Two cases of pinealgerminoma withgranulomatous inflammation

Kyung-Sub Moon1MDMD, Shin Jung1

MD PHDMD PHD,

Min-Cheol Lee2 MD PHDMD PHD, Hyo-Cheol Cheon1MDMD,

In-Young Kim1MDMD, Jung-Kil Lee1 MD PHDMD PHD,

Tae-Sun Kim1MD PHDMD PHD, Sam-Suk Kang1

MD PHDMD PHD

1Department of Neurosurgery, 2Department of Pathology, Chonnam National

University Research Institute of Medical Sciences, Chonnam National

University Hospital and Medical School, Gwangju, South Korea

Summary We report two cases of pineal germinoma with remark-

able chronic granulomatous inflammation. In the first case, the pineal

mass was totally removed via an occipital transtentorial approach as

symptoms were due to direct mass effect. In the second case,

endoscopic third ventriculostomy and tissue biopsy was performed to

alleviate worsening hydrocephalus. Pathological examination of

specimens of both cases showed chronic granulomatous inflamma-

tion associated with a few germ cell tumor nests, which demon-

strated positive staining for placental alkaline phosphatase. Both

patients received post-operative craniospinal irradiation with no

subsequent neurological deficits. Follow-up magnetic resonance

imaging (MRI) of the second case showed an asymptomatic,

shrunken residual tumor mass. MRI of the first case showed no

residual or recurrent disease. Thus, a pineal mass with unusual

features on MRI and chronic granulomatous inflammation on histo-

pathology, should raise the suspicion of germinoma. In cases with

symptomatic mass effect, open resection can be considered. In

cases with lesser mass effect, conventional therapeutic modalities

without resection can achieve a good outcome, as for other germi-

nomas.

ª 2004 Elsevier Ltd. All rights reserved.

Journal of Clinical Neuroscience (2005) 12(3), 310–313

0967-5868/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jocn.2004.05.018

Keywords: germinoma, granulomatous inflammation, magnetic

resonance imaging, pineal gland, surgery, treatment

Received 21 April 2004

Accepted 28 May 2004

Correspondence to: Shin Jung MD, Department of Neurosurgery, Chonnam

National University Hospital, 8 Hack-Dong, Dong-Ku, 501-757, Gwangju,

South Korea. Tel.: +82 62 220 6606; Fax: +82 62 224 9865;

E-mail: sjung@chonnam.ac.kr

INTRODUCTION

Tumors of the pineal region are uncommon and account for 0.5–1% of intracranial neoplasms in adults, although there is a higherincidence of 3.2% in Japan and these tumors are 10 times morecommon in children than in adults.1,2 The majority of patientspresent with symptoms of intracranial hypertension due toobstructive hydrocephalus. Presentation may also be due to pres-sure on, or direct infiltration of, adjacent structures.3

The diagnostic tool of choice for pineal tumors is magnetic res-onance imaging (MRI), which can give preliminary informationon both the histological type and extent of disease. However,due to the diversity of tumors that occur in the pineal region, a

conclusive preoperative diagnosis is not possible, even withMRI, cerebrospinal fluid (CSF) cytology and tumor marker anal-ysis of blood and CSF. Thus, tissue diagnosis is essential.4 Distin-guishing germinoma from other tumors is particularly importantas they are highly radiosensitive and can be cured by conventionalradiation therapy alone. Tumor specimens for diagnosis may beobtained through direct operative approaches, stereotactic biopsy,or endoscopic biopsy.3–6 Selection of operative modality iscontroversial.Germinoma of the central nervous system is a rare germ cell tu-

mor usually arising in the pineal gland, the floor of the third ven-tricle and/or the suprasellar region. The embryological origin ofthese tumors is unknown, but current theories implicate an aberra-tion in primordial germ cell migration. Ultrastructural studies re-port that the morphological features of intracranial germinoma areidentical to those of germinoma (seminoma) elsewhere in thebody.7 Seminomas are usually accompanied by granulomatousinflammation, but thus is infrequent (4.7%) in intracranial germi-nomas.8 The granulomatous reaction in seminoma is usually notso extensive as to obscure the diagnosis. However, rarely the reac-tion is so pronounced in cerebral germinomas that there is diag-nostic confusion.9–11 In addition, the efficacy of radiationtherapy in granulomatous germinoma is unknown.We present the atypical radiological findings and therapeutic

strategies in pineal germinoma with chronic granulomatousinflammation.

