Table 1 Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors
Case | Age (yrs) | Sex | Primary disease | Site of metastasis | Clinical presentation | Sites of granulomatous/sarcoid-like lesions | Immune checkpoint inhibitors (dose) | Onset of granulomatous/ sarcoid-like lesions after initiation of immune checkpoint inhibitors (months) | Histologic features | Treatment of granulomatous/sarcoid-like lesions (dose) | Outcome of granulomatous/ sarcoid-like lesions | Disease response to immune checkpoint inhibitors | Follow up since initiation of immune checkpoint inhibitor (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 Anderson, 2014 [7] | 44 | M | Melanoma | Kidney, lungs, mediastinal and retroperitoneal LN, brain, bone, muscle, subcutis | Routine surveillance | Spleen | Ipilimumab (3 mg/kg, Q3WKS) Completed 4 cycles | 20 | Spleen biopsy: non-caseating epithelioid granulomata | None | Resolution of splenic lesion | Stable disease | 33 |
2 Firwana, 2016 [15] | 41 | M | Melanoma Colorectal carcinoma | Axillary LN | Bilateral, occipital neck pain, axillary and cervical LAD | Bilateral cervical, axillary, hilar, mediastinal, iliac and inguinal LNs | Ipilimumab (NR) | NR | Not available | Ipilimumab withheld Opioids and NSAIDs | Resolution of LAD | NR | NR |
3 Firwana, 2016 [15] | 57 | F | Melanoma | Chest wall | Flu-like symptoms, fatigue, skin with erythematous, painful nodules on lower extremity | Hilar, mediastinal LNs | Ipilimumab (NR) | NR | Hilar lymph node biopsy: poorly formed epithelioid granulomata with focal necrosis | Prednisone (1 mg/kg) | NR | NR | NR |
4 Eckert, 2008 [16] | 67 | F | Melanoma | Axillary, supraclavicular, spinal, LNs, subcutis, liver | Low-grade dyspnea, skin lesion on face | Facial skin, mediastinal LNs | Ipilimumab (0.3, 3, or 10 mg/kg, Q3WKS + 10 mg/kg 3WKS) | 7 | Face and bronchial biopsy: non-caseating granulomata | Ipilimumab withheld | Partial resolution of LAD | Stable disease | 11 |
5 Seve, 2009 [17] | 62 | F | Melanoma | Skin, liver | NR | NR | Ipilimumab (0.3, 3, or 10 mg/kg, Q3WKS) | 7 | Biopsy from skin and bronchus: consistent with sarcoidosis | Ipilimumab withheld | Resolution | Stable disease | 54 |
6 Vogel, 2012 [18] | 49 | M | Melanoma | Bilateral inguinal, pulmonary, mediastinal LNs, bilateral legs | Routine surveillance | Mediastinal and bilateral hilar LAD | Ipilimumab (3 mg/kg, Q3WKS) | 5 | Endobronchial biopsy: non-caseating granulomatous inflammation | None | Resolution of LAD | Complete remission | ~ 8 |
7 Wilgenhof, 2012 [19] | 48 | F | Melanoma | Bilateral lungs, mediastinum, axilla, retroperitoneal, breast | Dry cough, shortness of breath, fatigue | Skin of neck, axilla, mediastinum, and retroperitoneal LAD, lung, spleen | Ipilimumab (3 mg/kg, Q3WKS) | 1 | Transbronchial biopsy: non-necrotizing epithelioid granulomata | Completed 4 doses of Ipilimumab Methylprednisolone (48 mg) | Decrease in size of LAD and spleen | Progression of disease | 9 |
8 Berthod, 2012 [20] | 63 | M | Melanoma | Lung, liver, mediastinal LNs | Dry cough and dyspnea | Lung, pleura, perihilar tissue | Ipilimumab (3 mg/kg, Q3WKS) | 3.25 | Bronchial and lung biopsies: well-formed granulomata with giant cells and occasional necrosis | Prednisone (1.5 mg/kg) | Resolution of lung infiltrates | Progression of disease | ~ 6 |
