An Unusual Case of Langerhans Cell Histiocytosis

AUTHORS:
Maxia McEachron, MD¹ • Catherine Kurian, MS² • Michelle Solik, MD, MS³

AFFILIATIONS:
¹St. David’s South Austin Medical Center, Austin, Texas
²Marian University College of Osteopathic Medicine, Indianapolis, Indiana
³St. Vincent Hospital, Indianapolis, Indiana

CITATION:
McEachron M, Kurian C, Solik M. An unusual case of Langerhans cell histiocytosis. Consultant. 2020;60(4):12-15. doi:10.25270/con.2020.04.00002

Received February 21, 2019. Accepted May 23, 2019.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Maxia McEachron, MD, St. David’s South Austin Medical Center, 901 W Ben White Blvd, Austin, TX 78704 (maxia.mceachron@gmail.com)

A 34-year-old man with a history of new-onset insulin-dependent type 2 diabetes mellitus (T2DM) presented to a tertiary care center for evaluation of 1 month of generalized fatigue, anorexia, and weakness. He had received a diagnosis of T2DM 3 months prior to presentation and had been started on insulin and oral antihyperglycemic therapy.

Over the past several weeks, he had had decreased oral intake associated with worsening weakness and fatigue. He reported having nausea without vomiting. The patient’s wife, who accompanied him, repeatedly expressed concern that he had been confused and had not been his usual self with onset of these symptoms.

On review of systems, he reported having left-sided rib pain that he attributed to a recent fall. He denied experiencing headache, vision changes, shortness of breath, chest pain, abdominal pain, rash, weight changes, or bowel or bladder problems.

History. The patient had no history of recent travel or known toxic exposures. He was a nonsmoker and denied any use of alcohol or illicit drugs. His family history was significant for cardiac disease in his mother at an advanced age but was otherwise noncontributory. His only medications were glipizide, metformin, and insulin detemir for management of his T2DM. He denied taking any over-the-counter medications. He worked at a local Mexican restaurant busing tables.

Physical examination. At presentation, the patient was afebrile, with normal vital signs, although his blood pressure was noted to be on the low end of normal, with average systolic pressures of approximately 100 to 110 mm Hg. He was oriented to person, place, and time, but when asked to recall details from the past few days or weeks, he could not give a clear answer. He had no obvious dysarthria or word-finding difficulties; results of a neurological examination were normal, including motor strength.

The rest of the examination findings—including the heart, lungs, abdomen, and lymph nodes—were entirely normal. No obvious rashes or areas of joint swelling were present. His legs were nonedematous. His mucous membranes were noted to be dry. There were no appreciable masses, obvious hepatosplenomegaly, or areas of bony enlargement on examination of his left chest wall, where he identified having intermittent discomfort.

Diagnostic tests. Pertinent laboratory data on admission included an elevated sodium level of 161 mEq/L, a low-normal potassium level of 3.6 mEq/L, an elevated bicarbonate level of 29 mEq/L, an elevated creatinine level of 1.45 mg/dL (with a known baseline value of 0.7 mg/dL), and an elevated calcium level of 10.6 mg/dL. All other electrolyte levels were within normal limits.

Results of a complete blood cell count were within normal limits, but the erythrocyte sedimentation rate was noted to be elevated at 62 mm/h. Chest radiography findings were unremarkable and negative for infection or bony pathology. Urinalysis showed a specific gravity of 1.030, at the high end of normal range. A computed tomography (CT) scan without contrast of the head did not identify any acute ischemic or hemorrhagic process. Serum osmolality was elevated at 336 mOsm/kg, and urine osmolality was elevated at 665 mOsm/kg.

In light of the patient’s hypernatremia in the setting of poor oral intake, supported by the high urine osmolality noted at presentation, intravenous fluids (dextrose 5% in water) were initiated in an effort to improve his symptoms. His sodium levels were frequently monitored in order to prevent rapid overcorrection of hypernatremia. He was admitted to the hospital and monitored overnight.

NEXT: Diagnosis and Management

Diagnosis and management. Despite aggressive hydration, the patient’s sodium level improved only marginally—by the end of hospital day 1, it had only decreased by 4 mEq/L. He continued to exhibit episodes of confusion that did not coincide with his level of hypernatremia, especially in someone so young. His neurological examination findings remained unchanged.

