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Oncology
Pineal parenchymal cell tumors (PPT) are a rare group of tumors representing less than 1% of all primary central nervous system neoplasms. Originating from pineocytes or their precursor cells, these tumors pose unique challenges both during the diagnostic assessment and clinical management.
- pineal region
- pineal parenchymal tumor
- pineal gland
- biopsy
- intensity modulation radiation therapy
1. Introduction
Pineal parenchymal cell tumors (PPT) are a rare group of tumors representing less than 1% of all primary central nervous system neoplasms. Originating from pineocytes or their precursor cells, these tumors pose unique challenges both during the diagnostic assessment and clinical management. The World Health Organization (WHO) classification stratifies PPTs into distinct entities, ranging from the well-differentiated pineocytomas to the highly malignant pineoblastomas [1]. Among them, the intermediate category of pineal parenchymal cell tumors of intermediate differentiation (PPTID) remains a critically debated subset, presenting a spectrum of histologic features that defy easy categorization [2].
Tackling the management of these tumors remains a complex endeavor, primarily due to their rarity and the resulting limited pool of comprehensive studies. The inherent clinical heterogeneity exhibited by PPTs adds an additional layer of complexity.
2. Pathological Features of Pineal Parenchymal Tumors
According to the latest 2021 WHO classification of central nervous systems, two entities are defined at the opposite ends of the spectrum of pineal parenchyma tumors: pineocytoma (PC), a well-differentiated neoplasm, and pineoblastoma (PB), a poorly differentiated, aggressive neoplasm [1]. The pineal tumor of intermediate differentiation (PPTID) is located in the middle, representing a less defined group of neoplasms [5,6].
2.1. Pineocytomas
Pineocytoma was defined by the WHO in 2021 as a Grade 1 entity—a well-differentiated pineal parenchymal neoplasm exhibiting expansile growth that can result in compression of adjacent structures, leading to variable signs and symptoms [7]. The cut surface shows a well-circumscribed homogeneous or granular mass with a greyish-tan appearance. Histologically, it presents as a moderately cellular neoplasm composed of small, round, blue, and mature cells organized in sheets or showing large pineocytomatous rosettes, a hallmark feature, not present in the normal pineal gland. Gangliocytic differentiation can be variably present and a pleomorphic variant has also been described [8].
Mitotic figures are rarely present in pineocytomas [9,10,11]. The mean Ki67, in most cases, is <1% [11,12,13]. Pineocytomas exhibit strong positivity for synaptophysin, neuron-specific enolase, and NFP [2,9,13,14,15,16]. Other markers have shown variable positivity, including class III beta-tubulin, microtubule-associated protein tau, and chromogranin-A [2,9,14,15]. On average, the interval between the onset of symptoms and surgery was four years for pineocytomas [5]. To date, there have been no reported cases of metastasis in patients affected by pineocytoma [8,17]. The five-year survival in this group ranges from 86% to 91% [8,17]. A review highlighted that the extent of surgical resection is the main independent prognostic factor [18]. Immunoexpression of CRX, a transcription factor, and ASMT, a fundamental enzyme in the synthesis of melatonin, serves as a sign of a biological link to pinealocytes [19,20,21]. There are no recurrent genetic mutations in pineocytomas [22,23], but they exhibit a distinct methylation profile [24].
2.2. Pineal Parenchymal Tumors of Intermediate Differentiation
Pineal tumors of intermediate differentiation are characterized by intermediate malignancy between pineocytoma and pineoblastoma [4,7]. Histologically, they are composed of diffuse sheets or large lobules of monomorphic round cells that appear more differentiated than those observed in pineoblastomas. They can show two main microscopic patterns: they can be densely lobulated with an endocrine-arranged vascularity or diffuse, mimicking oligodendroglioma or neurocytoma. The nuclei are round with moderate atypia and “salt and pepper” chromatin [3,8]. According to the WHO in 2021, Grade 2 or 3 can be assigned based on histopathological features, highlighting the intrinsic heterogeneity of this neoplasm [1].
