Intracranial inflammation-rich germinoma mimicking haematological neoplasms: a diagnostic pitfall

Central nervous system (CNS) germinoma is a rare primary intracranial tumour that is pathologically composed of two distinct cell populations: large epithelioid tumour cells with round nuclei and prominent nucleoli, and small mature-appearing lymphocytes which typically outnumber the germinoma cells. Rarely (<5%) intracranial germinomas may elicit a granulomatous reaction, which may herald a better prognosis, and mask the scarce tumour cells, potentially leading to misdiagnosis. Herein, we present two cases of inflammation-rich CNS germinoma: one arose in a 43-year-old man with scattered large germinoma cells embedded in a dense B-cell infiltrate mimicking a Hodgkin lymphoma or small B-cell lymphoma; the other arose in a 19-year-old woman with scattered neoplastic cells associated with sheets of histiocytes, mimicking a histiocytic neoplasm or histiocytosis.

Case 1 was a 43-year-old man with a history of hypothyroidism that was treated with levothyroxin. He suffered from 1 year of poor memory, which worsened in the previous 2 months. He then developed polydipsia with polyuria. Laboratory chemistry studies showed findings consistent with diabetes insipidus, including hypernatraemia (Na, 167 mEq/L; normal range 136–145), hypokalaemia (K, 2.2 mEq/L; normal range 3.5–5.1), raised plasma osmolality (335 mOsm/kg), lower urine osmolality (520 mOsm/kg), urine sodium (47 mEq/L) and a low urine specific gravity (1.003). The hormone profile examination revealed panhypopituitarism but hyperprolactinaemia (prolactin, 42.93 ng/mL; normal range 3.46–19.4). Brain magnetic resonance imaging (MRI) showed an enhancing mass lesion, 3.3×3.1×2.7 cm in the sella and suprasellar region (Fig. 1A), and radiological considerations were craniopharyngioma, pituitary macroadenoma or other entities. On ophthalmological examination, a right eye total visual field defect was found. The patient underwent incomplete surgical excision of the mass and the tumour was grey, soft and well-capsulated with oozing.

Histological examination of the neoplasm showed a predominant small lymphocytic infiltrate without formation of germinal centres (Fig. 1B). In addition, large tumour cells were dispersed in the infiltrate. These large cells had vesicular nuclei, occasional conspicuous nucleoli, and abundant pale amphophilic cytoplasm (Fig. 1C). Lymphoma was considered initially, such as classical Hodgkin lymphoma or anaplastic large cell lymphoma, based on the morphological features. Immunohistochemical studies showed that the small lymphocytes were predominantly B-cells, positive for CD20 (Fig. 1D) with only a subset being CD3-positive (Fig. 1D, inset). Furthermore, the large tumour cells were negative for CD3, CD15, CD20, CD30, CD45, ALK and TdT. In situ hybridisation for Epstein–Barr virus-encoded RNA (EBER) was negative. Molecular studies to assess IGH genes showed no evidence of clonal rearrangement with a polyclonal smear pattern. Further review of the slides led to the consideration of germinoma. Immunohistochemical analysis showed that the large tumour cells were positive for SALL4 (Fig. 1E), OCT3/4 (Fig. 1F) and CD117 (c-KIT, Fig. 1G), confirming the diagnosis.

After the operation, spinal MRI showed no apparent lesion. The patient received radiation therapy of the entire ventricular system with a dose of 23.4 Gy in 13 fractions, followed by focal tumour boost to a total dose of 43.4 Gy in 23 fractions. The tumour responded well to radiotherapy and MRI revealed complete resolution of the tumour. At last follow-up, 28 months after diagnosis, there was no evidence of recurrence.

Case 2 was a 19-year-old woman who had 3 weeks of intermittent fever (38°C), headache, and blurred vision with haemianopia, accompanied with irregular menorrhoea for more than 1 year. Laboratory data showed a normal complete blood count and normal chemistry test results, but an elevated prolactin level (105.6 ng/mL; normal range 6–29.9). MRI revealed a suprasellar enhanced tumour, 2.8×2.1×1.6 cm (Fig. 2A). Tumour excision was performed and pathological examination showed a tumour composed predominantly of sheets of histiocytes arranged in nodular aggregates (Fig. 2B) associated with foci of necrosis (Fig. 2C, right) and small lymphocytes. Scattered large cells were also present (Fig. 2D). Acid-fast and PAS histochemical stains were negative. Immunohistochemical analysis showed that most cells were histiocytes positive for CD68 (Fig. 2E) and CD163, focally positive for S-100 (Fig. 2E, inset), and negative for CD1a, CD21 and CD30. B-lymphocytes and T-lymphocytes were evenly mixed with histiocytes, highlighted by CD20 and CD3 staining, respectively. In situ hybridisation for EBER was negative. Only few histiocytoid cells were weakly positive for CD117 (Fig. 2F). At that time, germinoma was not suggested due to rare CD117-positive cells and, instead a histiocytic proliferative lesion (histiocytosis) was suggested. After operation, the patient kept regular follow-up in outpatient department without further treatment.