9 Tissoot, 2013 [21] | 57 | M | Melanoma | Axilla | Subcutaneous nodules on arm | Skin, lung, bilateral hilar LNs | Ipilimumab (10 mg/kg, Q3WKS for 4 doses, followed by 10 mg/kg, Q12WKS) | 9 | Skin and mediastinal biopsy: non-caseating granulomata | Ipilimumab withheld | Skin and pulmonary lesions resolved, decreased size of mediastinal LNs | Remission | 12 |
10 Reule,2013 [22] | 55 | M | Melanoma | Axilla | Grouped erythematous papules | Skin, lung, hilar and mediastinal LNs | Ipilimumab (10 mg/kg, Q3WKS) | 1.5 | Subcarinal lymph node biopsy: negative for malignancy Skin biopsy: sarcoidal granulomata | Prednisone | Rapid improvement | Progression of disease | NR |
11 Murphy, 2014 [23] | 37 | M | Melanoma | Inguinal, pelvic LNs, vertebrae | Routine surveillance | Bilateral hilar and mediastinal LNs, brain | Ipilimumab (3 mg/kg, Q3WKS) | 6.25 | Transbronchial biopsy: non-caseating granulomata | Prednisolone (40 mg) | Resolution of LAD | Stable disease | 12 |
12 Toumeh, 2016 [24] | 26 | F | Melanoma | Axilla, adrenal gland, subcutis | Intermittent abdominal pain | Skin, mediastinal LNs, lung, peritoneal surface of liver | Ipilimumab (3 mg/kg, Q3WKS) | 1 | Mediastinal LN biopsy: cohesive clusters of epithelioid histiocytes and multinucleated giant cells Skin biopsy: non-necrotizing granulomata associated with tattoo pigment | Prednisone (60 mg) | Near complete resolution of Mediastinal LAD Enlargement of peritoneal nodules, confirmed as melanoma | Progression of disease | 4 |
13 Current report, Patient 2 | 33 | F | Melanoma | Axilla | Routine surveillance/staging studies | Skin of bilateral lower extremities, mediastinal and hilar LNs | Ipilimumab (3 mg/kg, Q3WKS) | 3 | Skin biopsy: collection of epithelioid histiocytes | None | Improvement of LAD | Remission | 8 |
14 van den Eertwegh, 2012 [25] | NR | NR | Prostate adenocarcinoma | NR | Surveillance studies | Lung | Ipilimumab (5 mg/kg, Q4WKS) | 2 | Lung biopsy: small, non-compact granulomata | Ipilimumab withheld Prednisone (NR) | Improvement | NR | NR |
15 Suozzi, 2016 [8] | 60 | F | Lung adenocarcinoma | LNs, brain | Nausea, vomiting, aphasia, confusion | Skin with multiple pink firm papules and annular plaques | Ipilimumab (1 mg/kg, Q6WKS) + Nivolumab (1 mg/kg, Q2WKS) | 7 | Skin biopsy: dermal granulomatous inflammation | Clobetasol ointment (0.05%) | Some improvement | Progression of disease | 10 |
16 Birnbaum, 2017 [9] | 63 | F | Lung adenocarcinoma | Pleura | N/A | Skin of neck, face, and periorbital, pruritic waxing and waning, erythematous papules and plaques | Nivolumab (3 mg/kg, Q2WKS) | 4.5 | Skin biopsy: nodular collection of epithelioid histiocytes with multinucleated giant cells | Methylprednisolone (24 mg) Hydroxychloroquine (200 mg) | Complete resolution | Stable disease | 6 |
17 Montaudie, 2016 [26] | 56 | M | Melanoma | Axilla, hilar, mediastinal LNs, liver, lung, | Dry cough and dyspnea | Bronchi, lung, parotid glands, cervical LNs | Nivolumab (3 mg/kg, Q2WKS) | 0.75 | Bronchial biopsy: non-caseating epithelioid granulomata | Prednisone (75 mg) | Resolution of lung nodules | Progression of disease | 3 |
18 Danlos, 2016 [27] | 57 | M | Melanoma | Skin, nasolabial fold | Surveillance studies | Cutaneous lip, subcutaneous tissue near prior scar, bilateral hilar, mediastinal LNs | Nivolumab (3 mg/kg, Q2WKS) | 10 | Biopsy of subcutaneous nodule: non-necrotizing epithelioid granulomata with giant cells and some birefringent material | None | Resolution of granulomata | Remission | 12 |
