Case of the Month

05/22 melanoma of unknown primary (MUP)

Manifestation: Lymph node metastasis right axilla

TxN3M1b (1), (AJCC 2017)

Staging cMRT and CT-thorax/abdomen: Pulmonary lymph node metastases

06-08/22 – 4 cycles of combined immunotherapy with ipilimumab 3mg/kg + nivolumab 1mg/kg

Since 08/22 – monotherapy with nivolumab (paused 11-12/22)

10 weeks after initiation of combined immunotherapy with ipilimumab and nivolumab, the patient presented with nausea, fatigue and impaired vision. First, immune-related hypophysitis was suspected (irHypophysitis) and subsequently hydrocortisone treatment was initiated. Later on the patient developed increasing hyponatraemia and impaired renal function. The hydrocortisone therapy was continued.

The endocrinological examination showed low cortisol (0,5 µg/dl; reference range: 6,2-18,0 µg/dl), and increased adrenocorticotropic hormone (ACTH) levels (570 pg/ml; reference range: 4-61 pg/ml)). As the ACTH provocation test was negative (low cortisol (0,6 µg/dl) 30min after administration of ACTH, irHypophysitis was ruled out and irAdrenalitis was diagnosed with primary adrenocortical insufficiency.

As hydrocortisone therapy improved symptoms, nivolumab was re-initiated without any further complications. Sodium, glomerular filtration rate (GFR) and creatinine returned to levels within the normal range.

We initiated systemic therapy with hydrocortisone with a dose of 30mg/day (20-10-0mg, later 20-5-5mg). Importantly, individual dose adjustments of hydrocortisone may be necessary (e.g. illness, infection, operation, stress, hyperthyreodism, etc.). Mineralocorticoids were replaced by fludrocortisone (Astotin H 0,05mg/day). Based on individual symptoms like decreased well-being or low libido, some patients also take dehydroepiandrosterone.

Nivolumab monotherapy was temporarily paused until symptoms subsided. In combination with the administration of hydrocortisone and fludrocortisone, Nivolumab was re-initiated without complications.

Endocrine adverse events occur in approximately 10% of patients treated with combined immunotherapy (Hattersley et al., ClinMed, 2021), thyroiditis (10-16%) and hypophysitis (17%) being the most common (Husebye et al., European Journal of Endocrinology, 2023). Adrenalitis with primary adrenal insufficiency (1%), diabetes mellitus and diabetes insipidus (0,9-2%) are rare however critical to diagnose (Husebye et al., European Journal of Endocrinology, 2022). Most endocrinopathies present with non-specific symptoms like fatigue, nausea, headache and arthralgia and can thus be missed (Braun GS et al., Nephrologe, 2020; Heinzerling et al., Dtsch Arztebl Int, 2019; Hattersley et al., ClinMed, 2021). Immunotherapy may be paused temporarily during endocrinological assessments.

Decreased fasting cortisol (morning) < 5 μg/dl and a change of less than 9 µg/dl after administration of 250µg of ACTH provide diagnostic clues for primary adrenal insufficiency (PAI) caused by i.e. irAdrenalitis. The classic short corticotropin test with ACTH is considered as the gold standard method to confirm the PAI. The electrolytes should also be checked as hyponatraemia and hyperpotassaemia can occur.

In the differential diagnosis of adrenal insufficiency, irHypophysitis has to be considered initially. IrHypophysitis occur in approximately 17% of patients receiving combined ICI therapy. If hypophysitis is suspected, checks for clinical signs like new severe headaches or complaints of vision changes, biochemical assessment of the hypothalamic-pituitary axis and MRI scan of pituitary are recommended (Husebye et al., European Journal of Endocrinology, 2022). Neurological examination should be performed once to rule out any other neurological causes. The pituitary hormones (GH, prolactin, LH, FSH, TSH, and ACTH) as well as target hormones should be measured. The corticotropic axis is most commonly affected. Low fasting cortisol (morning) 7-16 µg/dl and serum ACTH value not higher than normal (reference range 4-61 pg/ml) establish the diagnosis of secondary adrenal insufficiency caused by i.e. hypophysitis (Hattersley et al., ClinMed, 2021, Wolters Kluwer et al., UpToDate, 2023).  

