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### Immunohistochemistry |
IHC for p53 and TTF1-p40 doublestaining were performed on a Ventana Benchmark Ultra immunostainer (Roche, Basel, Switzerland). For detection and visualization of p53, mouse monoclonal anti-P53 diluted 1:2000 in Ventana diluent (double clone DO-7 + BP53-12 catno. MS-738-P, Epredia, Breda, the Netherlands) was used. In b... |
For detection and visualization of the TTF1 and p40 doublestaining, mouse monoclonal anti-TTF1 (clone 8G7G3-1, catno. M3575, Dako/Agilent, Glostrup, Denmark) was used and diluted 1/400 in diluent from Dako/Agilent (catno. S3022, Glostrup, Denmark). Sections were pretreated with CC1 (pH8.5) for 32 min at 100 °C and the ... |
After the immunohistochemical staining, the sections were rapidly dehydraded with grades of ethanol and cleared with xylene. All sections were mounted with Tissue Tek® coverslipping film (Sakura Finetek, Alphen aan de Rijn, the Netherlands). |
Six cases underwent Next Generation DNA Sequencing using custom lung panel designed to cover 27 genes [25]. |
## Results |
A total of 22 cases (3 biopsies and 19 resection specimens) with subepithelial growth, corresponding to 21 patients (one patient had in two years two metachronous SCC in separate lobes), were collected. Clinicopathological features are summarized in Table 1. |
[TABLE] Clinicopathological feature of all patients in the study |
Case n | Sex | Age | Smoking | ILD | Tumour location | CT appearance | Location | Pleura | Total Diameter (cm) | TNM 8th Edition 2017 | p53 IHC | Molecular analysis | Subepithelial pattern SCC | AF SCC (%) | Infiltrative SCC (%) | Previous biopsy | Relapse | FU period (months) |
Lepidic- subepithelial (%) | Alveolar-subepithelial (%) |
1 | M | 64 | yes | yes | LSL | subsolid | peripheral | PL1 | 1,7 | pT2aN0 | MU | not performed | 0 | 10 | 0 | 90 | not performed | no | 0 |
2 | F | 67 | unknown | no | RSL | solid | peripheral | PL0 | 6 | pT3N0 | MU | not performed | 0 | 40 | 0 | 60 | not performed | unknown | unknown |
3 | M | 69 | yes | no | LSL | solid | peripheral | PL0 | 1,2 | pT1bN0 | MU | not performed | 0 | 70 | 0 | 30 | not performed | no | 38 |
4 | M | 63 | unknown | no | RIL | solid | peripheral | PL0 | 2,8 | pT1cN0 | MU | not performed | 0 | 90 | 0 | 10 | unknown | unknown | unknown |
5 | F | 74 | yes | no | RSL | solid | central | NA | 1,5 | cT1bN0 | MU | TP53 ex7 c.725G > T (p.C242F) | 0 | 100 | 0 | 0 | unknown | no | 4 |
6 | F | 70 | yes | no | RSL | subsolid | peripheral | PL0 | 1,4 | pT1bN0 | MU | TP53 ex5 c.380C > A (p.S127Y) | 25 | 25 | 0 | 50 | not performed | no | 14 |
7 | F | 67 | unknown | no | LIL | subsolid | peripheral | PL0 | 1,8 | pT1bN0 | MU | TP53 ex4 c.313G > T (p.G105C) | 70 | 0 | 0 | 30 | yes | no | 6 |
8 | F | 81 | unknown | no | LSL | solid | peripheral | PL1 | 1,1 | pT2aN0 | MU | not performed | 15 | 5 | 0 | 80 | not performed | unknown | unknown |
9 | F | 75 | yes | no | RIL | subsolid | peripheral | PL0 | 2,5 | pT1cN0 | MU | not performed | 15 | 5 | 0 | 80 | unknown | unknown | unknown |
10 | F | 53 | unknown | no | LIL | solid | peripheral | PL0 | 5,2 | pT3N2 | MU | not performed | 75 | 15 | 0 | 10 | unknown | unknown | 10 |
11 | M | 69 | yes | no | LSL | cystic | peripheral | PL0 | 1,9 | pT1bN0 | MU | not performed | 75 | 15 | 0 | 10 | unknown | no | 12 |
12 | M | 75 | yes | no | RSL | solid | peripheral | NA | 2 | cT1bN0 | MU | not performed | 100 | 0 | 0 | 0 | not performed | no | 4 |
13 | M | 61 | unknown | no | RIL | subsolid | peripheral | PL0 | 2,1 | pT1cN0 | MU | not performed | 100 | 0 | 0 | 0 | unknown | unknown | unknown |
14 | F | 75 | former smoker | no | RSL | subsolid | central | NA | 2 | cT1cN0 | WT | KRAS ex4 c.344 G > A (p.G115E) (VUS), STK11 ex2 c.356A > G (p.N119S) (VUS),TP53 ex5 c.475G > C, (p.A159P) | 100 | 0 | 0 | 0 | unknown | no | 24 |
