2026 年 13 巻 p. 123-129
Immature teratomas of the pineal region are a subtype of non-germinomatous germ cell tumors typically associated with early recurrence. Ultra-late recurrence decades after initial treatment is exceedingly uncommon. We report an immature teratoma case in the pineal region that recurred 35 years after subtotal resection and chemoradiotherapy, showing somatic-type malignant transformation into adenoid cystic carcinoma-like adenocarcinoma.
A 16-year-old boy initially underwent ventriculoperitoneal shunting followed by tumor resection, after the pathological confirmation of an immature teratoma (grade 2 according to the ovarian teratoma grading system). A small residual lesion remained, and the patient's condition remained stable for more than a decade, but he was lost to follow-up. At 51 years of age, the patient presented with obstructive hydrocephalus and tumor regrowth. Preoperative serum and cerebrospinal fluid tumor markers levels were normal. An endoscopic biopsy revealed poorly differentiated adenocarcinoma. Resection through an occipital transtentorial approach indicated tumor infiltration into the bilateral thalamus. Histology showed glandular and cartilaginous components with marked atypia and immunohistochemical features resembling adenoid cystic carcinoma, whereas germ cell markers were negative, thus establishing a diagnosis of teratoma with somatic-type malignant transformation. Despite ifosfamide, carboplatin, and etoposide chemotherapy (all at 50% dose) and stereotactic radiosurgery, the disease progressed with leptomeningeal dissemination, and the patient died 613 days after he underwent the second surgery.
This case represents the longest reported interval of recurrence for a central nervous system immature teratoma and highlights the possibility of long-term tumor dormancy followed by malignant transformation. Lifelong surveillance is therefore warranted in patients with residual immature teratomas.
Central nervous system (CNS) germ cell tumors (GCTs) occur predominantly in children and young adults, and among the nongerminomatous subgroup, immature teratomas (IMT) are characterized by immature derivatives of all 3 germ layers, and they represent the most biologically aggressive entity.1) Although IMT has a relatively high recurrence rate, most recurrences occur within several years of treatment, and a relapse beyond a decade is considered to be very rare.2)
Reports of ultra-late recurrence of intracranial teratomas are extremely limited. Only sporadic cases have been described, including an IMT recurring 21 years after initial treatment, a recurrence of germinoma 20 years after resection of IMT/teratocarcinoma, and malignant transformation into adenocarcinoma arising from a mature teratoma or pineal nongerminomatous GCT.3-6) However, no recurrence has been reported more than 30 years after the initial treatment.
The somatic-type malignant transformation (MT) of teratomatous components is well recognized in gonadal GCTs, in which very late recurrence, namely, from 10 to 30 years after the initial therapy, often involves teratomas or somatic-type malignancies, thus suggesting long-term tumor dormancy and its eventual breakdown.7,8) Tu et al.9) proposed that dormant progenitor tumor stem cells may remain quiescent for decades, later reactivating under microenvironmental changes and causing MT. A similar mechanism may underlie late events in CNS teratomas.
We herein present a highly unusual case of pineal IMT that recurred 35 years after the initial surgery, with a recurrent tumor showing somatic-type MT that transformed into an adenoid cystic carcinoma (ACC)-like carcinoma. This case represents the longest latency ever reported in CNS teratoma, and provides important insights into tumor dormancy and malignant progression.
(-35 years): Onset occurred at age 16 with headache, nausea, and ocular pain. A neurological examination revealed bilateral papilledema and upward gaze palsy. Head computed tomography (CT) revealed a pineal region tumor and acute hydrocephalus. Tumor markers were assessed preoperatively. The serum human chorionic gonadotropin (hCG) levels were <1.0 mIU/mL. Cerebrospinal fluid levels of these markers were also low. After ventriculoperitoneal shunt surgery, trial radiotherapy was administered using lateral opposed fields (field size, 6 × 6 cm) to the pineal region, delivering 20 Gy in 14 fractions, but there was no appreciable reduction in tumor size. Subsplenial suboccipital craniotomy was performed for tumor resection (Figure 1A).
Preoperative imaging and initial histopathology.
(A) Axial non-contrast CT showing a pineal region mass with acute obstructive hydrocephalus.
(B) Postoperative non-contrast CT showing the subtotal removal of the tumor through the subsplenial approach, with a small residual lesion remaining on the tectal side.
(C) Hematoxylin and eosin (H&E) staining showing dense collagenous stroma containing cartilage, keratinizing stratified squamous epithelium, and glandular structures lined by a mucin-producing columnar epithelium reminiscent of either a gastrointestinal or respiratory epithelium, and representing elements of all 3 germ layers.
(D) Glandular component (H&E staining).
(E) A stratified squamous epithelium with a preserved basal layer and no overt cytologic atypia (H&E staining).
(F) Cartilage showing marked atypia, including multiple chondrocytes (3-5 per lacuna) and occasional mitotic figures, supporting the diagnosis of immature teratoma (H&E staining).