Treatment usually involves lifelong hormone replacement therapy (corticosteroid and mineralocorticoid). Due to the risk of acute adrenal crisis, patients will need to be educated to increase the dose in stress situations (infections, trauma etc.) and should carry an emergency card with them at all times.

Adrenalitis is a rare side effect of immune checkpoint inhibitors. Prompt diagnosis and treatment with hydrocortisone as well as patient education is essential.

• 09/2019 - Cutaneous Melanoma (tumor thickness 2.8 mm, Mitose index > 4)
• 01/22 - pT3 N1c M1b
• Pulmonary and lymph node metastases
• Excision of In-transit metastasis on right nasal septum
• Histologically confirmed lung metastasis
• 03/22 – Staging - PR
• BRAF wild type
• 09/22 – Staging – SD
• CT chest/abdomen and cMRI: persistent PR, DD avitality of the pulmonary lesions

• 02-05.2022 –  4 cycles of combined immunotherapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg) followed by
• 9 x nivolumab q2w

After the 2nd cycle( on week 3) of combined immunotherapy with immune checkpoint inhibitors (ICI) ipilimumab and nivolumab, the patient presented with immune-related hepatitis (irHepatitis) and immune-related thyroiditis (Grade II) (irThyroiditis).

After week 20 of ICI (4th cycle ipilimumab/nivolumab and 4th nivolumab), the patient suffered from weight loss (110 kg) and muscle loss. As the ACTH provocation was positive, immune-related hypophysitis (Grade II) (irHypophysitis) was diagnosed.

After completion of 4th ipilimumab/ nivolumab and 9th nivolumab (week 30), the patient complained of severe vertigo and left sided hearing loss (irVestibulopathy and irCochleitis).

irThyroiditis (Grade 3 CTCAE) at week 3

Hyperthyroidism was treated with a beta-blocker on 03/22, and subsequently Hypothyroidism with L-thyroxine (50 µg) from 05/22 onwards.

Oral Corticosteroid therapy (50 mg) was started and then tapered.

Hyperthyroidism in irThyroiditis is a result of direct immune induced destruction of thyreocytes which releases the stored thyroid hormone from the thyroid follicles into the blood circulation. Hence, carbimazole is not useful in irThyroiditis induced hyperthyroidism as it acts by decreasing the uptake and concentration of inorganic iodine by thyroid and also reduces the formation of di-iodotyrosine and thyroxine.

irHypophysitis (Grade 2 CTCAE) at week 20

Hydrocortisone 20 mg/day was substituted.

irVestibulopathy and irCochleitis (Grade 3/4) at week 30

The patient was referred to an ENT specialist and started on prednisone (SDH) 200 mg i.v. for 3-5 days.

Upon therapy, the hearing loss improved, the vertigo subsided and the patient gained bodyweight and muscle mass.

On account of stable disease, the ICI was stopped on 9/22.

Most frequently, immune-related Adverse Events (irAEs) affect a wide range of organs like skin, colon, liver, pituitary, thyroid, and lungs, although uncommon events involving the heart, nervous system, and other organs do occur. The onset develops predominantly within the first 6-12 weeks after treatment initiation.

Combining treatment with ipilimumab and nivolumab has resulted in a reported 18%-22% all-grade hepatitis and overall with 8%-11% having severe hepatitis. (Remash D, et al. World J Gastroenterol. 2021)

Hyperthyroidism due to irThyroiditis occurs on account direct thyreocyte destruction and hence carbimazole, which acts by inhibiting thyroid hormone synthesis is not indicated in irHyperthyroidism. (Iyer PC, et al. Thyroid. 2018).

Neurological immune-related adverse events occur in 1%–5% of patients on ICI therapy (Koch EAT, et al. J Immunother. 2021). Moreover, ICI-mediated ototoxicity is rare or under reported due to a small number of case reports published till date. (Rosner S, et al. J Immunother Cancer, 2020) of patients (refs voskens JCO, and others). It may develop isolated as a single irAE or in concert with other irAEs as in this case. Manifestation of ICI-mediated ototoxicity ranges from isolated hearing loss, tinnitus, vestibular symptoms with hearing loss, visual and hearing loss or Vogt-Koyanagi-Harada syndrome (VKH) with ocular, dermatologic and neurologic involvement. It is important to distinguish between isolated hearing changes and hearing changes as part of a collective syndrome to institute appropriate management.

