Pineal parenchymal tumor of intermediate differentiation with late spinal dissemination 13 years after initial surgery: illustrative case

Abstract

BACKGROUND

Pineal parenchymal tumors of intermediate differentiation (PPTIDs) are rare in the pineal gland. A case of PPTID that disseminated to the lumbosacral spine 13 years after the total resection of a primary intracranial tumor has been reported.

OBSERVATIONS

A 14-year-old female presented with headache and diplopia. Magnetic resonance imaging revealed a pineal tumor that induced obstructive hydrocephalus. A biopsy and endoscopic third ventriculostomy were performed. Histological diagnosis revealed a grade II PPTID. Two months later, the tumor was removed via craniotomy because the postoperative Gamma Knife surgery was ineffective. Histological diagnosis confirmed PPTID, although the grade was revised from II to III. Postoperative adjuvant therapy was not performed, because the lesion had been irradiated and gross total tumor removal was achieved. She has had no recurrence in 13 years. However, pain around the anus newly appeared. Magnetic resonance imaging of the spine revealed a solid lesion in the lumbosacral spine. The lesion was subtotally resected, and histological diagnosis revealed grade III PPTID. Postoperative radiotherapy was performed, and she had no recurrence 1 year after radiotherapy.

LESSONS

Remote dissemination of PPTID can occur several years after the initial resection. Regular follow-up imaging, including the spinal region, should be encouraged.

Pineal parenchymal tumors are uncommon entities, accounting for less than 1% of all intracranial tumors.¹ The World Health Organization (WHO) reclassified pineal parenchymal tumors into five entities: pineocytoma, pineal parenchymal tumor of intermediate differentiation (PPTID), papillary tumor of the pineal region, desmoplastic myxoid tumor of the pineal region, and pineoblastoma. PPTID malignancy varies from WHO grade II to III.² Five-year overall survival rates of patients with grades II and III PPTIDs are 74% and 39%, respectively, whereas the recurrence rates are 26% and 56%, respectively.³ This range of malignancy has prevented the establishment of standard treatment. Resection is often chosen as the initial treatment because total resection can decrease the recurrence rate. Conversely, postoperative radiotherapy or chemotherapy remains controversial.^3–11 PPTID recurrence is not rare, but remote dissemination of PPTID several years after the initial surgery is extremely rare.^6,12–20

We describe a case of remote dissemination of PPTID at the lumbosacral spine 13 years after initial tumor removal of intracranial PPTID.

Illustrative Case

A 14-year-old female presented with headache and diplopia. Bilateral papilledema and left eye abduction disorders were also observed. Magnetic resonance imaging (MRI) revealed a solitary mass lesion in the pineal region with contrast enhancement on T1-weighted imaging, which induced obstructive hydrocephalus (Fig. 1). The patient had no relevant medical or family history. Initially, a biopsy of the lesion and endoscopic third ventriculostomy were performed. Histological examination revealed hypercellular proliferation, small cells with round-shaped nuclei, scant cytoplasm, and some mitoses (Fig. 2A and B). The cell arrangements were nonspecific, and rosette formation was not observed. Immunohistochemical examination revealed positive expression of neurofilament protein (NFP) and synaptophysin (Fig. 2C and D) and negative expression of glial fibrillary acidic protein and olig2. The MIB-1 index value was 14.5% (Fig. 2E). The histopathological diagnosis was WHO grade II PPTID. Radical tumor removal via craniotomy was the next treatment option, but the patient’s family preferred other treatment options. Therefore, it was decided to proceed with palliative radiation therapy on the condition that surgical tumor removal would be performed if the tumor did not shrink within a few months. Gamma Knife surgery was performed with a total dose of 16 Gy. However, the lesion did not show shrinkage 2 months after irradiation. Therefore, gross total removal of the tumor was performed via craniotomy as originally planned. Immunohistochemical examination of the specimen revealed more atypical and proliferative cells with spindle-shaped nuclei than in the biopsy specimen, and the MIB-1 index was 19.9%. The final histopathological diagnosis was PPTID, although the WHO grade was revised from II to III. Postoperative adjuvant therapy was not performed, because the lesion had already been irradiated, and gross total tumor removal was achieved. After surgery, the preoperative clinical symptoms improved, but the diplopia persisted slightly.

FIG. 1.

Preoperative T1-weighted (A) and T2-weighted (B) MRI scans show a round mass lesion in the pineal region causing obstructive hydrocephalus. The lesion is well enhanced on axial (C) and sagittal (D) T1-weighted imaging.

FIG. 2.

A biopsy specimen stained with hematoxylin and eosin shows two patterns of tumor cells: small cells with round nuclei (A) and medium-sized cells with spindle nuclei (B). Immunohistochemical examinations show positive expression of synaptophysin (C), NFP (D), and an MIB-1 index in medium-sized spindle cells of 14.5% (E).