(G) Follow-up MRI obtained 11 years after the initial surgery. Axial gadolinium-enhanced T1-weighted MRI showing a stable right-sided residual mass without enlargement.
CT: computed tomography; MRI: magnetic resonance imaging
The intraoperative findings revealed a mixture of fibrous white components, dark red cauliflower-like areas, and rice-grain-like white components constituting a predominantly highly vascular tumor. No direct infiltration into the Galen venous system was observed. The most robust adhesion was found around the pineal gland and quadrigeminal plate; this area was partially preserved, causing a subtotal removal (Figure 1B). A pathological examination revealed cartilage, glandular tissue, a stratified squamous epithelium, and immature mesenchymal cell clusters within the fibrous stroma. Nuclear atypia and mitoses were observed in the cartilage tissue, leading to a diagnosis of IMT (grade 2, according to the ovarian teratoma grading system) (Figure 1C-F). Postoperatively, definitive radiotherapy was delivered using lateral opposed fields (field size, 7 × 7 cm) totaling 35.7 Gy in 21 fractions. In addition, 13 courses of vincristine 0.02 g/kg + nimustine (2 mg/kg) were administered. The residual lesion did not enlarge. After a magnetic resonance imaging (MRI) follow-up at 11 years (Figure 1G), outpatient visits ceased, and long-term follow-up was discontinued thereafter.
Recurrence after 35 years(0 years): Thirty-five years after the initial surgery, the patient presented with nausea and an impaired consciousness. MRI revealed recurrent hydrocephalus and a renewed enlargement of the pineal region tumor (Figure 2A and B). Serum alpha-fetoprotein (AFP) was 2 ng/mL; Human chorionic gonadotropin (hCG) was <0.5 mIU/mL, and free Beta-human chorionic gonadotropin (β-hCG) was <0.1 ng/mL. The cerebrospinal fluid levels of these markers were also low. CT showed no discontinuity of the shunt system; however, shunt malfunction was suspected. Endoscopic third ventriculostomy and a tumor biopsy revealed findings consistent with poorly differentiated adenocarcinoma.
Imaging and intraoperative findings at recurrence.
(A, B) An axial and coronal gadolinium-enhanced T1-weighted MRI showing a marked enlargement of the pineal mass with obstructive hydrocephalus.
Endoscopic third ventriculostomy and a tumor biopsy were performed, followed by tumor removal through an occipital transtentorial approach.
(C) Intraoperative views obtained through the occipital transtentorial approach indicating a hypervascular, soft tumor with poor demarcation from the bilateral thalami.
(D, E) A postoperative axial and coronal gadolinium-enhanced T1-weighted MRI showing a residual tumor along the thalamic infiltration margins.
MRI: magnetic resonance imaging
Subsequently, tumor resection was performed using an occipital transtentorial approach. The tumor was hypervascular and relatively soft, with indistinct borders with the bilateral thalamus; a part was unavoidably left behind (Figure 2C-E).
Histopathological findingThe tumor comprised cartilaginous and glandular components. The glandular tissue showed marked atypia and areas of necrosis. The findings were consistent with adenocarcinoma (Figure 3A-C). Immunohistochemistry showed diffuse c-kit positivity, mosaic-like S-100 positivity, p63 and calponin positivity at the margins of the nests, and a Ki-67 positivity rate of approximately 40%. In contrast, germ cell markers, such as AFP, β-hCG, Placental alkaline phosphatase (PLAP), and Spalt-like transcription factor 4 (SALL4), showed negative (Figure 3D).
Histopathological findings of the recurrent tumor (somatic-type malignant transformation).
(A) The tumor comprised glandular and cartilaginous components (hematoxylin and eosin [H&E] staining).
(B) Glandular structures displaying marked cytologic atypia (H&E staining).
(C) Areas of necrosis, consistent with adenocarcinoma arising in a teratomatous background (H&E staining).
(D) Immunohistochemistry shows diffuse c-kit positivity, mosaic S-100 reactivity, and p63/calponin positivity at the peripheral nests, with a Ki-67 index of approximately 40%. Germ cell tumor markers (AFP, β-hCG, PLAP, SALL4) are negative.
Based on the above findings, the diagnosis was teratoma with malignant transformation and adenoid cystic carcinoma-like adenocarcinoma components.
AFP: alpha-fetoprotein; β-hCG: Beta-human chorionic gonadotropin; PLAP: Placental alkaline phosphatase (PLAP); SALL4: Spalt-like transcription factor 4
Based on the previously mentioned findings, the diagnosis was teratoma with MT and ACC-like adenocarcinoma components. Comprehensive genomic panel testing was not performed for recurrent tumors, and no molecular genetic analysis was available.
