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NI FEATURE: PATHOLOGY PANORAMA - ORIGINAL ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 2  |  Page : 491-502

Primary pineal tumors – Unraveling histological challenges and certain clinical myths


1 Department of Pathology, Tata Memorial Centre, Homi Baba National Institute, Mumbai, Maharashtra, India
2 Department of Pathology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas, Mumbai, Maharashtra, India
3 Department of Pediatric Oncology Division of Medical Oncology, Tata Memorial Centre, Homi Baba National Institute, Mumbai, Maharashtra, India
4 Department of Neurosurgery Division of Surgical Oncology, Tata Memorial Centre, Homi Baba National Institute, Mumbai, Maharashtra, India
5 Department of Neurosurgery, King Edward Memorial Hospital and Seth Gordhandas Sunderdas, Mumbai, Maharashtra, India
6 Department of Radiation Oncology, Tata Memorial Centre, Homi Baba National Institute, Mumbai, Maharashtra, India

Date of Web Publication13-May-2019

Correspondence Address:
Dr. Sridhar Epari
Department of Pathology, Tata Memorial Centre, Homi Baba National Institute, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.258045

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 » Abstract 


Background: Pineal gland tumors range from the well-differentiated “pineocytoma” [World Health Organization (WHO) grade I], which have a very good prognosis, to the aggressive and poorly differentiated “pineoblastoma” (WHO grade IV) with “pineal parenchymal tumor of intermediate differentiation” (PPTID; WHO grades II and III) occupying intermediary differentiation and prognosis. Papillary tumor of the pineal region (PTPR; WHO grades II and III) is a distinct entity with propensity for recurrence and spinal dissemination. However, the diagnostic criteria to differentiate these entities, especially between WHO grades II and III of both PPTID and PTPR, remain nebulous.
Objective: To evaluate the relative frequency of the individual entities and histomorphological (including the proliferation indices) features across the spectrum of pineal parenchymal tumors (PPTs) [including PTPRs] along their course.
Design: All cases of PPTs were retrieved, reviewed, and graded based on the histological criteria defined in the literature.
Results: PPTID, more commonly seen in young adults, was the most common subtype of PPT. This was followed by pineoblastoma which was more commonly seen in children. Clinical progression was seen in both grades II and III of PPTID; however, it was more commonly seen in cases with a MIB1 labeling index of >10%. PTPRs (both grades II and III) showed an aggressive histological transformation and also intraparenchymal metastasis.
Conclusion: PPTIDs are the most common adult primary PPTs and have the potential to progress and disseminate in both grades II and III. Both grades of PTPRs have a metastatic potential. These findings suggest the need for postoperative adjuvant therapy in both grades of PPTID and PTPR.


Keywords: Pineal gland, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, papillary tumors of the pineal region, pineal anlage tumor
Key Message: Pineal gland tumors represent a histological continuum. In the present single-institutional study on the histology of primary pineal tumors, the characteristic histological and immunohistochemical features that distinguish them into various types and grades are being presented.


How to cite this article:
Verma A, Epari S, Bakiratharajan D, Sahay A, Goel N, Chinnaswamy G, Shetty P, Moiyadi A, Goel A, Gupta T, Jalali R. Primary pineal tumors – Unraveling histological challenges and certain clinical myths. Neurol India 2019;67:491-502

How to cite this URL:
Verma A, Epari S, Bakiratharajan D, Sahay A, Goel N, Chinnaswamy G, Shetty P, Moiyadi A, Goel A, Gupta T, Jalali R. Primary pineal tumors – Unraveling histological challenges and certain clinical myths. Neurol India [serial online] 2019 [cited 2019 May 22];67:491-502. Available from: http://www.neurologyindia.com/text.asp?2019/67/2/491/258045


Pineal tumors account for 0.2%–2% of all intracranial tumors.[1],[2],[3],[4] Pineal parenchymal tumors (PPTs), glial tumors, and germ cell tumors are the common pineal region tumors; while papillary tumor of pineal region (PTPR), meningeal tumors, hematolymphoid malignancies, and metastases are rare pineal region tumors. PPTs account for approximately 30%–50% of all tumors of the pineal region (TPR).[1],[5] Pineocytoma [World Health Organization (WHO) grade I], PPT of intermediate differentiation (PPTID; WHO grades II and III), and pineoblastoma (PB; WHO grade IV) form the spectrum of primary PPTs. PTPRs were first introduced in 2007 as distinct entities and were retained in the subsequent current 2016 update on WHO classification of central nervous tumors.[6] The WHO classification of pineal tumors has evolved over the years based on the histological, immunohistochemical, and clinical features.[7] This is one of the biggest single-institutional study on the histology of primary pineal tumors since the WHO 2007 classification, which has brought a lot of changes in the classification of primary pineal tumors.