15 | F | 63 | yes | yes | RSL | solid | peripheral | PL0 | 2,3 | pT1cN0 | MU | not performed | 60 | 0 | 10 | 30 | yes | no | 23 |
16 | F | 69 | former smoker | yes | RIL | solid | peripheral | PL0 | 1,8 | pT1bN0 | MU | CDKN2A ex2 c.299C > A, (p.A100D) (VUS), TP53 ex7 c.725G > C (p.C242S) | 5 | 5 | 20 | 70 | yes | no | 17 |
17 | F | 71 | yes | no | LSL | solid | peripheral | PL0 | 1,4 | pT1bN0 | MU | not performed | 5 | 30 | 30 | 35 | not performed | no | 56 |
18 | M | 71 | yes | yes | RIL | solid | peripheral | PL0 | 4,5 | pT2bN0 | MU | not performed | 0 | 10 | 50 | 40 | not performed | no | 38 |
19 | F | 63 | yes | yes | LIL | subsolid | peripheral | PL0 | 1,7 | pT1bN0 | WT | not performed | 20 | 5 | 55 | 20 | yes | no | 33 |
20 | F | 51 | yes | no | LSL | solid | peripheral | PL0 | 3,2 | pT2aN0 | MU | not performed | 5 | 5 | 80 | 10 | not performed | no | 43 |
21 | F | 75 | former smoker | no | RML | solid | peripheral | PL1 | 2,8 | pT2aN0 | MU | no mutations detected | 10 | 10 | 80 | 0 | not performed | no | 34 |
22 | M | 75 | unknown | no | RIL | solid | peripheral | PL1 | 2 | pT2aN2 | MU | not performed | 10 | 10 | 80 | 0 | unknown | unknown | unknown |
The cohort included a higher proportion of female patients (n = 13, 62%) with a median age of 69 years (range 51–81 years). Among resected cases, the median tumour diameter was 2 cm (range 1,1–6 cm). In terms of pathological TNM, 11 of resected cases showed pT1 (0 pT1a, 7 pT1b and 4 pT1c), eight cases showed pT2 or pT3... |
All but two cases (95%) in the study cohort were peripheral SCC. |
The distribution of the two subepithelial growth patterns in the cohort was: 100% in four cases (three biopsies and one resection), n = 3 cases with 90%, n = 11 cases between 20 and 70%, and n = 4 with 10% of subepithelial growth (Fig. 2) (Table 1). |
In all cases, subepithelial growth was confirmed with double stain TTF1/p40. Most of the cases (20 out of 22, 91%) showed a mutation-type labeling for p53 corresponding to complete absence or strong positivity of immunoreactivity in at least 80% of the tumour cells (Fig. 3). Six cases were sequenced and of those all ex... |
Lepidic-subepithelial growth was mostly encountered at the periphery of the nodule with a central area of infiltrative SCC. Alveolar-subepithelial growth was located both central and peripheral within the tumor. Lepidic-subepithelial and alveolar-subepithelial growth pattern were both present in 11 cases (50%), while 5... |
Among resection specimens, four cases had preoperative biopsy and one of them showed fully lepidic-subepithelial growth in the biopsy, posing a diagnostic challenge. |
More histological pictures of subepithelial SCC are shown in supplementary material (Supplementary Fig. 1–6). |
On CT-scan seven cases (33%) showed a subsolid nodule and among them four cases had a subepithelial component ≥50% (Fig. 4); all the other cases except one presented radiologically as a solid nodule; a single case showed a cystic appearance. |
Four patients (19%) had concomitant interstitial lung disease. |
Follow up information was available in 15 out of 21 patients (71%), none of which experienced recurrence after a median follow-up time of 20 months (range 4–56); three patients died within three years after surgery for non-lung cancer related causes without signs of recurrence. |
Given the rarity of this growth pattern, we summarized the clinicopathologic features of cases previously reported in the English literature (Supplementary Table 1). |
## Discussion |
We systematically describe a SCC series with a rare and under-recognized growth pattern: the subepithelial growth pattern. In our series, as well as in most cases reported in the English literature, subepithelial SCC appear to be associated with good prognosis and in one third of cases the tumour nodules have a ground ... |