The nursing staff reported that overnight the patient had put out nearly 1000 mL of urine in one sitting, with increased urine output observed throughout the night. Consideration for a hormonal etiology was proposed, and bloodwork including thyroid function tests, cortisol level, and urine osmolality was sent. Interestingly—even after only one day in the hospital—his urine osmolality test result returned markedly different from what it had been at admission; it was now 202 mOsm/L (with confirmation on repeated testing), down from 665 mOsm/kg. His thyrotropin level was found to be normal at 2.67 mIU/L, but the free thyroxine level was found to be low at 0.5 ng/dL, concerning for hypothyroidism. A random measurement of morning cortisol level—which was checked in light of his marginal blood pressures and low-normal potassium level on hospital day 1—returned low at 1.4 µg/dL.

In light of the low urine osmolality with possible urine dumping, a desmopressin challenge (with 1 µg of intravenous DDAVP) was administered. The patient’s urine osmolality was observed to increase to 605 mOsm/kg, essentially confirming the diagnosis of diabetes insipidus (DI). An adrenocorticotropic hormone stimulation test was pursued but became uninterpretable due to incorrect collection technique. The patient was initiated on empiric intravenous hydrocortisone, oral levothyroxine, and oral desmopressin, resulting in a significant improvement (and eventual normalization) of his sodium levels and improvement in his level of confusion.

In the setting of possible adrenal insufficiency and findings of new hypothyroidism, as well as what was now perceived to be a possible new presentation of DI, a central hypothalamic or pituitary axis process was considered as possibly contributing to the patient’s constellation of symptoms. The follicle-stimulating hormone level was measured as low at 0.4 mIU/mL, the luteinizing hormone level was found to be below 0.1 mIU/mL, the prolactin level was elevated at 39.5 µg/L, the insulinlike growth factor 1 level was low at 24 ng/mL, and the free testosterone level was low at 0.2 pg/mL, all of which were consistent with panhypopituitarism.

Magnetic resonance imaging (MRI) of the head and pituitary with and without contrast revealed a 2.1 × 1.5 × 1.9-cm infiltrating hypothalamic lesion with extension along the proximal infundibulum (Figure 1).

Figure 1. MRI of the head and pituitary with and without contrast. An infiltrating lesion within the hypothalamus, measuring 2.1 × 1.5 cm orthogonally in the sagittal plane and 1.9 cm transversely, avidly enhances on postcontrast imaging. The lesion involves the proximal infundibulum without thickening distally. The lesion widens the optic tracts and displaces the optic chiasm anteriorly. There is a T2- weighted hyperintense signal within the distal optic tracts and optic chiasm.

Angiotensin-converting enzyme, α-fetoprotein, and human chorionic gonadotropin tumor markers were assessed to evaluate for an infiltrative versus malignant process, the results of all of which returned negative.

NEXT: Diagnosis and Management (Continued)

CT scanning of the chest, abdomen, and pelvis with and without contrast revealed evidence of an ill-defined pancreatic lesion, as well as a possible lytic lesion in the left ninth rib with concern for other similar-appearing lesions in the pelvis and sacrum. MRI of the abdomen and pelvis with and without contrast confirmed evidence of these bony lytic lesions within the rib and pelvis and identified a lytic lesion in the left femur, as well (there was no discernable pancreatic lesion on MRI). A nuclear medicine (NM) bone scan was performed, which also confirmed the presence of the corresponding lytic lesions (Figure 2).

Figure 2. NM whole-body bone scan showing an abnormal left ninth rib and right posterior ilium, corresponding to the lytic defects observed on CT scans. A focal area of increased activity is visible involving the left distal tibia just above the ankle joint.

At this point, the differential diagnosis included Langerhans cell histiocytosis (LCH), lymphocytic hypophysitis, and occult malignancy. Given the patient’s constellation of hormonal abnormalities, mental status changes, and evidence of bony lytic lesions, highest credence was given to LCH.