 » Materials and Methods Top


All the TPR diagnosed during the period of 2007–2016 were retrieved from the pathology departmental archives and reviewed. The PPTs, including PTPRs, formed the study sample. The clinical details (age, gender, radiological size, presence or absence of metastases, and follow-up) were retrieved from the electronic medical records. All these cases were reviewed along with the relevant immunohistochemical markers [Table 1] and classified as pineocytoma (WHO grade I), PPTID (WHO grade II), PPTID (WHO grade III), PB (WHO grade IV), PTPR (WHO grade II), and PTPR (WHO grade III) based on the criteria as described below.
Table 1: Technical details of the antibodies used in this study

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  1. Pineocytoma (WHO grade I): Tumor with predominant lobular architecture (with or without focal presence of diffuse areas), minimal nuclear variation, absence of all the atypical morphological features [like nuclear pleomorphism, mitotic activity, microvascular proliferation (MVP), and necrosis], and MIB1 labeling index (LI) of ≤2% were included in this category.[8],[9] Cases with presence of any of the atypical features were classified as PPTIDs of varying grades as described below
  2. PPTID (WHO grade II): Tumors with presence of any of the atypical features described above along with a mitotic count of ≤5/10 high-power field (hpf) and the MIB1 LI between 3% and 10%[9],[10]
  3. PPTID (WHO grade III): Tumors with histological features as described above, along with a mitotic count of >5/10 hpf and/or the MIB1 LI of >10%. Even cases with focal hypercellular areas of primitive embryonal cell morphology (resembling PB), that is, mixed tumors, were also included in the category of PPTID, WHO grade III[9],[10]
  4. PB (WHO grade IV): Tumors with diffuse areas of primitive embryonal cell morphology, Homer–Wright rosettes, apoptosis, frequent mitoses, and necrosis with retained integrase interactor 1 (INI1) protein. Tumors of pineoblastomatous morphology with ectomesenchymal differentiation in the form of extensive melanin pigment deposition and/or rhabdomyoblastic and/or cartilaginous differentiation were classified as pineal anlage tumor (PAT; WHO grade IV)[11]
  5. PTPR (WHO grade II): Tumors composed predominantly of papillae lined by single- to multilayered monomorphic polygonal epithelioid or columnar cells with moderate amount of clear or eosinophilic cytoplasm without necrosis or MVP. A mitotic count of ≤5/10 hpf and MIB1 LI of ≤10% was present[6],[12]
  6. PTPR (WHO grade III): Tumors histologically similar to PTPR (WHO grade II) but with presence of necrosis, MVP, nuclear atypia, and mitotic count of >5/10 hpf and/or MIB1 LI of >10%.[6],[12]



 » Results Top


A total of 152 TPR were retrieved and reviewed. A total of 61 cases were of nonprimary pineal origin [glial tumors (n = 28), germ cell tumors (n = 23), meningioma (n = 5), atypical teratoid/rhabdoid tumor (AT/RT; n = 2), metastatic lung carcinoma (n = 1), ependymoma (n = 1), and extramedullary myeloid neoplasm (n = 1)]. In all, 91 were primary pineal region tumors, of which 8 cases of primary pineal tumor were excluded due to suboptimal histomorphological preservation. Thus, the study group comprised 83 cases (7 were in-house operated cases, while 76 were referral samples), and as per the criteria mentioned in “Materials and methods,” 74 were primary PPTs [5 (6.8%) were pineocytomas (WHO grade I), 31 (41.9%) PPTIDs (WHO grade II), 8 (10.8%) PPTIDs (WHO grade III), 30 (40.5%) PB (WHO grade IV)] and 9 PTPR [6 were WHO grade II and 3 were WHO grade III].

Pineocytoma (WHO grade I; n = 5)

The age range of the patients was 28–60 years with a mean age of 44.2 years and a median age of 44 years [interquartile range (IQR): 55 (Q3) -34 (Q1) =21 years] [Table 2]. A marginal male predominance with a male: female (M: F) ratio of 3:2 was seen. The mean radiological tumor size was 3.3 cm (n = 4; range: 2.2–4.6 cm). Histologically, all cases showed a lobular arrangement with monomorphic cytology. Pineocytomatous rosettes and dystrophic microcalcification were noted in two (40%) cases each. Synaptophysin was positive in all three cases (n = 3), of which one was also positive for chromogranin. Glial fibrillary acidic protein (GFAP) was negative in all these cases (n = 3). None of the cases showed p53 protein overexpression. MIB1 LI (n = 4) was <1% in three cases and was 1%–2% in one case [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d. Recurrence or leptomeningeal dissemination was not seen in any case. None except one case received any form of adjuvant treatment. Case 1 (34/M) received radiotherapy (RT) postsurgery due to the presence of a residual tumor.
Table 2: Clinicopathological details of all cases of pineocytoma, WHO grade I

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Figure 1: (a-d) Pineocytoma (WHO grade I): (a) Tumor composed of uniform cells in lobules having eosinophilic and clear cytoplasm with calcification (H and E: ×100), (b) diffuse synaptophysin (IHC: ×100), (c) MIB1 labeling <1% (IHC: ×100), and (d) pineocytomatous rosettes (IHC: ×100). (e-h) PPTID (WHO grade II): (e) Tumor in lobules with no mitotic activity (H and E: ×100), (f) diffuse synaptophysin (IHC: ×100), (g) MIB1 LI of 4%–5% (IHC: ×100), and (h) positive NFP (IHC: ×100). (i-l) PPTID (WHO grade III): (i) Tumor in lobules with moderate atypia (H and E: ×100), (j) diffuse synaptophysin (IHC: ×100), (k) MIB1 LI of 12%–15% (IHC: ×200), and (l) negative NFP (IHC: ×200). (m-p) Pineoblatoma (WHO grade IV): (m) Diffuse sheet of embryonal round cell tumor with hyperchromatic nucleus (H and E: ×100), (n) diffuse synaptophysin (IHC: ×100), (o) MIB1 LI of 20%–25% (IHC: ×100), and (p) negative neurofilament protein (IHC: ×100). LI: labeling index; NFP: neurofilament protein; PPTID: pineal parenchymal tumor of intermediate differentiation; H and E: hematoxylin and eosin; IHC: immunohistochemistry; WHO: World Health Organization

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PTID (WHO grades II and III; n = 39)

The age range of the patients was 6–62 years with a mean age of 32.1 years and a median age of 29 years [IQR: 45 (Q3) -20.25 (Q1) = 24.75 years]. No gender predilection was seen (M: F 1:1.1). The mean radiological tumor size was 3.3 cm (n = 21; range: 1.6–7.1 cm). Thirty-one cases were of WHO grade II and 8 cases were of WHO grade III. In six cases of PPTID, MIB1 LI was not available and these tumors were graded based on the mitotic count alone.