Head MRI was performed annually for 12 years, and no recurrence was detected. However, 13 years after resection, the patient presented with new symptoms of pain around the anus. Spinal MRI was performed for the first time, and a mass lesion in the lumbosacral spine was detected (Fig. 3A–C). However, head MRI performed simultaneously revealed no recurrence (Fig. 3D and E). The spinal lesion was resected surgically. The lesions were strongly attached to the S2 nerve root; therefore, the lesion partially remained. Histological examination of the spinal lesion revealed small cells with round nuclei, nonspecific cellular arrangement, and no necrosis (Fig. 4A). Immunohistochemical examination revealed the positive expression of NFP and synaptophysin (Fig. 4B and C). The MIB-1 index was 10%–20% (Fig. 4D). These findings were consistent with those of PPTID, and the final diagnosis was spinal dissemination of WHO grade III PPTID. Postoperatively, proton beam therapy was performed with a total dose of 50 Gy: whole brain and spine (30 Gy) and the surgical site of the sacral spine (20 Gy). The patient had no neurological deficits, except for mild numbness in her left hip and thigh. Spinal and head MRI revealed no recurrence 1 year after radiotherapy.

FIG. 3.

Spinal T1-weighted (A), T2-weighted (B), and contrast-enhanced T1-weighted (C) MRI scans 13 years after the tumor resection showed a solidly enhanced lesion at the S1–2 level of the cauda equina. Head axial (D) and sagittal (E) contrast-enhanced T1-weighted MR images taken simultaneously, revealing no evidence of local recurrence.

FIG. 4.

Hematoxylin and eosin staining of the spinal lesion shows small cells with round-shaped nuclei, nonspecific cellular arrangement, and no necrosis (A). Immunohistochemical examinations show positive expression of synaptophysin (B), NFP (C), and the MIB-1 index of 10%–20% (D).

Discussion

Observations

PPTID first appeared in the 2000 WHO classification. PPTID is located at an intermediate position between pineocytoma and pineoblastoma. In the 2021 WHO classification, PPTID was subdivided into WHO grades II and III, although the histological grading criteria have not been precisely defined.² PPTID occurs in a wide age range, from children to adults, without gender specificity. The pathological findings of PPTID are small, round cells with moderate to hypercellular proliferation and a slightly wider cytoplasm. Mitoses are low to moderate, and necrosis is absent. Because PPTID includes grades II and III malignancy, the tumor cells have diverse characteristics; some are well differentiated like in pineocytoma, and others are similar to those of pineoblastoma. Immunohistopathologically, neuronal cell markers, such as synaptophysin and NFP, are positive, whereas glial cell markers are negative. The MIB-1 index is reportedly 3%–10%. Jouvet et al.⁴ classified PPTID into grades II and III using the mitotic index and NFP expression; grade II has mitoses less than 6/10 high-power fields and NFP positive expression, and grade III has mitoses more than 6/10 high-power fields and NFP negative expression.

The standard treatment for PPTID has not been established, because of few PPTID reports and the wide range of malignancy. In general, PPTID grade III is treated similarly to pineoblastoma.^3–5 Postoperative radiotherapy for PPTID grade III is often recommended, although a chemotherapy protocol has not been established.^6,7 However, the effectiveness and necessity of postoperative radiotherapy for PPTID grade II are controversial.^8,9 Das et al.¹⁰ reported that five patients with PPTID (grade II 3, grade III 2) underwent postoperative external beam radiotherapy for residual lesions. The residual tumor sizes were reduced by more than 50% in four patients, and the other tumor size was stable. All the residual lesions had no progression for 21.4 months of median follow-up. Ahn et al.¹¹ reported that four patients with PPTID underwent cyberknife radiation surgery after biopsy and endoscopic third ventriculostomy. There was no description of the WHO grade for any of the cases. Two lesions disappeared completely, and one partially regressed. The remaining one lesion with a high MIB-1 index (30%) showed local progression, and the patient finally died. The three surviving patients did not experience tumor progression during 42 months of median follow-up. These reports indicate a good response of PPTID to radiotherapy. In our case, because the initial diagnosis was PPTID grade II, radiotherapy was performed after biopsy with the expectation of tumor shrinkage. However, the tumor did not shrink. Therefore, we performed tumor resection via craniotomy.

