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Table 1 Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors

From: Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients

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)
  1. Abbreviations: M male, F female, NR not reported, LN lymph nodes, LAD lymphadenopathy, Q every, WKS weeks
  2. aHistory of sarcoidosis before immune checkpoint therapy
  3. bTwo patients’ information was not reported
  4. cOne patient had both melanoma and colorectal carcinoma
  5. dSome patients had multiple sites of sarcoidosis. Other sites included spleen, parotid gland, axial skeleton, eye, cervical and retroperitoneal lymph nodes