PPTID (WHO grade II; n = 31)

The age range of the patients was 6–54 years with a mean age of 32.5 years and median age of 31 years [IQR: 45 (Q3) -22 (Q1)=23 years] [Table 3]. The M: F ratio was 1:1.2, and the mean tumor size was 3.0 cm (n = 18; range: 1.6–7.1 cm). Fifteen (48.4%) cases were diagnosed based on the mitotic activity of >1 and ≤5/10 hpf, while in the rest 16 cases, although the mitotic activity was not easily evident, the MIB1 LI was in the range of 3%–10%. All cases exhibited a diffuse sheeting architecture. Focal nesting and lobular architecture was noted in three cases (9.7%). Sudden anisonucleosis with a few large atypical cells was noted in seven (22.6%) cases. Spotty necrosis was seen in a single case (Case 9, 13/male; 3.2%) but was graded as grade II due to lack of requisite mitotic activity, and the MIB1 LI in this case was 8%–10%. MVP was seen in two cases (Case 15, 23/M and Case 17, 49/M; 6.5%), but these patients did not show requisite mitotic activity and the MIB1 LI was 7%–9% and 8%–10%, respectively. Foci of dystrophic calcification were seen in eight cases (25.8%). Both pineocytomatous rosettes (in eight cases; 25.8%) and Homer–Wright rosettes (in two cases; 6.5%) were seen. Synaptophysin was positive in all the cases (n = 16). None of the cases showed p53 protein overexpression (n = 8). Neurofilament protein (NFP) was positive in four cases (28.6%; n = 14). MIB1 LI ranged between 3% and 6% in 19 cases and between 7% and 10% in 7 cases [Figure 1]e,[Figure 1]f,[Figure 1]g,[Figure 1]h. Four showed progression – one (Case 23, 40/F) showed local progression, where the tumor had a mitotic count of 2–3/10 hpf, while the other three cases [Case 7 (18/M), Case 19 (24/F), and Case 32 (28/M)] had subsequent leptomeningeal spinal dissemination. However, none of these cases showed necrosis and MVP. The mitotic rate of the tumors in these cases was ≤5/10 hpf and the tumors had an MIB1 LI of <10%. Two of the three cases that showed leptomeningeal dissemination (Case 7, 18/M and Case 19, 24/F) received only postsurgery RT, while the third case (Case 32, 28/M) received both RT and chemotherapy (CT) after surgery. No treatment-related information was available for the case showing local progression (Case 23, 40/F). Of the 27 cases with no history of progression, postsurgery RT was given in only 18 cases while the rest did not receive any adjuvant therapy.
Table 3: Comparison of clinicopathological features of pineoblastoma WHO grade IV, PPTID WHO grade III, and PPTID WHO grade II

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PPTID (WHO grade III; n = 8)

The age range of the patients in this category was 6–62 years with a mean age of 30.4 years and a median age of 24.5 years [IQR: 41.5 (Q3) -19 (Q1)=22.5 years] [Table 3] and [Table 4]. The M: F ratio was 1.7:1 with a mean tumor size of 5.5 cm (n = 3; range: 4.5–7 cm). One case (Case 43, 6/M) showed a focal hypercellular area of primitive embryonal cell morphology (reminiscent of PB), comprising approximately 10%–15% of the total area (indicative of the presence of a mixed tumor), and the tumor in one case (Case 42, 22/F) showed the presence of diffuse melanin pigment [Figure 2]. In six cases, the mitotic activity was ≤5/10 hpf with a MIB1 LI >10%, while the remaining two cases showed >5 mitosis/10 hpf and an MIB1 LI of >10%. Interestingly, necrosis and MVP were not seen in any of these cases. Dystrophic calcification was seen in three cases (37.5%). Pineocytomatous rosettes were seen in only one case (12.5%), while Homer–Wright rosettes were seen in three cases (37.5%). Synaptophysin was positive in all the cases (n = 4). Focal (labeling in < 50% of tumor cells) p53 protein positivity was seen in a single case; however, none of the cases showed diffuse p53 positivity. NFP was negative in all three cases. MIB1 LI ranged between 11% and 15% in four cases and between 16% and 20% in three cases [Figure 1]i,[Figure 1]j,[Figure 1]k,[Figure 1]l. Four cases showed progression – an isolated local progression was seen in one case (Case 42, 22/F) in which the tumor had shown the presence of melanin pigment; however, on histological examination, the tumor showed a lobular architecture with a mitotic count of 5–6/10 hpf and did not resemble a primitive embryonal tumor. Thus, in this case, a diagnosis of PPTID, grade III was favored over a PB. One case (Case 44, 27/F) had local progression with spinal cord metastasis after 6 months. The tumor in this case showed a mitotic count of 5–6/10 hpf and an MIB1 LI of 15%–18%. Isolated spinal metastasis was seen in one case (Case 39, 62/M) after 3 years. In this case, mitotic activity could not be identified on histology of the primary tumor, but MIB1 LI was 15%–20% and the tumor also showed Homer–Wright rosettes. The tumor in Case 40 (38/M), that developed intraparenchymal metastasis (cerebellar) after 15 months, showed only rare mitosis and had an MIB1 LI of 11%–15%. Of these four cases, three (case numbers 39, 40, and 44) received RT after surgery, while the details were not available in other case (Case 42, 22/F). Of the cases with no history of progression, two received RT while the details in the other two cases were not available.
Table 4: Clinicopathological details of all cases of PPTID (WHO grade III)

