Case of the Month

04/22 nodular melanoma

pT4b pN3c M1b, St. IV (AJCC 2017)

BRAF mutated

04/2022 tumor resection (R1) and axillary lymph node dissection

06-08/2022 monotherapy with nivolumab

06/2022 tumor resection (R0)

08-09/2022 radiotherapy

08-09/2022 2 cycles of combined immunotherapy with ipilimumab 3mg/kg + nivolumab 1mg/kg (stopped)

Since 12/2022 BRAF/ MEK inhibitor therapy with BRAFTOFI (Encorafenib) + MEKTOVI (Binimetinib)

After 2 doses of combined immunotherapy with ipilimumab and nivolumab, the patient presented with immune-related hepatitis (irHepatitis), immune-related hypophysitis (irHypophysitis) and immune-related myocarditis (irMyocarditis). Subsequently prednisolone treatment was initiated. Due to the high dose corticosteroid therapy, the patient developed steroid-related diabetes mellitus.

In further laboratory tests to exclude other conditions, we report a newly discovered serum reactivity to purkinje cell cytoplasmic antibodies without anti-Yo specifity. Control analyses were performed to rule out a panel of previously described paraneoplastic antibodies known to be associated with paraneoplastic cerebellar degeneration. The patient presented without any neurological symptoms. Cranial MRI was normal.

As corticosteroid therapy improved symptoms of irMyocarditis and irHepatitis, prednisolone was tapered. For irHypophysitis treatment, hormone replacement therapy was continued with hydrocortisone. BRAF/ MEK inhibitor therapy was initiated.

We initiated a systemic therapy with prednisolone with an initial dose of 80mg/day and then tapered.

Hypophysitis treatment usually involves lifelong hormone replacement therapy. Hydrocortisone with a dose of 30mg/day was substituted. Due to the risk of acute adrenal crisis, patients needs to be educated to increase the dose in stress situations (infections, trauma etc.) and should carry an emergency card with them at all times.

If a patient has a positive test for purkinje cell cytoplasmic antibodies, a follow-up with FDG-PET/CT to identify any underlying lesion is advised. Further neurological assessments are planned.

The immunotherapy was permanently discontinued due to the risk of irMyocarditis, irHypophysitis and irHepatitis. Positive tests for purkinje cell cytoplasmic antibodies often appear to be unrelated to the development of neurological diseases, therefore interruption of immunotherapy may not be required.

Paraneoplastic cerebellar degeneration is an uncommon disorder that can be associated with different types of cancer. The most commonly associated cancers are small cell lung cancer, gynecologic cancer and lymphoma. Purkinje cell cytoplasmic antibody type 1 with anti-Yo specifity (PCA-1) predominantly associate with cerebellar degeneration (Wolters Kluwer et al., Uptodate, 2023).

But, a positive test for paraneoplastic antibodies, as the purkinje cell cytoplasmic antibody, does not indicate the presence or development of a neurological disease. Many patients can have a positive test at low titers.  Even when detected at high titer, neurological symptoms or physical findings are not mandatory (Wolters Kluwer et al., Uptodate, 2023). To identify first signs of a neurological disorder, regular physical examinations are advised. FDG-PET/CT should be performed once to rule out cerebellar degeneration. MRI scans are often unremarkable.

Case reports reported of ipilimumab induced cerebellar degeneration in lung cancer patients (Hardwick et al., Neuropathology and Applied Neurobiology, 2021). Purkinje cell cytoplasmic antibody type 1 with anti-Yo specifity (PCA-1) tests were detected at low titer. Symptoms included severe ataxia, dysarthria, dizziness and double vision. Methylprednisolone and infliximab were initiated to improve symptoms.

Generally, treating the underlying cancer is the best way to control a paraneoplastic cerebellar degeneration (Elsevier, ScienceDirect, 2023).

A positive test for paraneoplastic antibodies is a very rare side effect of immune checkpoint inhibitors. Further research is now needed to evaluate the exact role of purkinje cell cytoplasmic antibodies without anti-Yo specifity. Neurological monitoring has to be indicated to detect changes in the clinical status of tumor patients.

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.