be maintained. Additional studies are needed to assess whether earlier discontinuation of checkpoint inhibition is feasible in patients with sustained responses to minimize late irAEs.

Background: Malignant melanoma is an aggressive malignancy that can present as a poorly differentiated neoplasm. Loss of S100 and melanA antigenicity can make pathologic identification difficult, especially in those patients who lack a cutaneous primary lesion. Immunostaining with SOX10, a key nuclear transcription factor in the differentiation of neural crest progenitor cells to melanocytes, has a high reported sensitivity and specificity for pathologic identification of melanoma in difficult cases.

Case Report: A 69-year-old male with a history of heavy tobacco use presented to the otolaryngology clinic with a left parotid mass. He underwent a parotid gland biopsy, which was significant for a high grade, poorly differentiated malignancy of unclear primary source. A staging PET/CT demonstrated localized hypermetabolic activity in the draining left cervical lymph node basins. He underwent a left modified radical neck dissection and parotidectomy. Pathologic assessment demonstrated a 3.9 × 1.6 × 1.6 cm3 poorly differentiated carcinoma with perineural invasion and 8/85 lymph nodes involved. Morphologically, it had features of a high grade epithelioid tumor with spindle cell features. Immunohistochemical (IHC) stains were negative for epithelial markers (AE1/3, EMA, CK5/6, CAM5.2), smooth muscle actin, CD34, S100, and melanA. Given the concern for a spindle cell melanoma that lost its antigenicity for S100 and melanA, a SOX10 IHC stain was performed.

The SOX10 immunostain demonstrated strong, diffuse positivity which secured the diagnosis of malignant melanoma. Molecular testing for BRAF and KIT mutations was negative. The nal diagnosis was a stage IVA (pT2pN2bM0) malignant melanoma of the parotid gland without a cutaneous primary lesion. The patient received a course of adjuvant radiation to a total dose of 66Gy and will complete one year of adjuvant immunotherapy with Nivolumab.

Conclusion: Malignant melanoma can present as a poorly differentiated malignancy and may be difficult to diagnose by providers, especially in the absence of a typical clinical history and a primary cutaneous lesion. In cases where the standard melanoma immunostains are negative, IHC staining with SOX10 can help secure the diagnosis with high sensitivity and specificity.

Background: Malignant melanoma is an aggressive malignancy that can present as a poorly differentiated neoplasm. Loss of S100 and melanA antigenicity can make pathologic identification difficult, especially in those patients who lack a cutaneous primary lesion. Immunostaining with SOX10, a key nuclear transcription factor in the differentiation of neural crest progenitor cells to melanocytes, has a high reported sensitivity and specificity for pathologic identification of melanoma in difficult cases.

Case Report: A 69-year-old male with a history of heavy tobacco use presented to the otolaryngology clinic with a left parotid mass. He underwent a parotid gland biopsy, which was significant for a high grade, poorly differentiated malignancy of unclear primary source. A staging PET/CT demonstrated localized hypermetabolic activity in the draining left cervical lymph node basins. He underwent a left modified radical neck dissection and parotidectomy. Pathologic assessment demonstrated a 3.9 × 1.6 × 1.6 cm3 poorly differentiated carcinoma with perineural invasion and 8/85 lymph nodes involved. Morphologically, it had features of a high grade epithelioid tumor with spindle cell features. Immunohistochemical (IHC) stains were negative for epithelial markers (AE1/3, EMA, CK5/6, CAM5.2), smooth muscle actin, CD34, S100, and melanA. Given the concern for a spindle cell melanoma that lost its antigenicity for S100 and melanA, a SOX10 IHC stain was performed.

The SOX10 immunostain demonstrated strong, diffuse positivity which secured the diagnosis of malignant melanoma. Molecular testing for BRAF and KIT mutations was negative. The nal diagnosis was a stage IVA (pT2pN2bM0) malignant melanoma of the parotid gland without a cutaneous primary lesion. The patient received a course of adjuvant radiation to a total dose of 66Gy and will complete one year of adjuvant immunotherapy with Nivolumab.

Conclusion: Malignant melanoma can present as a poorly differentiated malignancy and may be difficult to diagnose by providers, especially in the absence of a typical clinical history and a primary cutaneous lesion. In cases where the standard melanoma immunostains are negative, IHC staining with SOX10 can help secure the diagnosis with high sensitivity and specificity.

Background: Malignant melanoma is an aggressive malignancy that can present as a poorly differentiated neoplasm. Loss of S100 and melanA antigenicity can make pathologic identification difficult, especially in those patients who lack a cutaneous primary lesion. Immunostaining with SOX10, a key nuclear transcription factor in the differentiation of neural crest progenitor cells to melanocytes, has a high reported sensitivity and specificity for pathologic identification of melanoma in difficult cases.

Case Report: A 69-year-old male with a history of heavy tobacco use presented to the otolaryngology clinic with a left parotid mass. He underwent a parotid gland biopsy, which was significant for a high grade, poorly differentiated malignancy of unclear primary source. A staging PET/CT demonstrated localized hypermetabolic activity in the draining left cervical lymph node basins. He underwent a left modified radical neck dissection and parotidectomy. Pathologic assessment demonstrated a 3.9 × 1.6 × 1.6 cm3 poorly differentiated carcinoma with perineural invasion and 8/85 lymph nodes involved. Morphologically, it had features of a high grade epithelioid tumor with spindle cell features. Immunohistochemical (IHC) stains were negative for epithelial markers (AE1/3, EMA, CK5/6, CAM5.2), smooth muscle actin, CD34, S100, and melanA. Given the concern for a spindle cell melanoma that lost its antigenicity for S100 and melanA, a SOX10 IHC stain was performed.