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Figure 2: Pineal parenchymal tumor of intermediate differentiation (WHO grade III) showing diffuse melanin pigment [H and E – (a): ×200, (b): ×400]

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PB (WHO grade IV; n = 30)

The age range of the patients was 2–35 years with a mean age of 10.9 years and a median age of 9.5 years [IQR: 17 (Q3) -4.25 (Q1) =12.75 years] [Table 3]. Twenty-seven (90%) cases presented with their tumor in the first two decades of life. Interestingly, three cases were diagnosed at 22, 26, and 35 years of age. Nine cases were <6 years of age, eight were between 6 and 10 years, five were between 11 and 15 years, and five were between 16 and 20 years. A male predominance (M:F ratio 1.5:1) in the cohort was noted. The mean radiological tumor size was 3.4 cm (n = 14; range: 1.6–5.6 cm). Histologically, cellular wrapping, which is a feature of anaplasia, was noted in a single case (Case 51, 3/F). Homer–Wright rosettes were seen in three (10%) cases. Two were further characterized as PAT – one (Case 45, 2/M) showed additional rhabdomyoblast-like and strap cell (myogenic differentiation) morphology, and the other (Case 73, 26/F) showed the presence of prominent melanin pigment within the small round cells and in the extracellular areas resembling a retinal anlage tumor/progonoma/melanotic neuroectodermal tumor of infancy [Figure 3]a,[Figure 3]b,[Figure 3]c,[Figure 3]d. Apoptosis was a common finding in all the included tumors, and eight (26.7%) tumors showed the presence of necrosis. Dystrophic calcification was seen in seven (23.3%) tumors. Synaptophysin was positive in all tumors (n = 13), while chromogranin was positive in three (75%) of four tumors. Focal p53 positivity was seen in six tumors (54.5%; n = 11). Glial fibrillary acidic protein (GFAP) was negative in tumor cells and showed a background astrogliotic staining pattern. Neurofilament protein (NFP) was focally positive in two of four (50%) tumors. MIB1 LI ranged between 10% and 20% in six, 20% and 30% in six, 30% and 40% in two, and >40% in four tumors [Figure 1]m,[Figure 1]n,[Figure 1]o,[Figure 1]p. The strap cells in one of the PAT were positive for desmin and negative for smooth muscle antigen [Figure 3]d. Spinal metastasis was noted in 10 cases. Of these, five cases had additional metastasis [to fourth ventricle (Case 48, 3/M), infundibulum (Case 49, 3/M), cerebellum (Case 52, 4/M), cerebral cortex (Case 56, 6/M), and multiple bones (Case 65, 13/F; humerus, rib, and pelvis), respectively]. Isolated spinal metastasis was seen at presentation in five cases (Case 45, 2/M; Case 47, 2/F; Case 71, 20/M; Case 58, 9/M; and Case 70, 20/M). The three cases of >20 years age group did not show progression. All the cases who showed spinal dissemination underwent CT and RT after surgical excision, except for Cases 45 and 58 where postsurgery treatment details were not available. Of the cases with no history of progression, 7 cases underwent CT and RT, while postsurgery treatment details were not available in 13 cases. [Table 5] elaborates the clinicopathological features of all cases of PPTs with progression.
Figure 3: (a and b) PAT with melanocytic differentiation showing abundant intracellular melanin pigment [H and E: (a) ×40, (b) ×400]. (c and d) PAT with rhabdomyoblastic differentiation showing tumor with embryonal morphology and interspersed rhabdomyoblasts and strap cells [H and E: (c) ×200]; (d) desmin positivity in these interspersed rhabdoid and strap cells (IHC: ×100). PAT: Pineal anlage tumor

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Table 5: Clinicopathological features of primary pineal parenchymal tumors with progression

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PTPR (WHO grades II and III; n = 9)

The age range of the patients was 14–69 years with a mean age of 34.8 years and a median age of 37 years [IQR: 43 (Q3) -19 (Q1) = 24 years] [Table 6]. Young adults and elderly patients were the affected population. Males were twice more commonly affected (M: F 2:1). The mean radiological tumor size was 2.4 cm (n = 5; range: 1.1–4 cm). Six were grade II and three were grade III tumors. MIB1 LI was not available in one case.
Table 6: Clinicopathological details of all cases of papillary tumor of pineal region (WHO grades II and III)

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PTPR (WHO grade II; n = 6)