CASE REPORTS

Case 1

A 19-year-old man sought medical attention for intermittentheadaches, which had worsened over six months and were asso-ciated with nausea and diplopia. Physical examination revealedno impairment of mental status or gait and no sensory or motordeficits. Extraocular movements were full however diplopia wasaggravated on upward gaze. Ophthalmologic examination re-vealed no papilledema. An MRI scan demonstrated a 3 · 2 · 2cm mass in the pineal region. The lesion showed heterogeneoushypointensity on T1- and T2-weighted images (Fig. 1(a)) andheterogeneous enhancement after administration of gadolinium(Fig. 1(b)). The mass was multilobulated, surround by edemaand extended into both the thalamus and midbrain. Serum a-fetoprotein was elevated (2.30 ng/ml, normal 0.0–0.7). No otherhematological or biochemical abnormalities were found, andother tumor markers including human chorionic gonadotrophin(HCG) and carcinoembryogenic antigen (CEA) were within nor-mal limits. Surgery was performed via the occipital transtentorialapproach as a non-germinomatous pineal tumor was consideredin the differential diagnosis and there were symptoms of masseffect. At operation, a hard, gray mass was located in the pinealgland and the posterior third ventricle, which was easily demar-cated from the peritumoral brain. Some cystic areas were pres-ent. Frozen section examination of biopsies taken frommultiple sites showed only chronic granulomatous inflammation.The mass was totally removed without injury to the hypothala-mus, brain stem or neighboring vessels. Examination of paraffinsections showed typical chronic granulomatous inflammationconsisting of aggregates of epithelioid histiocytes, focal non-caseating necrosis and multinucleated giant cells (Fig. 2(a)). Ina few areas there were germ cell nests, which were composedof large cytoplasm-rich neoplastic cells with reactive lympho-cytic infiltrates (Fig. 2(b)). Examination for a-fetoprotein,b-HCG, CEA, and placental alkaline phosphatase (PLAP) asmarkers of germ cells was performed; lysozyme for epithelioid

Journal of Clinical Neuroscience (2005) 12(3) ª 2004 Elsevier Ltd. All rights reserved.

310 Moon et al.

cells and pan-T and pan-B antigen for infiltrating lymphocyteswas also examined. Epithelioid cells were positive for lysozyme,infiltrating lymphocytes were positive for Pan-T, indicating theywere T lymphocytes and germ cell nests showed positive immu-nostaining for PLAP. Thus, the diagnosis was germinoma withchronic granulomatous inflammation. Post-operatively, thepatient received whole neuraxis radiation therapy and two yearslater, was free asymptomatic without recurrence of the mass onfollow-up MRI (Fig. 1(c) and (d)).

Case 2

A 22-year-old man was admitted to our hospital with sudden dete-rioration of mental status and vomiting. One month earlier, he had

developed intermittent headaches. On examination he was drowsywith upward gazing limitation but no other neurological deficits.MRI demonstrated a 3 · 2 · 2 cm mass in the pineal region.The lesion showed heterogeneous hypointensity on T1- and T2-weighted images (Fig. 3(a)) and heterogeneous enhancement afterthe administration of gadolinium (Fig. 3(b)). The mass was mul-tilobulated with associated obstructive hydrocephalus. The serumb-HCG was elevated (11 mIU/ml, normal 0.0–5.0). There were noother hematological or biochemical abnormalities and other tumormarkers including a-fetoprotein and CEA were in the normalrange. Endoscopic third ventriculostomy and biopsy was per-formed as we suspected symptoms were primarily due to hydro-cephalus. Frozen section examination of biopsy samples showedonly chronic granulomatous inflammation. Paraffin section

Fig. 1 Case 1. (a) Preoperative T2-weighted axial MRI demonstrates a mixed hypointense tumor in the pineal gland with peritumoral edema. (b) Preoperative

axial gadolinium-DTPA-enhanced T1-weighted MRI shows heterogeneous enhancement with cystic components. (c) T1-weighted axial MRI and (d) gadolinium-

DTPA-enhanced T1-weighted axial MRI two years after surgery, reveal no residual or recurrent tumor.