Most of SCC are central tumours with one third of cases that are peripherally located. Peripheral SCC were related to a better outcome compared to central SCC at the same stage [1, 7, 8], especially when more than 70% of AF pattern is present [11]. This pattern is associated with excellent prognosis, with no evidence o... |
Assuming its favorable prognostic role, AF growth has been proposed to represent a pre-invasive phase in an hypothetical progression to invasive SCC [7, 10] and Guerrieri and colleagues [19] proposed a step-wise progression of SCC from “lepidic-subepithelial” to infiltrative, passing through “alveolar subepithelial” pa... |
Assuming its favorable prognostic role, treatment decisions could also rely on the presence of the subepithelial component, in both medical and surgical approaches (for example giving the opportunity of a more conservative surgery or denying a chemotherapy) especially in early stages. This is also true for AF SCC: lung... |
The presence of subepithelial growth was mostly evidenced at the edge of the tumour, giving in some cases (7 out of 22) a ground glass appearance at CT-scan, similarly to adenocarcinoma with lepidic growth, as previously observed [12–14, 16, 18]. The presence of subepithelial growth at the periphery of the tumour shoul... |
Lepidic adenocarcinoma is characterized by neoplastic cells TTF1 positive laying on the alveolar wall, while in lepidic-subepithelial SCC atypical squamous cells (p40 positive and p53 mutated) are encountered under normal or reactive pneumocytes. |
In adenosquamous carcinoma both adenocarcinoma and SCC must be encountered (at least 10% of each component) as separate parts of the same tumor or intermixed; on the contrary in subepithelial growth of SCC adenocarcinoma cells are not present. The difference between the reactive pneumocytes type 2 and neoplastic cells ... |
Limitations of our study are represented by the limited number of cases in our cohort (even if this is the largest series of subepithelial SCC to our knowledge) and by the small number of cases that underwent comprehensive molecular characterization. However, 91% of cases showed a mutation-type labeling for p53 in IHC ... |
In conclusion, subepithelial growth is a rare but important to recognize growth pattern of peripheral SCC with two different models of growth: lepidic-subepithelial and alveolar-subepithelial, with corresponding peripheral ground glass radiological pattern. Subepithelial growth should not be mistaken for adenosquamous ... |
Legends of Supplementary Figures |
Suppl. Figure 1 Examples of lepidic-subepithelial growth pattern (case A-B) and alveolar- subepithelial growth of squamous cell carcinoma (C-D). (A, C Haematoxylin–eosin; B, D double stain TTF1 brown and p40 red). |
Suppl. Figure 2 Two cases of squamous cell carcinoma with lepidic-subepithelial growth at the edge of the tumour. At low power (A and E) the lepidic-subepithelial growth mimic the lepidic growth of adenocarcinoma. A-D Case 1, E–H Case 2. C-D and G-H correspond to a high magnification view of the lepidic-subepithelial c... |
Suppl. Figure 3 Squamous cell carcinoma with predominant lepidic-subepithelial growth. Low power view (A and B) and high-power view (C and D). Image C shows the tumour growing mostly as scattered cells under pneumocytes (lepidic-subepithelial pattern) with some focal areas of alveolar-subepithelial growth. The tumoral ... |
Suppl. Figure 4 Alveolar-subepithelial squamous cell carcinoma (SCC). Low power view (image A) and high magnification (B, C, D) of the tumour. Tumour nests of SCC grow within the alveolar spaces under normal pneumocytes TTF1 positive. (A,B,C Haematoxylin–eosin; D double stain TTF1 brown and p40 red). |