A CT-guided biopsy of a lytic lesion in the ilium was pursued, but core biopsy results revealed only evidence of fibrosis. Neurosurgery specialists were consulted and recommended stabilization of the patient’s hormonal imbalances and repeated outpatient imaging for possible brain biopsy consideration. He was later discharged to home on thyroid hormone replacement therapy, corticosteroids, desmopressin, and his previously prescribed antidiabetes medications.

Outcome of the case. At a neurosurgery follow-up visit 1 month later, MRI of the brain and pituitary with and without contrast revealed evidence of a slight increase in the size of the hypothalamic/suprasellar mass. The patient was admitted to the hospital to undergo craniotomy with biopsy and partial resection of the hypothalamic mass. Brain biopsy pathology revealed evidence consistent with BRAF V600E mutation-positive LCH. The patient was evaluated by hematology-oncology specialists; brain radiation therapy was initiated with plans for subsequent chemotherapy based on his response.

NEXT: Discussion

Discussion. LCH is a rare neoplastic disorder characterized by a clonal proliferation of Langerhans cells, with migration/infiltration into other organs. LCH can affect patients of any age; the prevalence among adults is 1 to 2 cases per million, with a slight male predilection.¹ LCH is commonly associated with a recurrent BRAF V600E mutation in approximately 50% of cases, which contributes to this abnormal proliferation of Langerhans cells in the body.²

The clinical presentation of LCH is variable, and the condition can affect a variety of organs including the bones, skin, pituitary, central nervous system (CNS), lungs, liver, or lymphoid organs.³ Therefore, a comprehensive evaluation is essential in making the diagnosis.

Bony infiltration is observed in 80% of patients with LCH.⁴ The most commonly implicated areas include the skull, mandible, ribs, pelvis, and spine.⁵ Patients may report pain and limited range of motion in a particular area, but they also may be asymptomatic. The CNS—particularly the hypothalamic-pituitary region (HPR)—is infiltrated in up to 50% of patients with LCH.⁶ As was observed in our patient’s case, HPR infiltration may be demonstrated by symptoms of polyuria or polydipsia (stemming from DI), or with symptoms consistent with disturbances in levels of thyroid, growth, or gonadotropin hormones.⁴

Nearly half of LCH cases initially present with cutaneous symptoms varying from nonspecific erythematous scaly papules to lesions similar to those observed in eczema.⁷ Lung involvement is typically observed among patients who use tobacco, and symptoms may include dyspnea or nonproductive cough.⁴

Given the widespread variability in presentation, it is imperative that the clinician complete a thorough history and physical examination and order appropriate diagnostic tests based on those clinical clues. Imaging can be helpful, especially if hormonal deficiencies are obvious during the initial workup. However, a diagnosis of LCH can only be made via biopsy and immunohistochemical analysis.

Examination of a biopsy specimen may reveal an accumulation of Langerhans cells along with a mixed infiltrate of lymphocytes and eosinophils.⁵ Birbeck granules, which are rodlike, tennis racquet–shaped structures noted in the cytoplasm of hyperproliferating Langerhans cells, are indicative of LCH on cytology examination. Positive staining for CD1a, S100, and CD207/langerin—all of which are transmembrane proteins expressed in normal Langerhans cells for antigen presentation—confirms the diagnosis of LCH.⁸

Genetic analysis may also reveal the recurrent BRAF V600E mutation, which is most commonly observed among patients with LCH, as was the case in our patient.

Management of LCH is determined by the extent of disease; if it is primarily localized to a single system (eg, the skin), patients may be treated empirically with a trial of corticosteroids and observed for clinical improvement.⁷ However, most cases of LCH are quite extensive (ie, multisystemic), in which case radiation and chemotherapy options are typically offered.⁶
Prognosis in LCH is highly variable and depends on patient response to medical therapies and progression of disease, if any. Most studies report a nearly 50% 10-year survival rate among patients with LCH who have high-risk organ involvement.⁴

Take-home message. This patient’s case demonstrates the importance of a broad differential diagnosis and avoidance of anchoring bias. This patient’s initial presentation—a young, otherwise healthy individual with an elevated sodium level and confusion—was not consistent with DI, but a thorough evaluation and an evolving differential diagnosis led to the diagnosis of DI, adrenal insufficiency, and hypothyroidism, which in turn led to consideration of a possible central HPR pathology and the discovery of panhypopituitarism and, ultimately, LCH.

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