Atypical presentation and diagnostic pitfalls: a case of rapidly progressive bilateral proptosis in a child aged 18 months.

We report an atypical presentation of non-Hodgkin lymphoma (NHL) in a child aged 18 months who presented with rapidly progressive bilateral proptosis. Computerized search using Medline did not reveal a similar presentation of NHL in such a young child. It stresses the need for an early histopathological study including immunohistochemistry and demonstrates the dramatic local response to combined radiotherapy and chemotherapy even in advanced stages without any ocular side-effects.

There has been a progressive increase1 in the incidence of lymphoma over the years with frequent reports of varying and atypical presentations and a bewildering number of confusing classifications which still do not fit all the cases. This is especially true with respect to non-Hodgkin lymphoma (NHL). This case report discusses the difficulties encountered in diagnosis, the need for an early incisional biopsy and a complete immunohistopathological study with all the markers. It also highlights the fact that lymphomas respond dramatically to combined radiotherapy and chemotherapy.

Case History

An 18-month-old female child presented with a history of rapidly increasing prominence of both eyes of two months duration. It was first noticed in the left eye, the right eye was involved two to three days later. The child had occasional fever and did not have any major eye or systemic disease before the onset of prominence of the eyes. Her brother, five years old, was healthy.

The child weighed 9 kg and was afebrile. Examination of the eyes revealed an axial proptosis which measured 22 mm right and 23 mm left eye at an outer intercanthal distance of 82 mm. Lid edema, prominent vessels over the lids and lagophthalmos were more pronounced in the left than the right eye [Fig. 1]. There was gross congestion and chemosis of the conjunctiva and exposure keratitis in the left eye. The conjunctiva was mildly congested in right eye and the cornea was clear. Ocular motility was restricted in all directions of gaze in both eyes. Pupils were normal and reactive in both the eyes and vision appeared normal. Fundus examination of right eye revealed a normal optic disc but the left eye showed an edematous disc. Based on clinical findings, neuroblastoma, granulocytic sarcoma, multifocal eosinophilic granuloma and inflammatory pseudotumor were considered in the differential diagnosis.

Figure 1

Clinical appearance, A and B - at presentation, C - immediately after incision biopsy and D - 2.5 months after starting therapy

Blood examination revealed hemoglobin of 10.9 gm%, erythrocyte sedimentation rate (ESR) of 35 mm, bleeding time of 1 min 25 sec and clotting time of 7 min 02 sec and blood counts were normal. Peripheral blood smear showed microcytic hypochromic picture without any abnormal or atypical cells and adequate platelets. Routine ENT and pediatric referral did not reveal any abnormality. Chest X-ray was normal. Computerized tomography [Fig. 2] showed diffuse infiltration of the orbit and erosion of medial wall of the orbit bordering the nose and lateral wall of the nose bordering the infratemporal fossa on both sides. Adjacent paranasal sinuses were normal. A malignant lesion was suspected and orbital biopsy was advised.

Figure 2

Computerized tomography showing erosion of medial orbital walls into nose and lateral wall of the nose bordering infratemporal fossa on both sides

An incisional biopsy was done from both orbits to confirm a single bilateral etiology. Histopathological sections [Fig. 3] study showed solid sheets of predominantly undifferentiated cells along with a few interspersed elongated and fusiform cells with central nucleus and eosinophilic cytoplasm. The undifferentiated cells were round to elongated with large pleomorphic nucleus and prominent single to multiple nucleoli with numerous atypical mitosis. Amidst these there were also a few vacuolated cells. These features favored the diagnosis of undifferentiated rhabdomyosarcoma. Immunohistochemistry was advised to confirm the diagnosis. Bone marrow was positive for malignant cells and cerebrospinal fluid showed metastasis to the brain. Ultrasound scan of the abdomen and pelvis showed hepatomegaly with multiple small hypoechoic lesions. Renal function tests were normal. Serum calcium (12 mg/dl) and phosphorus (7 mg/dl) were slightly higher than normal. Liver function tests were normal except serum alanine transaminasae (50 U/L).