PPTIDs are positive for synaptophysin [9,13,25], while showing variable positivity for NFP and chromogranin-A [2,9,16,26]. As in pineocytoma, CRX is expressed as well as ASMT/HIOMT, which acts as both a diagnostic and prognostic marker [19,20,21]. Mitotic activity ranges from low to moderate [7]. The mean proliferation index Ki67 is significantly different from pineocytomas and pineoblastomas, with values ranging from 3.5% to 16.1% [22,25,27,28]. PPTIDs are less aggressive neoplasms compared to pineoblastoma, with a higher probability of localized disease at diagnosis. A more favorable prognostic difference between these entities can be observed by comparing the median overall survival of PPTID against PB (165 months vs. 77 months) and progression-free survival (93 months vs. 46 months) [29]. Jouvet et al. and Fauchon et al. have proposed a prognosis-oriented classification of PPTIDs with mitotic count and neuronal differentiation assessed by anti-NFP immunohistochemistry [9,17]. Low-grade PPTID, corresponding to WHO grade 2, was defined as having <6 mitosis per 10 HPF and expression of NFP in many cells [9]. Five-year survival in this group was 74%, and relapse occurred in 26%, mostly in the first site of the neoplasm after some delay [17]. High-grade PPTID, corresponding to WHO grade 3, was defined as having <6 mitosis without NFP expression by immunohistochemistry or >6 mitosis with NFP expression. Five-year survival in this group was 39%, and relapse occurred in 53%, mostly outside the pineal region [9,17]. Low-grade and high-grade prognostic groups showed a difference in the Ki67 proliferation index (5.2% vs. 11.2%) [10]. Nevertheless, the latest WHO classification of CNS tumors acknowledges that definite histological grading criteria are still missing.
It has been demonstrated that PPTIDs can harbor KBTBD4 small in-frame insertions [30]. The copy-number profile of PPTIDs is relatively flat, with some cases of broad gains or losses, particularly chromosome imbalances resembling those observed in pineoblastomas, though minor [22,24]. PPTIDs have a distinct methylation profile that can be further distinguished into two subtypes whose prognosis is still to be established: PPTID-A and PPTID-B [24].
2.3. Pinealoblastomas
Pineoblastoma is a malignant Grade 4 neoplasm—a poorly differentiated, highly cellular, malignant embryonal neoplasm arising in the pineal gland. Upon gross examination, they appear as partially defined invasive masses—soft and friable, pinkish-grey. Pineoblastomas appear as small round blue tumors composed of highly cellular sheets of small cells without a defined pattern. They show irregular, hyperchromatic nuclei with an occasional small nucleolus, high nuclear-to-cytoplasmic ratio, scant cytoplasm, and faint cell borders [3,7].
Pinealoblastomas exhibit positivity for synaptophysin and NSE [9]. Staining positivity for NFP and chromogranin A is significantly less frequent compared to pineocytomas [9,16,31]. There is no loss of SMARCB1/INI1 staining in pineoblastomas, a useful feature to distinguish them from atypical teratoid rhabdoid tumors [32]. Pineoblastoma is a neoplasm characterized by a high mean proliferation index, ranging from 16.9% to 50.1% [10,13,21,22]. It stands out as the most aggressive neoplasm of the pineal region, with frequent craniospinal dissemination and extracranial metastasis [3,17,33,34]. In older series, overall survival in pineoblastoma was reported to be as low as 1.3 years; however, recent studies indicate a better median overall survival time, reaching 4.1–8.7 years [35,36]. Negative prognostic predictors for pineoblastoma include disseminated disease at diagnosis, young age, and partial surgical resection [37]. The prognosis of pineoblastoma is extremely unfavorable, with patients often succumbing within two years from diagnosis [5].
From a cytogenetic perspective, structural alterations of chromosome 1 have been observed, and there may be losses of chromosomes [2,6,7,14,17] with some rare focal gains [22,38,39]. Reports also mention copy number variations and/or mutually exclusive mutations of DICER1, DROSHA, and DGCR8 [24,40,41,42,43]. DNA methylation profiling has identified four subgroups of pineoblastomas: miRNA processing altered type 1, miRNA processing altered type 2, RB1 altered, and MYC/FOXR activated [24,41,43]. These subgroups carry prognostic implications, with the miRNA processing altered type 2 subtype showing an overall good prognosis, while the outcomes of RB1-altered and the MYC/FOXR2-activated subgroups are notably poor.
This entry is adapted from the peer-reviewed paper 10.3390/jcm13051266
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