The age range of the patients was 14–69 years with the mean and median ages of 36.5 and 38 years, respectively [IQR: 42 (Q3) -22 (Q1) =20 years). The M: F sex ratio was 5:1 with a mean size of 2 cm (n = 4; range: 1.1–3.2 cm). Mitotic activity and atypical histological features were not seen in any of these cases. However, MIB-1 LI was available for five cases and ranged from 1% to 4%. All showed the typical histomorphology of papillary architecture with monomorphic polygonal epithelioid or columnar cells with moderate amount of clear or eosinophilic cytoplasm. No fibrillary matrix was seen in any case. No necrosis, mitosis, or MVP was seen in any case. AE1/AE3 was positive in four cases (80%; n = 5), while EMA was negative in all cases (n = 5). B-cell lymphoma 2 (Bcl2) immunoreactivity was seen in three cases (100%; n = 3). S100 protein expression was seen in four cases (75%; n = 5). Focal positivity for GFAP was seen in one (20%; n = 5) case, and synaptophysin was negative in all cases (n = 5). Focal positivity for p53 protein was seen in four cases [80%; n = 5; [Figure 4]. One (Case 79, 39/M) of the cases of PTPR (WHO grade II), who was one of the three cases reported earlier by the author, developed parietal lobe metastasis after 72 months of the primary surgery.[13] The metastases showed similar histological phenotype as the primary (MIB1 LI 2%–4%) without any aggressive/atypical histological features. Case 79 (39/M) who developed intraparenchymal metastasis received RT post excision. Of the cases with no history of progression, four cases underwent RT, while postsurgery treatment details were not available in one case.
Figure 4: (a-f) Papillary tumor of pineal region (WHO grade II). (a and b) Papillary tumor lined by single- to multilayered epithelioid or columnar cells with moderate clear to eosinophilic cytoplasm [H and E: (a) ×200, (b) ×400], (c) Diffuse AE1/AE3 positivity (IHC: ×200), (d) immunonegativity for EMA (IHC: ×400), (e) MIB1 labeling index of 6%–8% (IHC: ×400), (f) focal GFAP positivity (IHC: ×400). AE1/AE3: mouse monoclonal pancytokeratin antibody (AE1/AE3); EMA: epithelial membrane antigen; GFAP: glial fibrillary acidic protein

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PTPR (WHO grade III; n = 3)

The age range of the patients was 19–45 years with a mean age of 31.3 years and a median age of 30 years [IQR: 37.5(Q3) -24.5(Q1) = 13 years]. The M: F ratio was 1:2. The radiological tumor size was known in only one case, which was 4 cm. MIB1 LI was >10% in all the three cases. Mitotic activity was readily identified in all the three cases, necrosis in two cases, and MVP and anaplasia in a single case (Case 83, 19/F). One (Case 81, 30/F) of the cases showed conspicuous cytoplasmic vacuolation resembling signet ring cells. AE1/AE3 and EMA were positive in two (66.7%; n = 3), while EMA was also positive in the same cases. S100 protein expression was seen in two cases (66.7%; n = 3). Focal positivity for GFAP and synaptophysin was seen in one case each (50%; n = 2). p53 protein was negative in all the three cases. MIB1 LI ranged between 10% and 14%. The case (Case 81, 30/F) with cytoplasmic vacuolation developed cerebellar metastasis within 12 months of the initial surgery, and interestingly, the metastatic tumor histologically showed papillary architecture with additional areas of primitive round cell morphology (reminiscent of PB/primitive round cell tumor, possibly a pattern of dedifferentiation) along with a high mitotic activity and rosette formation, which was discordant with the histology of the primary, where no component of primitive embryonal cell morphology was identified [Figure 5]. Case 81 (30/F) who developed intraparenchymal metastases received adjuvant RT and CT, while details for the other two were not available.
Figure 5: (a-h) Papillary tumor of pineal region (WHO grade III). (a-d) Tumor of papillary architecture lined by columnar and polygonal cells with cytoplasmic vacuolation and areas of necrosis [H and E: (a) ×100, (b and c) ×400, (d) ×200], (e) positivity for AE1/AE3 (IHC × 200), (f) MIB1 labeling index of 10%–12% (IHC × 100), (g and h) metastatic site displaying focal papillary architecture and areas resembling pineoblastoma with numerous mitosis (encircled) and rosettes (arrow) [H and E: (g) ×200, (h) ×400]

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 » Discussion Top


Tumors of pineal parenchyma are rare with varying reported incidence between 0.2% and 2%; 2.7% and 11% in children and 0.4% and 1% in adults.[1],[2],[4],[5],[14],[15],[16],[17] As per the Central Brain Tumour Registry of the United States, TPR constituted only 0.18% of all the reported brain tumors between 2009 and 2013.[4] In the French registry, the primary pineal tumors were represented by 13% of pineocytoma, 66% of PPTID, and 21% of PB, while in the Lyon registry, it was represented by 20% of pineocytoma, 55% of PPTID, and 21% of PB.[17] In comparison to these large registries, the proportion of pineocytoma was lesser, while that of PB was higher in our institutional experience; this possibly was due to the referral bias of our hospital being a tertiary care center. Mena et al., in 1995 reported the proportion of pineocytoma, PB, and mixed pineocytoma and PB as 60%, 31%, and 19%, respectively.[18] A decrease in the reported incidence of pineocytoma and an increase in the incidence for PPTID is being observed since the 3rd WHO classification in 2000. The reported incidence of pineocytoma is decreasing over the years, while that of the intermediate category is increasing. This difference in proportion is expected as the classification and criteria have evolved over the time aided by better understanding of the clinical behavior of these tumors. A lot of cases that were diagnosed as pineocytoma previously showed leptomeningeal spread and were reclassified as PPTID after 2000.[1],[19],[20],[21] Since then, this is one of the biggest single-institutional study, especially from our subcontinent detailing the histomorphological features of the entire spectrum of primary pineal tumors.