Postoperative courseICE therapy (ifosfamide 450-500 mg/m2/day ×5 days, carboplatin [area under the curve 2.5] day 1, etoposide 50 mg/m2/day ×5 days, all at 50% of the standard dose) was administered for a total of 5 courses. Because the patient's performance status at recurrence was poor and he had already received cranial irradiation and multi-agent chemotherapy in adolescence, ICE was initiated at 50% of the standard dose to assess tolerability and hematological toxicity, with the option of subsequent dose escalation. However, significant myelosuppression developed even at this reduced dose, and further escalation to a full-dose ICE was deemed unsafe. Despite chemotherapy, follow-up MRI performed 5 months after surgery revealed progression of the bilateral thalamic lesions, and CyberKnife radiotherapy (30 Gy in five fractions) was subsequently administered (Figure 4A and B).
Post-treatment course during recurrence.
(A) Axial gadolinium (Gd)-enhanced T1-weighted MRI at 5 months postoperatively showing the progression of bilateral thalamic lesions.
(B) Stereotactic radiosurgery (35 Gy) was performed.
(C) Axial Gd-enhanced T1-weighted MRI at 7 months showing leptomeningeal dissemination. The patient’s condition subsequently deteriorated, and he died 613 days after the second surgery.
MRI: magnetic resonance imaging
Despite these treatments, MRI obtained 7 months postoperatively revealed new leptomeningeal dissemination accompanied by a gradual neurological decrease (Figure 4C). The patient's clinical condition continued to deteriorate, and he died 613 days after the second surgery. An autopsy was not performed at the request of the family.
This case describes an extraordinarily rare clinical course in which pineal IMT recurred 35 years after the initial treatment and showed somatic-type MT into an ACC-like epithelial malignancy.
IMTs are an uncommon subtype of nongerminomatous GCTs, and their long-term recurrence pattern remains poorly characterized.
Although the recurrence patterns of intracranial GCTs vary according to histology, the available series indicate that most recurrences occur within several years after treatment, making recurrence beyond 3 decades exceptionally unusual.10,11)
The natural history of CNS teratomas differs substantially between mature teratomas and IMT. In a series of 34 CNS teratomas, Sawamura et al.1) showed that mature teratomas can be cured by complete resection, whereas IMT and malignant teratomas have high recurrence rates, particularly after an incomplete removal.
The longest previously reported intervals are 21 years for recurrent IMT (Mano et al.3)) and 20 years in germinoma arising after IMT/teratocarcinoma resection (Iwamuro et al.4)). MT within CNS teratomas is similarly rare; Kim et al. reported an enteric-type adenocarcinoma arising from mature teratoma,5) and Freilich et al.6) described adenocarcinoma arising from pineal nongerminomatous GCT.5,6) To the best of our knowledge, no cases of MT with transformation into an ACC-like carcinoma have been reported, thereby making the pathological features of this case unique.
Insights from gonadal GCTs help explain such ultra-late recurrence. Testicular GCTs may recur 10-30 years after therapy, frequently with somatic-type malignancies, suggesting long-term dormancy of the teratomatous components.7,8) Tu et al.9) further conceptualized these events as a reactivation of dormant progenitor tumor stem cells, progressing from long-term quiescence → microenvironmental disruption → somatic-type MT. In our patient, residual teratomatous tissue after subtotal resection may have persisted in a dormant state and thereafter underwent MT decades later, potentially triggered by age-related immunological alterations or the accumulation of some type of genetic damage.
Somatic-type MT is notoriously chemoresistant. Spiess et al.12) indicated that MT arising in testicular teratomas is refractory to standard GCT chemotherapy, and Utsuki et al.13) likewise reported limited efficacy of chemotherapy in the MT of mature cystic teratomas. Consistent with these observations, our patient showed tumor progression despite receiving reduced-dose ICE therapy.
In summary, this case is distinguished by the following:
1. the longest reported latency (35 years) for a recurrent CNS teratoma,
2. the first documented ACC-like somatic-type MT in intracranial teratoma, and
3. new insights regarding tumor dormancy and malignant evolution.
These findings emphasize that long-term tumor control does not preclude ultra-late recurrence or malignant transformation. A lifelong follow-up is essential in patients with IMTs.
ConclusionsThis case shows an exceptionally rare instance of ultra-late recurrence in an intracranial IMT after 35 years, with somatic-type malignant transformation into an ACC-like carcinoma. These findings underscore that dormant teratomatous components may retain their malignant potential for decades and can undergo late malignant evolution. Clinicians should be aware that even long-term remission does not eliminate the risk of recurrence of GCTs with teratomatous elements. Therefore, lifelong surveillance should be considered, particularly in patients with IMTs or residual teratomatous tissue.
We thank the clinical staff and nursing team of Jichi Medical University for their dedicated care of this patient. We also thank the Department of Radiology and Department of Pathology for their expert diagnostic support. We are particularly grateful to the members of the Tokyo Brain Tumor Pathology Study Group for their valuable pathological insights and constructive discussions regarding this case. We also acknowledge the assistance provided by the operating room staff and medical technologists throughout the perioperative period.
All authors attest that they meet the current ICMJE criteria for Authorship.
All authors have no conflict of interest.
Ethics approval was not required for this single-patient case report, as per institutional policy. Written informed consent for publication was obtained from the patient and family.