Fig. 2 Case 1. (a) Chronic granulomatous inflammatory area of tumor consisting of histiocytes, multinucleated giant cells and small lymphocytes. The arrow

indicates a small germ cell nest (Hematoxylin and eosin, original magnification 40·). (b) Small foci of germ cells showing prominent nucleoli and clear cytoplasm

(Hematoxylin and eosin, original magnification 200·).

ª 2004 Elsevier Ltd. All rights reserved. Journal of Clinical Neuroscience (2005) 12(3)

311Pineal germinoma with granulomatous inflammation

examination showed typical chronic granulomatous inflammationand a few germ cell nests that demonstrated positive reactions foronly PLAP of the germ cell markers. The lesion was diagnosed asa germinoma with chronic granulomatous inflammation. After thebiopsy, the patient received whole neuraxis radiation therapy and2 years later he is asymptomatic with a small, subtle enhancingresidual mass on serial follow-up MRI (Figs. 3(c) and (d)).

DISCUSSION

Germinoma is the most common tumor in the pineal region andconstitutes up to 50% of all pineal tumors. It is characterized bythe presence of two types of cells: large primitive germ cells withabundant clear cytoplasm and sharp cytoplasmic borders, andsmall reactive lymphocytes.12 Granulomatous inflammation sur-rounding germinomas is a recognized feature of both gonadaland extragonadal germinomas, and is thought to be a reflectionof the host immune response to the neoplasm. The majority ofthe lymphocytes within germinoma tissue bear the surface anti-gens of T lymphocytes. Tumor infiltrating lymphocytes representa spontaneous cytotoxic capacity against tumor cells, thus theymay play a role in the regulation of tumor proliferation and in tu-mor surveillance.13 Furthermore, T lymphocytes produce chemi-cal mediators including tumor necrotic factor (TNF) andinterferon-c (IFN-c) that induce the adhesion and aggregation ofmonocytes (inducing the activated macrophages or epithelioidcells of granulomas) and increase DNA synthesis. Taken together,T lymphocytes not only exhibit autologous tumor cell killingactivity but also may be involved in granuloma formation ingerminomas.14

On MRI, germinomas are usually isointense or minimally hyp-ointense to gray matter on T1-weighted sequences and isointenseto slightly hyperintense on T2-weighted sequences. On bothT1- and T2-weighted imaging, a germinoma is generally a homo-geneous mass consistent with dense cellularity. Gadoliniumadministration produces marked, homogeneous enhancement.Small cysts are identified in 20–50% of cases.15 Cystic compo-nents and heterogeneous enhancement suggest heterogeneity intumor histology and suspicion of a non-germinomatous germ celltumor.16,17

As a wide variety of histological types of tumors occur in thepineal region, histological diagnosis is essential for optimal pa-tient management. Although CSF cytology, tumor marker exami-nation of blood and CSF and radiological features can besomewhat predictive of tumor type, management decisions,including the choice of adjuvant therapy, estimation of prognosisand the need for investigation for metastases, depend on accurateknowledge of the histological subtype. Tumor specimens for diag-nosis may be obtained through a variety of direct operative ap-proaches, or alternatively, by stereotactic or endoscopic biopsy.Open surgery allows resection and possibly improvement of theresponse to adjuvant therapy in malignant tumors (pineoblastoma,malignant teratoma, malignant germ cell tumors) and generallyclearly establishes a histological diagnosis. Benign tumors, whichcomprise one-third of all pineal tumors (teratoma, meningioma,pineocytoma, ependymoma) can be managed with surgery alone.The occipital transtentorial approach allows simultaneous internalshunting to resolve occlusion of the aqueduct.3,5

Germinomas rapidly respond to radiation therapy with a lowrecurrence rate. Therefore, biopsy alone should be used in cases

Fig. 3 Case 2. (a) Preoperative T2-weighted axial MRI demonstrating a mixed hypointense tumor in the pineal gland with ventricular dilatation due to

obstructive hydrocephalus. (b) Preoperative axial gadolinium-DTPA-enhanced T1-weighted MRI showing heterogeneous enhancement with cystic components.