Pineal tumors on histology are a continuous spectrum with pineocytoma showing the least aggressive features, while PB has the most aggressive features. Although the criteria distinguishing between PPTID grades II and III are not well-defined, most of the cases can be classified into one of the categories based on the MIB-1 LI. However, some of the cases show borderline features (like Case 43 showing areas of PPTID and PB, and Case 42 showing features of PPTID with diffuse melanin pigment), which require more elucidation. In this study, the cases are histologically classified based on the predominant morphology. The current 2016 WHO classification has also not set any clearly defined criteria (like the number of mitoses) to distinguish between grades II and III of PPTIDs and also of PPTRs.[5],[10] Studies have used mitotic count, MIB1 LI, and NFP expression for grading of PPTID.[9],[10] Jouvet et al., proposed that NFP (clone 2F11) expression can be used to distinguish between PPTID grades II and III as per their observation of very focal expression or absent NFP expression in grade III tumors when compared with grade II ones. However, they also raised concerns about interlaboratory variability in the NFP expression, which can be a limitation in its application for routine grading.[5] Yu et al., also could not confirm the utility of NFP expression to grade PPTID, and hence its role remains controversial.[22] However, in this study, NFP positivity was seen in 28.6% of PPTID grade II tumors and in none of the PPTID grade III tumors. However, interestingly, two cases (50%) of PB showed focal NFP positivity, thus raising questions on the reliability of NF expression for distinguishing low- and high-grade PPTs. Regarding mitotic activity, Jouvet et al., proposed a cut-off of <6 mitosis/10 hpf for the diagnosis of PPTID (WHO grade II).[5] However, the recent WHO classification does not give any cut-off values. In this study also, >5 mitoses/10 hpf were also considered one of the features for the tumor to be classified as PPTID, grade III. The authors, however, feel that there are several factors which affect the evaluation of the mitotic count like the amount of tissue resected for examination (tumor heterogeneity with sampling limitations), optimal tissue processing protocols (prolonged fixation protocols can lead to an erroneous low mitotic count, and poor processing will change the cytomorphology of mitotic figures leading to an erroneous low count), and also interobserver variability. These factors are especially important at a tertiary referral cancer center like ours (where the predominant cases are referral material of paraffin blocks from various other laboratories and institutions with often indifferent treatment protocols). These factors may limit the exclusive dependence on mitotic activity for the grading of PPTID. Fevre-Montange et al., in their study, reported the MIB1 LI range of 5.2% ±0.4% in PPTID (WHO grade II) and of 11.2 ± 2% in PPTID (WHO grade III).[9] The comparison of MIB1 LI with the pattern of progression in PPTID and PB is elaborated in [Table 7]. Cases with a mixed composition of pineocytoma and PB were initially included by Jouvet et al., with PPTID.[5] Case 43 (6/M), of the present series, displayed only scanty PB-like features, and thus was considered not distinctive enough to be labelled as PB (WHO grade IV). It was, therefore, classified as PPTID, WHO grade III. The updated 4th WHO classification defines PB as a tumor with any areas of primitive embryonal cell morphology and also includes tumors with mixed pattern of PPTID and PB; however, in this Case no. 43 of the present series, the areas of PB-like morphology were very scanty and the patient was also of a young age. These factors are still an issue of uncertainty in the histological typing of these lesions.[23] Divergent differentiation has not been reported in cases other than PB; Case 42 (22/F) of this study showed the presence of prominent melanin pigment similar to that seen in PAT but without the typical morphology of the primitive embryonal cell morphology. In view of the presence of extensive melanin pigment, the authors are not very certain of classifying this tumor as PB/PAT or PPTID, grade III. As the presence of melanin alone is a doubtful feature of a heterologous ectomesenchymal tumor, and also due to the lack of typical histomorphological features of a PB, this case was classified under the category of PPTID, grade III. The authors do acknowledge the fact that this case had a very aggressive biological behavior, thus raising a question of whether or not a high-grade PPT associated with the presence of extensive/diffuse melanin pigment should also be classified under the category of PB/PAT.
Table 7: Comparing MIB1 LI to progression in pineoblastoma, pineal parenchymal tumor of intermediate differentiation WHO grades III and II

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Stratification of PPTID into grade II or III was a challenge in some cases. The scant nature of the material precluded an optimal evaluation in most of such cases. For the sake of uniformity across the tumor specimens, despite the presence of occasional mitosis or spotty foci of necrosis in tiny tissues, these cases were classified as PPTID (WHO grade II) as the MIB1 LI was ≤10%. Cases without mitotic activity along with negative staining for NFP also posed a question but were classified as PPTID (WHO grade II) based on the MIB1 LI being not more than 10%. In this study, NFP expression was not taken into consideration for grading of these tumors. The distinction between PPTID (WHO grade III) and PB (WHO grade IV) was also difficult in two cases. One of the cases (Case 42, 22/F) showed the presence of diffuse melanin pigment in an otherwise PPTID (WHO grade III), which was discussed above. One case (Case 43, 6/M) diagnosed as PPTID (WHO grade III) showed predominant areas resembling a PPTID (WHO grade III) and also focally (10%–15%) presented with a PB-like area; however, in the authors' own experience, since PBs show a uniform histomorphology of monomorphic cells of primitive embryonal morphology, the scant focal undifferentiated area possibly represents dedifferentiation of the PPTID rather than differentiation in PB.

Pineocytomas (WHO grade I) are tumors that occur in the young and middle-aged people with a mean age of 43 years, and the finding of the mean age of 44.2 years in this study is concordant with this observation.[5],[24] They form 17%–30% of PPTs with a female preponderance, whereas in this study, their incidence was only 6.8% with no gender predilection, which is probably due to the referral bias of the institutional practice.[5],[19],[24],[25] The histological findings of lobular architecture with lack of mitotic activity and necrosis were typical and similar to the features reported in the literature. However, none of cases of pineocytoma in the present series showed ganglionic and/or glial differentiation and none showed pleomorphism, which is also reported in the literature as a rarity.[5],[8],[20],[21],[26] Pineocytomas are immunopositive for synaptophysin, neuron-specific enolase (NSE), and NFP.[5],[27] The MIB1 LI is very low in pineocytomas.[7],[9] The immunoprofile in this study is similar to that of other studies; however, this study is limited by the lack of evaluation for NSE.