Figure 3

H and E staining A (10X), B (40X) showing solid sheets of predominantly undifferentiated cells along with a few interspersed elongated and fusiform cells with central nucleus and eosinophilic cytoplasm. The undifferentiated cells are round to elongated with large pleomorphic nucleus and prominent single to multiple nucleoli with numerous atypical mitosis. Few vacuolated cells are also seen. Positive Leukocyte Common Antigen (C) and Vimentin stains (D)

In consultation with an oncologist a multimodal treatment was planned with radiotherapy and chemotherapy. As the patient′s left eye was at risk due to exposure keratitis and papilledema, it was decided to start local external beam irradiation followed by chemotherapy. A total of 46 cGy with 180 cGy per fraction were given over a period of five weeks. Lens was shielded from exposure to radiation. Chemotherapy was planned as per IRS-IV protocol with injection vincristine 1.5 mg/ m2 IV weekly for 12 weeks and on Week 16, injection dactinomycin 0.015 mg/Kg/day from Day 1 to Day 5, every three weeks up to 16 weeks, injection cyclophosphamide 2.2 g/m2 with mesna 440mg/m2 for one day per cycle every three weeks up to 16 weeks. Chemotherapy was interrupted due to anemia and low neutrophil counts requiring blood transfusion. Proptosis completely disappeared, the exposure keratitis of the left eye healed and disc edema totally subsided 2.5 months after starting therapy [Fig. 1]. Patient did not have any visual deficit in either eye. Unfortunately, patient expired 6.5 months after she was first seen in our hospital due to central nervous system infiltration. She did not develop any complications due to radiation during her follow-up.

As this was an unusual presentation, tissue block was sent for immunohistochemistry with an academic interest. The markers2 used were Cytokeratin (epithelial tumors), Vimentin (mesenchyme-derived neoplasms including lymphomas, melanomas, some sarcomas and certain neural tumors), Leukocyte Common Antigen (lymphoma), CD20 and CD79A (B-cell neoplasms), CD3, CD43 and CD 99 (T-cell neoplasms), CD 30 (anaplastic large cell lymphoma and Hodgkin disease), Desmin (rhabdomyosarcoma), Synaptophysin (neuroblastoma), Myeloperoxidase (granulocytic sarcoma), HMB45 (melanoma), TDT (lymphoblastic lymphomas and leukemia) and Ki-67 (proliferation-related marker). It was negative for all markers except Vimentin and Leukocyte Common Antigen [Fig. 3]. KI 67 was 60 to 70% positive. The immunohistochemistry report was unclassifiable high-grade NHL.3

Discussion

Lymphomas are solid malignant neoplasms that originate from leukocytes, mostly lymphocytes, dendritic histiocytes and plasma cells. Lymphoma occurs most commonly in lymph nodes and primary lymphoid tissue but also in extranodal sites, including the orbit, skin oropharynx, gastrointestinal tract and bone marrow. Systemic NHL in adults is usually seen in the fifth or sixth decade and presentation in childhood is extremely rare.4

Most orbital lymphomas are NHL and tend to present in the sixth and seventh decade and present anteriorly in the orbit.4 Presentation before the age of 20 is rare.4 In one reported case series,1 although NHL was the most frequent malignant tumor of the eye and ocular adnexae (55%), the youngest patient was 15-years-old (15 to 96) and the median age was 71 years.

In another review5 of 145 patients of lymphoma orbit and/ adnexa and/ocular, the youngest patient was three-years-old (three to 96 years) and the median age was 66 years and 10% were bilateral. Exophthalmia was seen in 27%. Kodsi et al. in their review of 340 orbital tumors in children found only 18.2% of them to be malignant6 (11.5% primary and 6.8% metastatic). Among 62 malignant tumors rhabdomyosarcoma (24) was the most common malignant neoplasm, with lymphoma (five) much less frequent.

Most of the lymphomas of the eye and its adnexa are NHL of B-cell type.7 Computed tomography demonstrates the molding of the mass to orbital structures, such as the globe and orbital bones, without bony erosion except in large cell lymphoma.4

Radiotherapy is effective in indolent forms and chemotherapy is applied in aggressive lymphomas and a combination of radio- and chemotherapy may even be more effective.8 The presence of bilateral involvement, extension to the subcutaneous tissue or temporalis fossa is associated with increased risk of dissemination.9 Higher grade and destruction of orbital wall suggest a poor prognosis.10

In conclusion, it was a rare presentation of a primary orbital NHL in a child aged 18 months presenting as rapidly progressive bilateral axial proptosis with an early metastasis. In this case the tumor was so poorly differentiated that it couldn′t be classified.3 Bony erosion of orbital and nasal wall instead of molding to the adjoining structures was seen. There was no radiation-induced complication in the eye with the dosage given, over a follow-up period of 6.5 months.