Cytopathological Diagnosis of an Unusual Cause of Malignant Hydrocele.

Testicular involvement in a case of acute lymphoblastic leukemia (ALL) is well reported, but occurrence of "isolated" malignant hydrocele is extremely uncommon. We herein report a case of a 22-year-old man who presented to our hematology clinic with fever and easy fatiguability of 2 weeks' duration. Examination revealed pallor, cervical lymphadenopathy, and bilateral scrotal swellings. He was diagnosed as a case of Philadelphia-positive ALL (B-cell type) based on peripheral smear, bone marrow examination, and flow cytometry of the marrow aspirate. Ultrasonography of scrotum revealed bilateral hydrocele with normal testes. Cytopathological analysis of the hydrocele fluid showed the presence of lymphoblasts. The patient was treated with modified BFM-90 protocol along with imatinib mesylate (600 mg/day). He achieved complete remission with a minimal residual disease of <0.001% at the end of induction therapy. However, the hydrocele persisted and a repeat cytological examination of the aspirate did not reveal any lymphoblasts. The patient was treated with consolidation (high-dose methotrexate), bilateral testicular irradiation, and re-induction following which the hydrocele disappeared. The patient is currently on maintenance phase of BFM-90 protocol and is alive at one year of follow-up. Contiguous spread from the subclinical testicular involvement is hypothesized as the mechanism for development of hydrocele in the current case. The role of cytopathology in the early diagnosis of testicular involvement in ALL is emphasized here.

Introduction

Hydrocele in a young boy is generally perceived as a benign entity. Surprisingly, its appearance can be deceptive. Although testis represents an important site of relapse in cases of acute lymphoblastic leukemia (ALL), it is rarely involved at the initial presentation (2%).1 Due to frequent microscopic infiltration (21% cases at baseline diagnosis and 64%–92% at autopsy) and poor specificity and positive predictive value of ultrasonography (USG), testicular biopsy remains gold standard for the diagnosis of testicular ALL.2,3 Occurrence of malignant hydrocele is extremely uncommon in ALL. This report presents an unusual case of “isolated” malignant hydrocele in a patient with ALL diagnosed by fine-needle aspiration cytology (FNAC). Diagnosis of testicular ALL and its management are also discussed along with the role of FNAC as a surrogate for testicular biopsy.

Case Report

We report a case of a 22-year-old man of Indian origin who reported to us with easy fatiguability and fever of 2 weeks’ duration. He denied any cough, burning micturition, headache, and rash or bleeding from any site. On examination, he was febrile (oral temperature – 101 °F) and his vitals were blood pressure 118/62 mmHg, pulse rate 124/minute, and respiratory rate 20/minute. General examination was remarkable for severe pallor, bilateral level III cervical lymphadenopathy (2.5 × 2.5 cm), and hepatomegaly (4 cm). Rest of the systemic examination was normal. Genital examination revealed bilateral tense, nontender, and transilluminant scrotal swellings (Fig. 1). Testes could not be palpated separately. Laboratory investigations revealed Hb 77 g/L, white cell count 80 × 109/L with 90% circulating blasts, platelets 10 × 109/L, and erythrocyte sedimentation rate 55 mm/hour. Biochemical investigations revealed serum sodium 140 mmol/L, potassium 3.5 mmol/L, total calcium 2.3 mmol/L, phosphorous 1.0 mmol/L, uric acid 0.20 mmol/L, and lactate dehydrogenase 1200 U/L. Liver and renal function tests were normal. Chest X-ray and electrocardiogram were unremarkable. Bone marrow aspiration revealed 95% blasts that were characterized by flow cytometry as B-lymphoblasts (positive for CD19, CD10, CD34, CD45, CD38, TdT, cytoCD79a, and cytoCD22 and negative for CD20, CD13, CD33, CD117, CD3, CD4, CD5, CD8, and CD7). Cerebrospinal fluid examination did not reveal any malignant cells. Molecular analysis of bone marrow aspirate by reverse transcriptase polymerase chain reaction was positive for bcr-abl (t(9,22)) and negative for TEL:AML, AF4:MLL, and E2 A:PBX (t(12,21), t(4,11), and t(1,19), respectively). Contrast-enhanced computed tomography scan of abdomen was unremarkable for any intra-abdominal lymphadenopathy. USG of the scrotum revealed bilateral hydrocele with internal echoes and normal size and echotexture of testes. Sonography-guided aspirate of the hydrocele fluid was performed. Fluid was straw colored on gross examination, and cytopathological analysis of the cytospin smears revealed presence of large a typical cells with opened chromatin and prominent nucleoli consistent with lymphoblasts (Fig. 2). The patient was diagnosed as a case of Philadelphia-positive ALL (Ph+ ALL) with malignant hydrocele and was administered induction chemotherapy using modified BFM-90 protocol (consisting of cyclophosphamide, vincristine, daunorubicin, prednisolone, and l-asparaginase) for ALL along with imatinib mesylate (600 mg/day). Induction period was complicated by fungal sinusitis and necrotizing gingivitis, which were managed by liposomal amphotericin B (3 mg/kg/day) and antibiotics (meropenem [1 g q8 hourly] and vancomycin [1 g q12 hourly]), respectively, for a total duration of 2 weeks. A repeat examination of bone marrow aspirate done at the end of induction (after four weeks) did not reveal any lymphoblasts, suggesting a morphological remission. A six-color flow cytometric analysis of the marrow aspirate using leukemia-associated immunophenotypic markers revealed a minimal residual disease of <0.001%. Clinically however, the hydrocele persisted. A repeat cytological examination of the hydrocele fluid failed to identify any lymphoblasts. The patient was given consolidation with high-dose methotrexate (12 g/m2) and testicular irradiation followed by re-induction as per BFM-90 protocol. The patient’s hydrocele disappeared after the re-induction phase. The patient is currently on maintenance phase with vincristine (monthly), 6-mercaptopurine (75 mg/m2 daily), methotrexate (25 mg/m2 weekly), and prednisolone (60 mg/m2 for 5 days a month) along with three monthly intrathecal methotrexate doses and is under our regular follow-up.