PPTID was the term first introduced by Schild et al., in 1993 to describe cases with intermediate histological and prognostic features. Subsequently, in the 3rd WHO classification 2000, PPTID was identified as a separate class of PPTs, and in the subsequent 4th WHO classification, they were further refined to grades II and III. The same system is retained in the recent 2016 updated 4th WHO classification, without any clearly defined criteria.[5],[10],[19],[21],[28] PPTIDs form 21%–54% of PPTs and their incidence was 52.7% in this study.[25],[29] They are predominantly seen in adults with a mean age of 41 years and a mild female (M: F 0.6:1) preponderance.[10] The mean age in this study was 32.1 years and showed no gender predilection. The mitotic count reported in literature is variable. In this study also, the presence of mitosis was not the only criterion to make a diagnosis of grade III PPTID, that is, having a marked pleomorphism per se (without mitotic activity) was not considered enough to make a diagnosis of PPTID, grade III, as has been reported in the literature.[10] The MIB1 LI was intermediate between that of pineocytoma and PB, justifying the retention of this category of tumors as an intermediate group of PPTs.[7] Based on the findings of Fevre-Montange et al., the mean MIB1 LI in PPTIDs (WHO grade II) is about 5.2 ± 0.4, which is significantly less than the value of 11.2 ± 2.0 seen in PPTID (WHO grade III) tumors.[9] Based on these findings, an arbitrary cut-off value of 10% in the MIB1 LI was also taken for making a distinction between grade II and III PPTIDs, especially in the cases with low or nonevident mitotic activity. Accordingly, the MIB1 LI ranged from 3% to 10% in PPTID, grade II; and, from 11% to 20% in PPTID, grade III in this study.

PBs are WHO grade IV tumors accounting for 24%–61% of all PPTs, whereas they constituted 40.5% in this study.[5],[19],[23],[25],[30] They are predominantly seen in the pediatric population and characterized by rapid tumor growth, which was also noted in this study. Cases of PB in adult patients have also been reported.[31],[32] Three cases (10%) in this study were above the age of 20 years. In contrast to the reported slight female preponderance (M: F 0.7:1) in the literature, a male preponderance (M: F 1.5:1) was noted in this study, which was probably related to the bias due the sociocultural factors.[23] They are positive for synaptophysin, NSE, and NFP, but show weaker staining characteristics when compared with PPTID and pineocytoma.[5],[7],[21],[33] Fevre-Montange et al., observed the mean MIB1 LI of 36.4 ± 6.2 in these tumors, and in this study, the MIB1LI ranged between 10% and 80%.[9] Bcl2 expression is reported to be associated with a poor prognosis; however, this study is limited due to the lack of evaluation of this factor.[34]

Cases of PB with divergent differentiation are termed as PAT. These tumors are considered as a subtype of PB by the current WHO classification but not considered as a separate entity.[11],[35],[36] These tumors show neuroectodermal with ectomesenchymal differentiation. Similar to PB, these tumors are seen in children with a mean age of 19.7 ± 33.2 months.[23],[35],[37] Two cases in this study showed the diffuse presence of melanin pigment, and one additional case showed rhabdomyoblastic differentiation. Of the two cases with melanin deposition, one of them had the morphology of PB, while the other had that of PPTID, grade III. The case with the primitive embryonal morphology was considered as PAT, while the other was not, as discussed above. In this study, Case 45 (2/M) showing the presence of rhabdomyoblasts was a 2-year old child, while the patient with melanotic differentiation (Case 73, 26/F) was a 26-year old adult. These tumors were first described by Schmidbauer and may show abundant melanin production, cartilaginous differentiation, or rhabdomyoblastic differentiation.[11] The neuroepithelial differentiation can be seen in the form of neuronal, glial, and retinal elements. The ectomesenchymal elements are seen in the form of rhabdomyoblasts and cartilage.[36] These components are seen together with pineoblastomatous areas. Fetal pineal gland contains abundant melanin pigment which decreases after birth. According to a study, the presence of the melanin pigment denotes the neuroectodermal differentiation capacity.[36] The presence of melanin pigment in a tumor may also indicate recapitulation of embryonal development. Although there is no sufficient evidence to label a PB as PAT by the mere presence of melanin, in this study, it was considered as PAT. Gudinaviciene et al. reported cases showing only mature elements without areas resembling a PB.[38] However, it is important to distinguish these tumors from teratomatous germ cell tumors containing cartilage and rhabdomyoblasts.[35],[36] The presence of areas of the classical PB may be helpful in establishing the diagnosis but may resemble primitive neuroepithelium. Absence of endodermal elements has been used by some authors to rule out a teratoma.[37] However, a small biopsy may not be representative in a case of teratoma. The serum and cerebrospinal fluid tumor marker levels, if elevated, suggest the presence of a germ cell tumor. In this study, none of the cases showed a mature tissue component and elevated tumor marker levels. All the cases in this study showed retained INI1 protein, excluding the possibility of an atypical teratoid/rhabdoid (AT/RT) tumor. PATs are similar to retinal anlage tumors on histology but have a worse prognosis, akin to a PB.[11],[36],[37],[39] The MIB1 LI in PAT is analogous to that seen in PB.