(c) Gadolinium-DTPA-enhanced T1-weighted axial MRI, one year after radiation therapy, revealing marked reduction in tumor size to a small enhancing

residual tumor. (d) Serial gadolinium-DTPA-enhanced T1-weighted axial MRI, two years after radiation therapy, with further reduction of the residual mass.

Journal of Clinical Neuroscience (2005) 12(3) ª 2004 Elsevier Ltd. All rights reserved.

312 Moon et al.

where suspicion of pure germinoma requires confirmation.3 Inac-curacy or uncertainty in the diagnosis of pineal germinoma mayoccur due to the incidence of mixed tumor types4 or coexistentgranulomatous inflammation.9–11 Both may be subject to samplingerrors with stereotactic biopsy as there is no reliable method to dif-ferentiate histologically different regions or areas of granuloma-tous inflammation on imaging.11 Immunohistochemical studiesusing PLAP can be useful to distinguish germinoma from granu-lomatous disease, supported by histopathology.9,10 However, Krai-choke et al.11 reported the unreliability of PLAP in germinomawith granulomatous inflammation and that repeated biopsy or opencraniotomy may be required for histologic diagnosis. Although fewtumor cells (<5% of total specimen) were found in our cases, thegerm cell nests showed positive staining for PLAP.Response of pineal germinoma with granulomatous inflamma-

tion to radiation therapy has not been investigated. Although theefficacy of radiation therapy for the granulomatous inflammationis unclear, this portion of the tumor is likely to be reduced afterconventional radiation therapy to the germinoma component, asoccurred in our second case, as the granulomatous inflammatoryprocess is likely to reflect the host immune response to the neo-plasm. In these cases, despite the possibility of early decompres-sion via open surgery, conventional therapeutic regimens,including biopsy and radiation therapy, are likely to produce goodresults in pineal germinomas with granulomatous inflammation.

CONCLUSION

A germinoma with chronic granulomatous inflammation shouldbe strongly suspected when a pineal mass on MRI demonstratesheterogeneous hypointensity on T1- and T2-weighted imagesand heterogeneous enhancement in the pineal mass and histopa-thology demonstrates chronic granulomatous inflammation. Histo-pathological confirmation should be attempted by careful serialsections of all biopsy specimens to identify neoplastic cells.Open surgery may be considered for germinoma with chronic

granulomatous inflammation to immediately treat mass effect,but where treatment of mass effect is not urgent, biopsy and radi-ation therapy may achieve good results as for other germinomas.

REFERENCES

1. Abay 2nd EO, Laws Jr ER, Grado GL, et al. Pineal tumors in children andadolescents: treatment by CSF shunting and radiotherapy. J Neurosurg 1981;55: 889–895.

2. Sano K. Pineal and posterior third ventricular tumors: a surgical overview. In:Apuzzo MLJ, editor. Surgery of the Third Ventricle. Baltimore, MD: Williams& Wilkins; 1998. p. 801–819.

3. Konovalov AN, Pitskhelauri DI. Principles of treatment of the pineal regiontumors. Surg Neurol 2003; 59: 250–268.

4. Edwards MSB, Hudgins RJ, Wilson CB, Levin VA, Wara WM. Pineal regiontumors in children. J Neurosurg 1988; 68: 689–697.

5. Bruce JN, Stein BM. Surgical management of pineal region tumors. ActaNeurochir (Wien) 1995; 134: 130–135.

6. Dempsey PK, Kondziolka D, Lunsford LD. Stereotactic diagnosis andtreatment of pineal region tumors and vascular malformations. Acta Neurochir(Wien) 1992; 116: 14–22.

7. Scheithauer BW. Neuropathology of pineal region tumors. Clin Neurosurg1985; 32: 351–383.

8. BurgerPC,ScheithauerBW.Tumors of theCentralNervousSystem. Washington,DC: Armed Forces Institute of Pathology; 1993, pp. 251–257.

