What autopsy findings would be expected in a patient who developed an untreated adrenal crisis superimposed on immune‑mediated hypophysitis after recent carboplatin‑based chemotherapy and checkpoint‑inhibitor immunotherapy?

Autopsy Findings in Untreated Adrenal Crisis with Immune-Mediated Hypophysitis

The autopsy would reveal markedly atrophic adrenal glands (typically <1 gram each, compared to normal 4-6 grams), a thin adrenal cortex with absent or minimal cortisol on immunohistochemical staining, lymphocytic infiltration of the anterior pituitary with selective loss of ACTH-producing cells, and evidence of hypovolemic shock including organ hypoperfusion. 1, 2

Adrenal Gland Pathology

• Severe bilateral adrenal atrophy is the hallmark finding, with each gland weighing approximately 0.9 grams (normal range 4-6 grams), reflecting chronic ACTH deficiency from hypophysitis 1
• The adrenal cortex appears markedly thinned and atrophic on gross examination, with loss of the normal yellow lipid-rich appearance 1
• Immunohistochemical staining for cortisol is negative or minimal in the adrenal cortex, confirming absence of glucocorticoid production 1
• The adrenal medulla is typically preserved, as it does not depend on ACTH stimulation 1
• No evidence of hemorrhage, necrosis, or infiltrative disease would be present in the adrenals themselves, distinguishing this from primary adrenal insufficiency 1

Pituitary Gland Pathology

• Lymphocytic infiltration of the anterior pituitary lobe is the defining feature of immune-mediated hypophysitis, with predominantly CD8-positive T cells 2
• Selective loss or marked reduction of ACTH-producing cells on immunohistochemical staining with anti-ACTH antibody, while other pituitary cell types (particularly growth hormone-producing cells) may be relatively preserved 1, 2
• CD68-positive macrophages and CD20-positive B-cells are also present within the inflammatory infiltrate 2
• IgG and C4d deposition on pituitary cells indicates type II hypersensitivity mechanisms, though IgG4 (the subclass of checkpoint inhibitors) is typically not detected 2
• The pituitary may show mild enlargement or edema in acute hypophysitis, though this is not always present at autopsy 3
• Absence of significant necrosis or fibrosis distinguishes checkpoint inhibitor-induced hypophysitis from other forms, particularly CTLA-4 antibody-induced disease 2

Biochemical Findings

• Extremely low or undetectable urine cortisol (e.g., 20 mg/L or less) and 17-OHCS concentration (e.g., 0.8 mg/L) confirm profound glucocorticoid deficiency 1
• Serum cortisol at time of death would be profoundly low (<2 μg/dL) with inappropriately low or normal ACTH levels, confirming secondary adrenal insufficiency 1, 4

Evidence of Adrenal Crisis and Shock

• Signs of hypovolemic shock including organ hypoperfusion, as adrenal crisis causes profound hypotension and vascular collapse 1
• Dehydration with evidence of prerenal azotemia and concentrated urine (though urine sodium may be inappropriately elevated due to lack of mineralocorticoid effect on renal tubules in secondary AI) 5
• Possible cerebral edema or other manifestations of severe hyponatremia if present 5
• No specific gross pathological findings in other organs that would explain death, making the diagnosis dependent on recognizing the endocrine pathology 1

Additional Findings Related to Checkpoint Inhibitor Therapy

• Programmed death-ligand 1 (PD-L1) expression on residual pituitary cells, indicating the mechanism of immune activation 2
• Possible evidence of other immune-related adverse events such as lymphocytic thyroiditis, colitis, or pneumonitis, though these are not universal 1, 2
• The underlying malignancy (in this case, likely lung cancer given carboplatin-based chemotherapy) would be present with variable response to treatment 6

Critical Distinguishing Features

• The combination of atrophic adrenals with lymphocytic hypophysitis definitively establishes secondary (central) adrenal insufficiency rather than primary adrenal disease 1, 2
• Absence of adrenal hemorrhage, tuberculosis, metastases, or autoimmune adrenalitis rules out primary adrenal insufficiency 5, 1
• The selective loss of ACTH-producing cells while other pituitary hormones may be preserved distinguishes this from panhypopituitarism 1, 2

Temporal Considerations

• These findings develop over weeks to months following checkpoint inhibitor initiation, with median onset of endocrine toxicities at 14.5 weeks (range 1.5-130 weeks) 7
• The adrenal atrophy reflects chronic ACTH deficiency, requiring weeks to months to develop fully 1
• Death from untreated adrenal crisis typically occurs within hours to days of the precipitating stress 1