The SOX10 immunostain demonstrated strong, diffuse positivity which secured the diagnosis of malignant melanoma. Molecular testing for BRAF and KIT mutations was negative. The nal diagnosis was a stage IVA (pT2pN2bM0) malignant melanoma of the parotid gland without a cutaneous primary lesion. The patient received a course of adjuvant radiation to a total dose of 66Gy and will complete one year of adjuvant immunotherapy with Nivolumab.

Conclusion: Malignant melanoma can present as a poorly differentiated malignancy and may be difficult to diagnose by providers, especially in the absence of a typical clinical history and a primary cutaneous lesion. In cases where the standard melanoma immunostains are negative, IHC staining with SOX10 can help secure the diagnosis with high sensitivity and specificity.

Purpose: Nivolumab is a fully human IgG4 programmed death 1 immune checkpoint inhibitor (ICI) antibody that has anti-tumor activity by selectively blocking the interaction of the programmed death 1 receptor with its two known programmed death ligands PD-L1 and PD-L2. In doing so, this immune checkpoint inhibitor removes the negative signal stifling T cell activation and proliferation within the tumor microenvironment and demonstrates favorable antitumor activity.

Case Report: We report an interesting case of immune checkpoint inhibitor-induced primary hypothyroidism with associated hypothyroid myopathy in a young patient with surgically resected stage IIIB melanoma receiving adjuvant nivolumab. He presented 12 weeks into therapy with severe myalgias, arthralgias, and intermittent disequilibrium of unclear etiology. Laboratory evaluation demonstrated a significant elevation in thyroid stimulating hormone and creatine kinase with an undetectable free T4 with standard laboratory measurement. With thyroid hormone replacement therapy alone, he had rapid improvement in his musculoskeletal symptoms and laboratory parameters over a threeweek period.

Discussion: This case emphasizes the serious nature of endocrine immune-related adverse events in patients receiving immune checkpoint inhibitors. Additionally, it highlights that unlike most other immunerelated adverse events, endocrine immune-related adverse events can generally be managed with adequate hormone replacement alone with swift improvements in symptoms. This allows patients to continue immune checkpoint inhibitors safely without immunosuppression which may dampen the anti-tumor activity of these agents.

Conclusion: This case highlights the importance of early recognition and the appropriate management of endocrine immune-related adverse events to maximize patient safety and good outcomes.

Purpose: Nivolumab is a fully human IgG4 programmed death 1 immune checkpoint inhibitor (ICI) antibody that has anti-tumor activity by selectively blocking the interaction of the programmed death 1 receptor with its two known programmed death ligands PD-L1 and PD-L2. In doing so, this immune checkpoint inhibitor removes the negative signal stifling T cell activation and proliferation within the tumor microenvironment and demonstrates favorable antitumor activity.

Case Report: We report an interesting case of immune checkpoint inhibitor-induced primary hypothyroidism with associated hypothyroid myopathy in a young patient with surgically resected stage IIIB melanoma receiving adjuvant nivolumab. He presented 12 weeks into therapy with severe myalgias, arthralgias, and intermittent disequilibrium of unclear etiology. Laboratory evaluation demonstrated a significant elevation in thyroid stimulating hormone and creatine kinase with an undetectable free T4 with standard laboratory measurement. With thyroid hormone replacement therapy alone, he had rapid improvement in his musculoskeletal symptoms and laboratory parameters over a threeweek period.

Discussion: This case emphasizes the serious nature of endocrine immune-related adverse events in patients receiving immune checkpoint inhibitors. Additionally, it highlights that unlike most other immunerelated adverse events, endocrine immune-related adverse events can generally be managed with adequate hormone replacement alone with swift improvements in symptoms. This allows patients to continue immune checkpoint inhibitors safely without immunosuppression which may dampen the anti-tumor activity of these agents.

Conclusion: This case highlights the importance of early recognition and the appropriate management of endocrine immune-related adverse events to maximize patient safety and good outcomes.

Purpose: Nivolumab is a fully human IgG4 programmed death 1 immune checkpoint inhibitor (ICI) antibody that has anti-tumor activity by selectively blocking the interaction of the programmed death 1 receptor with its two known programmed death ligands PD-L1 and PD-L2. In doing so, this immune checkpoint inhibitor removes the negative signal stifling T cell activation and proliferation within the tumor microenvironment and demonstrates favorable antitumor activity.

Case Report: We report an interesting case of immune checkpoint inhibitor-induced primary hypothyroidism with associated hypothyroid myopathy in a young patient with surgically resected stage IIIB melanoma receiving adjuvant nivolumab. He presented 12 weeks into therapy with severe myalgias, arthralgias, and intermittent disequilibrium of unclear etiology. Laboratory evaluation demonstrated a significant elevation in thyroid stimulating hormone and creatine kinase with an undetectable free T4 with standard laboratory measurement. With thyroid hormone replacement therapy alone, he had rapid improvement in his musculoskeletal symptoms and laboratory parameters over a threeweek period.

Discussion: This case emphasizes the serious nature of endocrine immune-related adverse events in patients receiving immune checkpoint inhibitors. Additionally, it highlights that unlike most other immunerelated adverse events, endocrine immune-related adverse events can generally be managed with adequate hormone replacement alone with swift improvements in symptoms. This allows patients to continue immune checkpoint inhibitors safely without immunosuppression which may dampen the anti-tumor activity of these agents.

Conclusion: This case highlights the importance of early recognition and the appropriate management of endocrine immune-related adverse events to maximize patient safety and good outcomes.