9. Gotoda H, Fujita M, Inoue K, et al. Cerebral germinomas with markedgranulomatous inflammation: granulomatous germinomas. Neuropathology1996; 16: 165–171.

10. Konno S, Oka H, Utsuki S, et al. Germinoma with a granulomatous reaction:problems of differential diagnosis. Clin Neuropathol 2002; 21: 248–251.

11. Kraichoke S, Cosgrove M, Chandrasoma PT. Granulomatous inflammation inpineal germinoma: a cause of diagnostic failure at stereotaxic brain biopsy. AmJ Surg Pathol 1988; 12: 655–660.

12. Jellinger K. Primary intracranial germ cell tumors. Acta Neuropathol 1973; 25:291–306.

13. Vaquero J, Coca S, Magallon R, Ponton P, Martinez R. Immunohistochemicalstudy of natural killer cells of tumor infiltrating lymphocytes of primaryintracranial germinoma. J Neurosurg 1990; 72: 619–625.

14. Zhao X, Wei YQ, Kariya Y, Teshigawara K, Uchida A. Accumulation ofgamma/delta T cell in human dysgerminoma and seminoma: role of autologoustumor killing and granuloma formation. Immunol Invest 1995; 24: 607–618.

15. Jones BV, Patterson RJ. Supratentorial tumors. In: William Jr SB, editor.Pediatric Neuroradiology. Philadelphia: Lippincott-Raven; 1997. p. 392–393.

16. Korogi Y, Takahashi M, Ushio Y. MRI of pineal region tumors. J Neurooncol2001; 54: 251–261.

17. Liang L, Korogi Y, Sugahara T, et al. MRI of intracranial germ-cell tumors.Neuroradiology 2002; 44: 382–388.

Intravenous immunoglobulintherapy for idiopathicpostoperative lumbosacralplexopathy

Dong-Hyuk Park MDMD, Youn-Kwan Park MDMD,

Joo-Han Kim MDMD

Department of Neurosurgery, Korea University Guro Hospital, Seoul, Korea

Summary We report a patient who developed an acute lumbosacral

plexopathy (LSP) following spinal surgery on lumbos segments. He

recovered dramatically following treatment with high-dose intrave-

nous immunoglobulin (IVIg). A 66-year-old man who underwent an

L4 to S1 decompressive laminectomy required re-admission after

developing contralateral leg pain. Follow-up lumbosacral magnetic

resonance imaging showed only mild postoperative changes. Ten

days after re-admission, he developed relatively rapid onset ipsilat-

eral inguinal pain and weakness of all his leg muscles with dimin-

ished sensation in a lumbosacral plexus distribution. Re-exploration

revealed no specific lesion except for adhesions and resulted in no

improvement. Following treatment with IVIg (0.4 g/kg daily) for five

days, he showed dramatic resolution of motor weakness and pain.

There has been no relapse following six months follow-up. Although

IVIg treatment does not guarantee a positive response in all types of

LSP, it should be considered for severe, rapidly progressive and

even for postoperative cases.

ª 2004 Elsevier Ltd. All rights reserved.

Journal of Clinical Neuroscience (2005) 12(3), 313–315

0967-5868/$ - see front matter ª 2004 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jocn.2004.05.014

Keywords: lumbosacral plexus neuropathy, intravenous immuno-

globulin, spinal surgery

Received 10 April 2003

Accepted 28 May 2004

Correspondence to: Youn-Kwan Park MD, Department of Neurosurgery,

Korea University Guro Hospital, 80 Guro-Dong, Guro-Gu, Seoul 152-705,

Republic of Korea. Tel.: +82 2 818 6066; Fax: +82 2 863 1684;

E-mail: ykapa@kumc.or.kr

INTRODUCTION

Lumbosacral plexopathy (LSP) is characterized by acute onset ofpain followed by weakness and altered reflexes and sensation.These changes should not be attributable to individual nerve roots

ª 2004 Elsevier Ltd. All rights reserved. Journal of Clinical Neuroscience (2005) 12(3)

313Immunoglobulin in lumbosacral plexopathy