Toddler With Progressive Proptosis From Acute Myelogenous Leukemia

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A 21-month-old female with no significant medical history presented with a 3-week history of progressive bilateral proptosis. She had been well until her right cheek became swollen and red. Her pediatrician recommended a trial of diphenhydramine for a possible allergic reaction. The child did not respond to the medication and during the next 3 weeks, there was progressive bilateral swelling of the upper and lower eyelids. The mother noted that her child's "eyes were bulging out." The right eye was affected more than the left.

A few days before presentation, the mother noted some "bumps" that had developed behind the child's right ear. The child was brought to the emergency department for evaluation.

The child's appetite and energy level had decreased during the past 3 weeks. She also had mild nasal congestion with mouth breathing. There was no history of fever, weight loss, night sweats, chills, nasal discharge, easy bleeding or bruising, trauma, or recent infections. The child had not complained of pain or tearing and could move her eyes without difficulty. There were no abdominal complaints (no diarrhea or constipation), and ambulation was normal.

The child was well-developed and well-nourished, and vital signs were normal. She had significant bilateral proptosis. Erythema of the upper and lower eyelids did not extend beyond the orbital rim. Extraocular movements were intact, and the pupils were equal, round, and reactive to light. The cheeks were firm, nontender, and prominent bilaterally, with the right side more prominent than the left. No distinct facial mass or enlarged parotid gland was appreciated.

The patient had multiple, firm, mobile, nontender lymph nodes palpable in the submandibular and cervical regions, measuring 0.5 to 1 cm in diameter. She had no other adenopathy. Findings from examination of the heart, lungs, abdomen, extremities, and skin were unremarkable. Cranial nerve function was fully intact, and neurological examination findings were normal.

Laboratory tests revealed a white blood cell count of 17.9 10³/?L, with 12% neutrophils, 0% bands, 83% lymphocytes, 5% monocytes; hemoglobin level, 11.7 g/dL; mean cell volume, 79.0 fL; and platelet count, 9210³/?L. Levels of serum electrolytes, liver enzymes, lactate dehydrogenase, and uric acid were all within normal limits.

A maxillofacial and brain CT scan revealed bilateral destructive soft tissue masses in the region of the maxillary sinuses. Bilateral circumferential soft tissue densities were seen in the extraconal regions of the orbit with severe proptosis. There was also significant cervical lymphadenopathy. There were no intracranial masses.

Because these findings suggested a malignant process, CT scans of the chest, abdomen, and pelvis were obtained. The images did not show any abdominal masses, but they did reveal multiple supraclavicular and axillary nodes. Levels of urinary homovanillic acid and vanillylmandelic acid were within normal limits.

On the second hospital day, a transoral maxillary sinus biopsy was performed and bilateral bone marrow aspirates were obtained. The marrow specimen showed extensive replacement of normal hematopoietic elements by immature monocytic cells. These findings were consistent with acute myelogenous leukemia (AML), FAB M5b subtype. The biopsy specimen from the right maxillary sinus showed soft tissue infiltration with myeloid leukemic cells, consistent with a chloroma. The leukemic cells had a complex karyotype with duplication of 1p and 3p; t(15;18)(q15;q21); deletion of 6p23 and 20p13; unbalanced t(10;11)(q21;q23) with a derivative chromosome 10 and interstitial deletion of 11q23. Findings from cerebrospinal fluid examination were normal and did not demonstrate any evidence of meningeal leukemia.

DIFFERENTIAL DIAGNOSIS OF PROPTOSIS

This patient's progressive bilateral proptosis was asymmetric and occurred over a 3-week period. The differential diagnosis for this presentation is broad and includes infectious, oncological, and endocrine diseases, as well as other conditions (Table). The pediatrician initially diagnosed an allergic condition and a course of diphenhydramine was attempted without improvement. Periorbital edema and erythema are often signs of an allergic reaction, but proptosis is not an underlying feature.

Table

Our patient was afebrile but had periorbital erythema on presentation. An infectious process must be considered in such cases. Orbital cellulitis can be a complicating feature of sinusitis that can present with proptosis.^1,2 Patients often have fever, leukocytosis, and limited eye movement. Many cases are unilateral and can often lead to abscess formation in the orbital or subperiosteal space. Intraorbital abscesses in conjunction with bilateral sinus thromboses have also been described as a cause of proptosis^.3

Proptosis, or exophthalmos, secondary to thyroid ophthalmopathy (such as Graves disease) can present with symmetric, bilateral proptosis secondary to hypertrophy or inflammation of the extraocular muscles.⁴ The absence of other findings that suggest hyperthyroidism makes this diagnosis unlikely.

Orbital pseudotumors are inflammatory lesions within the orbit that are not neoplastic.^5,6 They are a significant cause of bilateral proptosis in adults,⁵ but there have also been reported cases in children. ⁷ Common presenting findings include proptosis, pain on eye palpation or movement, ptosis, periocular edema and erythema, chemosis, and diplopia.⁶ Our patient had proptosis but lacked many of the other features described above.