Figure 1

Clinical photograph of the patient showing bilaterally enlarged, tense, and noninflamed scrotal sacs at the time of diagnosis. USG of the scrotum confirmed the presence of bilateral hydrocele.

Figure 2

A panel of microphotographs showing blasts with macrophages seen in lower three images of the panel from hydrocele aspirated fluid in a known case of leukemia (May Grunwald Giemsa (MGG) × 100 ×).

Discussion

ALL is the most common childhood cancer. Testis represents an important site of disease relapse and has been traditionally labeled as a “drug-sanctuary” site.4 Clinically overt testicular disease (OTD) occurs in 10%–23% cases at some time during the disease course (median 13 months from diagnosis).5 However, OTD at initial diagnosis is rare (1.1%–2.4%).6 Clinical, radiological (USG and MRI), and pathological (testicular biopsy) tools are available to diagnose testicular ALL. Importantly, testicular involvement may be occult, and microscopic infiltration has been demonstrated by bilateral wedge biopsies in 10%–33% patients at some time during first 3 years of therapy, 21% at the initial presentation and 64%–92% at autopsy. Therefore, testicular ALL frequently escapes clinical detection until organ enlarges to a significant size.2,5 Kayserili et al.3 reported results of USG (sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 75%, 50%, and 100%, respectively) for the diagnosis of testicular involvement in ALL. Considering the limitations of clinical and imaging techniques, testicular biopsy remains a gold standard for the diagnosis of testicular ALL. Malignant hydrocele has been reported in association with seminoma and mesothelioma of tunica vaginalis previously.7,8 Pre-operative cytological diagnosis in such cases may influence the choice of operative procedure (scrotal v/s inguinal). Occurrence of malignant hydrocele in ALL is extremely unusual. Even rarer is the presence of isolated hydrocele in a case of ALL without concomitant testicular enlargement. We could not find any case in the English literature documenting malignant hydrocele in a case of ALL. This may be due to the fact that cytological analysis of hydrocele fluid is performed and reported seldomly. In the setting of a testicular lump, the accompanying hydrocele goes unnoticed and orchidectomy is performed when the suspicion of testicular malignancy is high based on sonography findings. However, in situations when there is no accompanying testicular mass, cytoanalysis of hydrocele aspirate may provide an early diagnosis. Hydrocele in a case of testicular malignancy may arise due to either lymphatic occlusion by the lymph nodes/tumor or direct infiltration of malignant cells into the hydrocele cavity.7 Absence of intra-abdominal lymphadenopathy and normal testes ruled out first mechanism in our case. We hypothesize that our patient had microscopic testicular infiltration, not evident on USG, and malignant hydrocele resulted from contiguous spread. Presence of systemic symptoms (fever, easy fatiguability), enlarged cervical lymph nodes, organomegaly, and sudden appearance of bilateral hydrocele prompted an urgent FNAC of the hydrocele cavity in our case. Diagnosis of malignant hydrocele was successfully established by cytopathological analysis of the hydrocele aspirate, thereby avoiding the risk of trans-scrotal dissemination associated with testicular biopsy. Disappearance of lymphoblasts from the hydrocele cavity after induction therapy in our case explains its efficient penetration by the anticancer drugs. Consolidation with high-dose methotrexate led to disappearance of hydrocele in our case consistent with the reported effects of this drug on testicular ALL.9 Although there are no specific guidelines, extrapolating from data regarding testicular disease, we administered bilateral testicular irradiation to our case. Whether presence of bcr-abl is a risk factor for the development of malignant hydrocele needs to be validated in further studies. Present case not only describes an unusual finding of isolated hydrocele in a case of ALL but also highlights the role of FNAC as a relatively noninvasive method of providing a timely and accurate diagnosis, thereby avoiding the need for testicular biopsy. We summarize that although biopsy remains a gold standard to diagnose testicular involvement in ALL, in certain cases presenting with hydrocele (though rare), cytopathological examination of the fluid can act as a surrogate investigation and may avoid the need of an invasive procedure.