Six months later, temporal haemianopia and an elevated prolactin level reappeared. MRI showed a recurrent suprasellar tumour and the neoplasm was excised. The specimen showed a histiocyte-rich lesion with necrosis as shown previously. There were also many tumour cells with a distinct cell membrane, a large nucleus and clear cytoplasm (Fig. 2G). These cells were divided into poorly demarcated lobules by lymphocyte-infiltrated fibrous septa. Immunohistochemical analysis showed that the neoplastic cells were positive for CD117 (Fig. 2H) and PLAP (Fig. 2I). Therefore, a diagnosis of germinoma was established, and a review of the previous specimen found that the large cells shown in Fig. 2D were also germinoma cells, although few and scattered. After the operation, the patient received four cycles of BEP (bleomycin, etoposide, and cisplatin) chemotherapy and two cycles of EP (etoposide plus cisplatin) and radiotherapy. Unfortunately, a new tumour mass was noted 3 years later which was excised at another hospital. A diagnosis of anaplastic astrocytoma was rendered (Fig. 3) and based on the current 5th edition of the World Health Organization (WHO) classification of CNS tumours, it should be deemed as radiation-associated diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. She received temozolomide therapy. In the next 3 months, the patient had many seizures. Computed tomography (CT) scan showed one mass lesion around the basal ganglia and a residual glioma was suspected. After admission, anticonvulsant, dexamethasone and mannitol were administered for management of seizures and elevated intracranial pressure. However, there were still episodes of seizure, accompanied by electrolyte imbalance and worsened conscious disturbance. The patient died 5 years after her initial presentation with symptoms.

Gonadal germinoma, together with nasopharyngeal carcinoma, melanoma and renal cell carcinoma, is a highly immunogenic tumour and can elicit a strong anti-tumoural immune response composed predominantly of lymphocytes and histiocytes. This phenomenon is rare in intracranial germinoma with a reported frequency of around 4.5%. Knowledge of this immune response is important as the inflammatory cells may mask the neoplastic cells possibly leading to a misdiagnosis of lymphoma, sarcoidosis, granulomatous inflammation or histiocytic neoplasm.^{,  ,  ,} 

CNS germ cell tumours account for 2–3% of all primary intracranial neoplasms in eastern Asia. About 70% of patients are between the ages of 10 and 24 years and 73% are male. The most common type is germinoma (41%), followed by mixed germ cell tumours (32%) and teratoma (20%). About 80% of CNS germ cell tumours arise along the midline, extending from the pineal gland to the suprasellar region. Pathologically, germinomas are characterised by large neoplastic cells showing a central nucleus with one or more prominent nucleoli surrounded by abundant clear cytoplasm. In addition, these tumours usually contain numerous infiltrating lymphocytes. In most (∼75%) cases, the infiltrating lymphocytes are seen adjacent to nests of neoplastic cells imparting a two-component pattern. In the remaining cases (∼25%), lymphocytes overwhelmingly outnumber few and isolated neoplastic cells, which therefore may mimic a lymphoma or lymphocytic hypophysitis. The reactive lymphocytes in germinomas are usually dominated by T-cells, but B-cells and plasma cells may be conspicuous, suggestive of a humoral immune response against the neoplastic cells. In the first case we report, there were dense lymphocytic infiltrates and a few large anaplastic cells, which had some resemblance to Hodgkin and Reed–Sternberg cells in classic Hodgkin lymphoma or anaplastic large cell lymphoma at a glance. The subsequent immunohistochemical analysis showed extremely numerous B-cells in the background where CD20-labelled cells outnumbered CD3-labelled cells, mimicking a B-cell lymphoma. However, the B-cells were polyclonal, shown by molecular assessment of IGH. In addition, further immunohistochemical analysis clarified the nature of the large tumour cells, which argued against a diagnosis of lymphoma.

Germinoma can also provoke an intense granulomatous response, as illustrated in the second case we report. The frequency of a granulomatous response in CNS germinoma has been reported as 2.9–4.3%.^, When the neoplastic cells are greatly outnumbered by histiocytes, there is potential for diagnostic error such as sarcoidosis, granulomatous hypophysitis or histiocytic neoplasm (histiocytosis). However, the clinical manifestations (age and sex) and typical imaging findings (a well-defined enhancing mass) are helpful clues to the correct diagnosis. As shown in Case 2, in retrospect, any CD117 (c-KIT)-positive cells in the sellar region of children or young adults should lead to the diagnosis of germinoma being seriously considered with an appropriate workup. Immunohistochemical analysis to assess germinoma-associated markers such as SALL4, OCT3/4 and PLAP is very helpful.

In conclusion, we present two cases of germinoma that had a florid reactive inflammatory reaction of lymphocytes and histiocytes, mimicking lymphoma and a histiocytic neoplasm, respectively. Pathological specimens obtained by CNS biopsy or partial excision are sometimes very small. It is important to avoid performing many haematological markers by immunohistochemical analysis so that the specimen will not be exhausted. These two cases serve as a reminder to pathologists that germinoma can contain numerous lymphocytes and histiocytes and mimic a haematological neoplasm.