Neuroblastoma is the most common extracranial solid tumor in children and accounts for 8% to 10% of all childhood cancers.⁸ Presenting signs and symptoms depend on the location of the primary tumor and the extent of disease. Localized disease may be asymptomatic, whereas patients with metastatic disease may be severely ill with fever and bone pain. Eye involvement in patients with metastatic disease is a result of periorbital soft tissue infiltration of tumor, which can produce proptosis and periorbital hematoma or ecchymosis (commonly called "raccoon eyes").⁹

Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma; 40% of cases occur in the head and neck region. About 7% of cases of rhabdomyosarcoma arise from the orbit and manifest as proptosis and ophthalmoplegia.¹⁰ These are unilateral tumors.

Optic glioma is a primary neoplasm of the optic nerve. In children, it is mostly benign and is classified as a grade I astrocytoma. It may also be associated with neurofibromatosis type 1. Approximately one third of optic gliomas present with proptosis. Other symptoms may include decreased visual acuity, abnormal pupillary function, decreased color vision, and nystagmus. Proptosis is most common in children 6 years or younger.¹¹

Retinoblastoma is a malignant intraocular tumor of childhood that is associated with inactivation of the tumor-suppressor retinoblastoma gene. Patients may present with leukocoria, strabismus, or signs of intraocular inflammation.¹² Proptosis can be caused by orbital infiltration in advanced stages of the disease.

The histiocytoses include a group of diverse diseases that arise from proliferation of monocytes, macrophages, or dendritic cells. Unilateral proptosis usually results from osteolysis of the orbits by inflammatory mediators followed by mass effect from soft tissue extension into the orbital fossa. This can be seen, for instance, in Langerhans cell histiocytosis. ¹³ Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a rare, idiopathic, polyclonal histiocytosis that may also involve the orbits as a site of extranodal disease with resulting proptosis.¹⁴

Lymphoma is the third most common cancer in children and adolescents and accounts for 15% of all childhood cancers.¹⁵ When proptosis is the presenting symptom, the cause is usually Burkitt lymphoma. This presentation is more common with the endemic form of this cancer.

Acute myelogenous leukemia accounts for approximately one fifth of pediatric leukemias and is the seventh most common pediatric malignancy. ^16,17 AML typically presents with findings related to the involvement of the bone marrow. These include anemia, thrombocytopenia with a bleeding tendency, and fevers either from the disease itself, or from infection due to decreased production of mature granulocytes. Blasts are often, but not always, present in the peripheral blood. Although there were no peripheral blasts in our patient, the diagnosis may have been suggested by the slightly low platelet count.

At times, as in this case, AML may also present with an extramedullary collection of leukemic cells that form an isolated mass-a granulocytic sarcoma.¹⁸ This mass is also known as a chloroma because of its greenish appearance on gross examination, which is caused by the pigmented enzyme myeloperoxidase.¹⁹ When this mass is present within the orbit, the patient may present with proptosis, lid edema, and chemosis. Our patient had bilateral proptosis and lid edema as her manifestation of leukemic orbital involvement. Ocular involvement of leukemia as a chloroma may be either unilateral²⁰ or bilateral.²¹ Proptosis secondary to diffuse infiltration of the lacrimal gland and infiltration of individual extraocular muscles has also been described.^22,23

AML is commonly classified with the French-American-British (FAB) system, which divides AML into 9 different subtypes based on morphology and immunohistochemistry. In this case, the bone marrow identified features consistent with AML, FAB M5b subtype.²⁴ More recently, a new classification system has been developed by the World Health Organization, which includes the molecular and cytogenetic features of the leukemia.²⁵ Approximately 10% of patients fall into a poor prognosis group because of adverse genetic features of their leukemic cells. Included in this group are patients whose leukemic cells have complex karyotypes, such as that seen in our patient.²⁶

OUTCOME OF THE CASE

Our patient was treated according to a pilot protocol (AAMLO3P1) for patients with newly diagnosed AML.²⁷ In addition to chemotherapy, gemtuzumab ozogamicin, a monoclonal antibody against CD33 conjugated to calicheamicin (a potent antitumor antibiotic), was also administered during the first and fourth cycles of chemotherapy.²⁸

Our patient achieved remission after her first cycle of aggressive induction chemotherapy. She then received 4 additional courses of intensive chemotherapy. All therapy was completed and blood counts returned to normal within 7 months of diagnosis. Therapy has been discontinued for 18 months and the patient continues to do well-growing and developing normally.

Clinical Highlights, Teaching Messages

Proptosis in pediatric patients is a serious condition that must be evaluated thoroughly to determine the underlying pathological process. The differential diagnosis is broad and includes a variety of conditions such as infectious, oncological, and anatomic processes. Many of these conditions can present with unilateral or bilateral proptosis.

In a series by Oakhill and colleagues,²⁹ 27 children with unilateral proptosis were studied over an 8-year period. In 15 children (55%), malignancy was the underlying cause: rhabdomyosarcoma was the most common type identified (5 of 27 cases). In another study by Sindhu and coworkers,² hospital records were examined over a 10-year period to evaluate the cause in patients who presented with proptosis. No distinction was made between unilateral and bilateral proptosis in this study. Of 57 patients with proptosis, orbital cellulitis was the most common diagnosis: 22 cases (40%) were identified.

A careful history and a complete physical examination help narrow the differential and focus the workup. The rapidity of onset of the proptosis, the presence or absence of pain or inflammation, and any systemic signs are important factors in the evaluation. Imaging characteristics, laboratory or biopsy findings, and the response to treatment are other important components in the evaluation of children with proptosis.

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