PPTID recurrence is occasionally observed. However, remote dissemination more than 1 year after the initial surgery is extremely rare, and only 10 cases have been reported (Table 1).^6,12–20 The time to recurrence from the initial surgery ranges from 3 to 21 years. The spinal cord appeared to be a common site for remote dissemination (seven cases). Treatments for remote dissemination lesions varied: surgery alone (two cases), surgery followed by radiotherapy (one case), surgery followed by radiotherapy and chemotherapy (two cases), radiotherapy alone (two cases), radiotherapy and chemotherapy without surgery (one case), and not available (two cases). On the basis of the final outcome of the 10 cases, although some were not available, a combination of surgery and adjuvant therapy for remote dissemination lesions may have had a favorable outcome (cases 1, 3, and 9).

TABLE 1.

Reports of PPTID or PC with distant metastasis more than 1 year after treatment of primary lesion

Case No.	Authors & Year	Age (yrs)/Sex	Initial Pathology (grade)	Location	Treatment	Pathology at Recurrence	Location at Recurrence	Time to Recurrence (yrs)	Treatment at Recurrence	Final Outcome
1	Ito et al., 199412	42/M	NA	Pineal body	RT	PC (PPTID?)	T10/T4, T7	11/15	Removal + RT/ removal	No deficit
2	Kurisaka et al., 199813	10/F	PC/PB mixed	Pineal body	Debulking, chemo	NA	T7/T9–lumbar	0.75/2	RT/RT	Under RT
3	Kim et al., 200914	47/F	PPTID (III)	Pineal body	Biopsy, RT	PB	Cerebellum	4	Biopsy, RT, chemo	Tumor reduction
4	Stoiber et al., 201015	52/F	PC	NA	Biopsy, RT	NA	Brain, spine	4	RT	Dead
5	Komakula et al., 201116	15/F	PPTID	Pineal body	Debulking, chemo, RT	NA	Multiple metastases	21	NA	Dead
6	Bielle et al., 201417	41/F	PPTID (II)	Pineal body	STR, RT	PPTID (III)	Posterior fossa	12	Biopsy	NA
7	Patil et al., 201518	25/F	PPTID (II)	Pineal body	Surgery	NA	TSC, LSC	3	Surgery	NA
8	Chatterjee et al., 201919	6/M	PPTID	NA	Surgery, RT	NA	Spine	NA	Surgery, RT	Alive
9	Bando et al., 201920	63/F	PC	Pineal body	GTR	NA/PPTID	Pineal body/CSC, LSC, LV	2/6	RT/biopsy, RT, chemo	Tumor free, no deficits
10	Kunigelis et al., 20216	11/M	PPTID (III)	Pineal body	GTR, RT	NA	LSC	9	RT, chemo	NA

CSC = cervical spinal cord; GTR = gross total resection; LSC = lumber spinal cord; LV = lateral ventricle; NA = not available; PB = pineoblastoma; PC = pineocytoma; PPTID = pineal parenchymal tumor of intermediate differentiation; RT = radiotherapy; STR = subtotal resection; TSC = thoracic spinal cord.

In our case, the reason for remote dissemination without local recurrence after a long period remains unclear. Tiny tumor tissue may have been released into the cerebrospinal fluid at the time of the initial biopsy or the second surgery. The tissue reached the caudal side of the cerebrospinal fluid space by gravity, engrafted at the lumbosacral spine, and grew slowly. The primary pineal lesion may not have recurred because it was surgically resected with preoperative radiotherapy. There are two clinical points that can be corrected in the present case. First, the interval from initial radiation therapy to radical surgical tumor removal was only 2 months. This should have been a longer interval for postradiation observation. Next, spinal MRI scans were not performed before the initial surgery or during the follow-up period. Regular whole-spine MRI scans could detect the disseminated tumor asymptomatically. In conclusion, even low-grade PPTIDs can disseminate to distant sites several years after initial surgery. This finding indicates the importance of maintaining long-term follow-up for postoperative PPTID.

Lessons

Remote dissemination of PPTID several years after the initial surgery is extremely rare. However, regular follow-up should not be discontinued, because disseminated tumors can be detected even after a few decades. Our report demonstrates the importance of a long-term follow-up. In addition, because disseminated lesions often appear in the spinal region, regular whole-spine MRI scans, as well as whole-brain scans, could help detect remote dissemination before progression.

Disclosures

Dr. Kato reported grants from the Japan Society for the Promotion of Science during the conduct of the study.

Author Contributions

Conception and design: Tanei, Kato, Nishimura, Nagashima. Acquisition of data: Kato, Nishimura, Abe. Analysis and interpretation of data: Tanei, Kato, Nishimura, Nagashima, Nishii. Drafting the article: Tanei, Kato. Critically revising the article: Tanei, Kato, Ishii, Saito. Reviewed submitted version of manuscript: Tanei, Kato, Nishimura, Nagashima, Saito. Approved the final version of the manuscript on behalf of all authors: Tanei. Administrative/technical/material support: Fukaya. Study supervision: Tanei, Nishimura, Saito.