PTPRs are of uncertain histiogenesis occurring in the pineal region. They were first described as a separate entity by Jouvet et al., in 2003 and were included as a separate entity in the WHO 2007 classification.[40] Ependymal cells of subcommissural origin are the possible cells of origin, based on the ultrastructural findings (like presence of microvilli and zipper-like junctions) and gene expression (ZFH4, RFX3, TTR and CGRP and SPDEF) findings.[40],[41] However, the gene expression profiling results of PTPRs are different from that of PPTs, and PTPRs were thus identified as a distinct entity.[41],[42] Although the initial study by Jouvet et al., showed a female predominance for PTPRs, while the initial reports of papillary pineocytoma were seen predominantly in males, the larger series on PTPRs do not report any gender predilection. In this study, however, a male predominance (M:F 2:1) was observed.[6],[18],[40],[43],[44],[45] They are seen in young adults and elderly patients with a wide age range of 5–66 years, and a mean and median age of 35 and 29 years, respectively. These findings were similar to that of this study where the mean and median ages were 34.8 and 37 years, respectively.[6],[40],[46] They are well circumscribed on radiology and range in size from 2.5 to 4 cm. In this study, the radiological tumor size ranged between 1.1 and 4 cm. These tumors show papillae with a fibrovascular core lined by single- to multilayered columnar cells and had a similar morphology in this study.[7],[13] Vacuolated signet ring-like cells described in one of our case (Case 81, 30/F) has also been once previously described in literature.[40] The mitotic count is variable (range 0–13/10 HPF), but necrosis is often seen particularly in PTPR (WHO grade III). In this study, the mitotic count of >5/10 hpf and/or the MIB1 LI of >10% were taken as features of PTPR grade III. Six cases had a mitotic count of ≤5/10 hpf but had an MIB1 LI of >10%. MVP is rarely seen in these tumors.[6],[21] In this study, MVP was seen in one case (Case 83, 19/F; 11.1%) of PTPR. PTPRs are immunoreactive for pancytokeratins like AE1/AE3, and particularly for CK18.[46] Hasselblatt et al.,[47] reported a focal cytokeratin staining in 20% of cases, while Poulgrain et al., have also reported a negative AE1/AE3 staining.[48] CK18 was not done in any of our cases, while AE1/AE3 was positive in six of eight cases. Vimentin, synaptophysin, NSE, and S100 protein are also positive in the tumor. A similar immunostaining was seen in this study. GFAP and EMA are generally negative or focal and help to differentiate them from an ependymoma and a choroid plexus tumor. GFAP staining is seen particularly in the perivascular areas. AE1/AE3 and EMA help to differentiate a PTPR from a papillary meningioma. NFP is rarely positive. However, the most important feature of PTPRs, as per the authors' observations, is the histological lack of fibrillary matrix with a conspicuous immunonegativity for GFAP, coupled with immunopositivity for at least one epithelial marker (CK [cytokeratin] or EMA) but without the perinuclear dot-like positivity pattern. The MIB1 LI in the literature ranges between 1% and 29.7%.[6],[7],[13],[21],[40],[46],[49] In this study, the MIB1 LI ranged between 1% and 14%. A mitotic activity of ≥3/10 HPF and an MIB1 LI of ≥10% are significantly associated with recurrence and may be the criteria required for differentiating between grade II and III tumors.[12] Local recurrence and progression in PTPR are common and have been reported in up to 63%–70% cases.[12],[46] These lesions are also reported to be having a metastatic potential, with spine being the most common site.[40],[46],[50] In the largest series by Fevre-Montange et al., 2 of 29 cases with an available follow-up developed spinal metastasis.[46] Sato et al., described a case of multicentric PTPR with lesions at the pineal and suprasellar regions at presentation, who on follow-up had leptomeningeal spread.[51] Cerebellar metastasis has been described in one another study, where a 25-year old female patient developed a satellite lesion and local progression 23 months after the initial resection.[48] In this study, two cases developed intracranial metastasis (one to the parietal lobe and the other to the cerebellum) and none showed a spinal dissemination. The histology of parietal metastasis (Case 79, 39/M) was similar to that of the primary, whereas the cerebellar metastases in a case (Case 81, 30F) showed a discordant histology of primitive round cell morphology. Similar to the present case (Case 81, 30/F), Heim et al., also reported a case of PTPR with areas of anaplastic small cell component, where the conventional PTPR area was juxtaposed to the lesser differentiated cellular solid areas composed of cells of primitive embryonal cell morphology. The high-grade area showed an increased mitotic activity and a higher MIB1 LI than the conventional PTPR. Cytokeratin was positive in both the areas.[52]

In conclusion, PPTs can display a morphological continuum. Despite the presence of the suggested criteria, it may be difficult to grade these tumors, especially in borderline cases and in cases with a scant tumor tissue. Pineocytomas do not have a propensity to progress and are actually rarer than previously thought. PPTIDs are the most common PPTs and have the potential for dissemination irrespective of their grade, although dissemination is more common in grade III tumors. In view of the difficulty of grading them and in establishing the exact typing, and the relative potential of the tumor to disseminate in both the grades, one may consider introducing a broad umbrella term of “high-grade PPT, not other specified (NOS).” PB and PAT are seen in a predominantly pediatric population. Some of these tumors may have a propensity to developing distant metastasis, to areas like the bone. Interestingly, in this study, none of the cases of PB >20 years of age had presented with tumor dissemination. This raises the possibility of a different biological behavior in PB in patients >20 years. However, the authenticity of this statement needs to be evaluated in a larger prospective study. PTPRs may show a varied morphology and immunohistochemical features and also may have a metastatic potential as seen in PPTIDs, but more commonly exhibit parenchymal rather than leptomeningeal/spinal metastases. Finally, the authors do acknowledge the fact that this study is largely limited by a lack of well-defined criteria for grading of these lesions and a lack of molecular studies in the literature.

Ethics statement

The study was approved by our Institutional Ethics Committee

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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