19a Cotlier, 2016 [28] | 72 | F | Hodgkin lymphoma | N/A | Enlarging asymptomatic nodules | Skin of upper extremities, axial skeleton, eye, lung, bilateral hilar and mediastinal LNs | Pembrolizumab (200 mg, Q3WKS) | 6 | Biopsy of skin nodule: focal dermal epithelioid granulomata | Pembrolizumab withheld Prednisone | Complete resolution of Skin nodules, LAD, and FDG-avid lesions | Remission | 13 |
20 Firwana, 2016 [15] | 37 | F | Melanoma | Spleen, radius | Joint pain, cough, granulomatous lesions in the arm near surgical scar and bilateral skin nodules of lower extremity | Cervical, axillary, mediastinal, retroperitoneal LAD | Pembrolizumab (Not reported) | NR | Right lung wedge resection: sarcoidosis | Pembrolizumab withheld | Partial resolution of LAD | NR | NR |
21 Current report, Patient 1 | 79 | M | Melanoma | Hilar, mediastinal LNs, liver, adrenal | Subcutaneous nodules | Skin, mediastinal, hilar, peritracheal, retroperitoneal | Pembrolizumab (2 mg/kg, Q3WKS) | 20 | Biopsy of skin nodule: non-caseating epithelioid granulomata | Pembrolizumab withheld Intralesional triamcinolone | Persistence of skin nodules, stable LAD | Remission | 25 |
22 Current report, Patient 3 | 68 | M | Melanoma | LNs, skin, humerus, brain | Surveillance studies | Mediastinal, paratracheal LAD | Pembrolizumab (2 mg/kg, Q3WKS) | 6 | Biopsy of paratracheal lymph nodes: “negative for melanoma” | None | Resolution of LAD | Remission | 24 |
23 Brahmer, 2012 [29] | NR | NR | Melanoma | Lymph node | NR | NR | Anti-PD-L1 (10 mg/kg, Q2WKS) | NR | NR | NR | NR | NR | NR |
24 Burillo-Martinez, 2017 [10] | 60 | F | Melanoma | Peritoneal | Plaques, nodules | Skin of upper and lower extremity, bilateral hilar and mediastinal LAD | Pembrolizumab (2 mg/kg, Q3WKS) | 1.2 | Biopsy of skin nodule: lobular granulomatous panniculitis | Pembrolizumab withheld Prednisone | Complete resolution | Complete remission | 6 |
25 Tetzlaff, 2017 [11] | 57 | F | Ovarian cancer | Liver, peritoneum | Tender subcutaneous nodules | Skin of upper and lower extremities | Nivolumab (3 mg/kg, Q2WKS) + Ipilimumab (1 mg/kg, Q6WKS) | 10 | Biopsy of skin nodule: septal and lobular panniculitis with giant cells and septal fibrosis | None | Complete resolution | No evidence of disease | 16 |
26 Tetzlaff, 2017 [11] | 39 | F | Melanoma | Axillary LNs | Tender subcutaneous nodules | Skin of lower extremities, buttock | Neoadjuvant setting: Nivolumab, 3 doses (1 mg/kg, Q3WKS) + Ipilimumab, 3 doses (3 mg/kg, Q3WKS) Adjuvant setting: Nivolumab (3 mg/kg, Q2WKS) | 7 | Biopsy of skin nodule: septal and lobular panniculitis with giant cells and septal fibrosis | All melanoma therapy withheld Systemic steroids Hydroxychloroquine | Nodules dissipated | No evidence of disease | 12 |
Total | Median (range) 57 (26-79) | M:Fb 11:13 | Melanoma = 20 Other =6c | Skin, lung, and hilar/mediastinal LNs = 10 Lung, hilar/mediastinal LNs = 9 Skin only = 4 Other = 6d | Ipilimumab = 14 Nivolumab = 3 Pembrolizumab = 5 Anti-PD-L1 = 1 Combined ipilimumab + nivolumab = 3 | Median (range) 6 (0.75-20) | Immune checkpoint inhibitor withheld = 10 Systemic steroids = 12 Localized = 2 | Resolution =14 Improvement = 9 Stable = 1 NR =2 | Stable = 5 Remission = 10 Progression =6 NR =5 | Median (range) 11.5 (3-54) |