In the absence of ocular involvement, a diagnosis of Cogan Syndrome was not made.

ICI-mediated ototoxicity occurs early in the treatment course (within ~4 months of initiating ICI). The association between irAEs and ICI efficacy is controversial and may depend on the site of toxicity. Retrospective studies suggest that site-specific toxicities may have a correlation with ICI efficacy (Martins F, et al. Nat Rev Clin Oncol, 2019)

The mechanisms underlying the development of ICI-mediated ototoxicity are currently unknown. Preclinical rat models of ICI-mediated ototoxicity demonstrated significant differences in auditory brainstem responses (ABR) in those treated with ICIs vs controls, as well as pathologic evidence of a reduction in the outer hair cells and flattening of the organ of Corti in those treated with ICI. (Kuzucu İhsan, et al . Cureus 2019) Interestingly, ototoxicity has also been reported from adoptive cell therapy for melanoma. The proposed mechanism of this toxicity could involve auto-antigenicity against melanocyte specific antigens such as MART-1 present in the inner ear, uvea and epithelium of the skin (Plonka PM et al. Exp Dermatol, 2009).

ICI related ototoxicity is a rare side effect of immune checkpoint inhibitors that health care providers should be aware of and that requires interruption of ICI therapy and prompt administration of systemic corticosteroids to ensure restitution ad integrum.

• 01/2021 Nodular malignant melanoma left knee
  • 06/2022: lymph node metastasis left inguinal, complete resection
  • pT2aN1bM0, IIIB (AJCC 2017)

• 07/2022 Adjuvant immunotherapy with pembrolizumab

After 2 doses of adjuvant immunotherapy with the immune checkpoint inhibitor pembrolizumab, the patient presented with bilateral hearing loss. Furthermore, they developed dyspnea and leg edema. Troponin and nt-pro-BNP were slightly elevated. The D-dimer was slightly elevated and the ECG showed an S1Q3 type, thus we ruled out a pulmonary artery embolism using CT angiography. Echocardiography showed preserved systolic function and diastolic dysfunction (HFpEF, heart failure with preserved ejection fraction). A cardiac catheter examination could rule out a stenosis requiring intervention.

A cardiac MRI showed focal transmural late gadolinium enhancement (LGE) of the basal inferior wall. Since, in addition to inflammatory changes, cardiac metastases were also part of the differential diagnosis, a PET-CT was performed for further clarification. Finally, we agreed on ICI-myocarditis as the most likely cause. A myocardial biopsy was not performed due to the difficult localization.

We initiated systemic therapy with prednisolone with an initial dose of 1000 mg, which was reduced to 1 mg/kg after 5 days and then tapered. A weight reduction of 4 kg could be achieved through a negative fluid balance. A follow-up cardiac MRI is planned.

The immunotherapy was permanently discontinued.

Myocarditis is a rare side effect of immunotherapy (incidence ca. 1%) with a very high mortality (50%), therefore cardiac biomarkers should be regularly monitored during immunotherapy. Before starting therapy, a baseline ECG and troponin determination should be performed. Biomarker abnormalities or clinical symptoms should be followed by cardiac evaluation. Troponin and ECG taken together are abnormal in 50-90% of cases of ICI-myocarditis, cardiac MRI shows changes in 25-50% of cases. Echocardiography is often unremarkable. A cardiac catheter examination should be performed once to rule out coronary artery disease; myocardial biopsy is gold standard. Immunotherapy should be interrupted or discontinued and systemic corticosteroid therapy (1-2 mg/kg or even 1g/day) initiated. In therapy-refractory cases, mycophenolate mofetil (MMF), infliximab or anti-thymocyte-globuline (ATG) have been suggested as second-line therapies (ASCO-Guidelines, Schneider BJ, J Clin Oncol, 2021). Case reports reported on the successful use of abatacept and alemtuzumab as second-line therapies for ICI-myocarditis (Salem JE, N Engl J Med, 2019; Esfahani K, N Engl J Med, 2019).

Myocarditis is a rare side effect of immune checkpoint inhibitors with extremely high mortality, therefore monitoring of cardiac biomarkers and good side effect management is crucial.