Suppl. Figure 5 Case of SCC with both lepidic-subepithelial and alveolar-subepithelial growth pattern at the edge of the tumour. C and D correspond to high magnification areas at the periphery of the tumour. (A Haematoxylin–eosin; B,C,D double stain TTF1 brown and p40 red). |
Suppl. Figure 6 Biopsies of lung tumours showing squamous cell carcinoma (SCC) growing under normal pneumocytes. Images A and B correspond to a case of lepidic-subepithelial pattern of SCC, highlighted by p40 positive cells; pictures C and D show the biopsy of a case with alveolar-subepithelial SCC. (A,C Haematoxylin–e... |
## Supplementary Information |
Below is the link to the electronic supplementary material. |
## Author contribution |
Federica Filipello: Writing, Conceptualization. Francesca Ambrosi: Investigation. Hans Blaauwgeers: Investigation. Johanna Grefte: Investigation. Wim Vos: Investigation. Luisella Righi: Investigation. Erik Thunnissen: Conceptualization, Investigation. Teodora Radonic: Writing, Supervision, Conceptualization, Investigat... |
## Declarations |
### Competing interests |
The authors have no competing interests related to this manuscript. |
## Footnotes |
## References |
## Associated Data |
### Supplementary Materials |
b1916c2c0b77b7bcd3f249552aabd64da797ba1ccda4ec0446529d147e3c2438 pmc13368955.txt |
PMCID: PMC13513445 |
TITLE: Beyond Oligodendroglioma: An Integrated Diagnostic Approach to CNS Tumors with Oligodendroglioma-like Morphology, with a Focus on Morphological Pitfalls, Immunoprofiles, and Molecular Signatures |
LICENSE: https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. |
ABSTRACT: Oligodendroglioma-like morphology, classically recognized by round nuclei, optically clear cytoplasm, and perinuclear halos, is one of the most familiar patterns in neuropathology but also one of the most diagnostically misleading. Although historically associated with oligodendroglioma, this phenotype is now... |
## 1. Introduction |
Over the past two decades, the classification of central nervous system tumors has evolved from a predominantly morphology-centered system to an integrated morphomolecular framework. Histology remains the indispensable first diagnostic tool of neuropathology, but it can no longer be considered sufficient to define tumo... |
This conceptual transition is particularly relevant for lesions showing oligodendroglioma-like or clear-cell morphology. The classic “fried egg” appearance, with round nuclei and perinuclear halos, was historically regarded as highly suggestive of oligodendroglioma. It is now clear that the same appearance may be encou... |
Within contemporary practice, the pathologist’s task is therefore not merely to recognize an oligodendroglioma-like pattern, but to determine which biological entity is producing it. Morphology functions as the entry point of a diagnostic algorithm. It should trigger an appropriately prioritized sequence of clinico-rad... |
This review proposes a structured and practical approach to CNS lesions with oligodendroglioma-like or clear-cell morphology. The main goal is to offer a diagnostic workflow that can be adapted to centers with variable access to advanced molecular diagnostics. |
## 2. Oligodendroglioma-like Morphology: A Pattern, Not a Diagnosis |
Oligodendroglioma-like morphology does not denote a specific nosological entity. It describes a recurring microscopic phenotype characterized by relatively uniform round cells, optically clear cytoplasm, perinuclear halos, and, in some cases, a delicate capillary network. The cytoplasmic clearing often reflects fixatio... |
Recognition of this convergence is critical. A true oligodendroglioma, IDH-mutant and 1p/19q-codeleted, has a distinct prognosis and therapeutic sensitivity. By contrast, an IDH-wildtype glioblastoma with small cell or oligodendroglioma-like morphology, a supratentorial ZFTA-fused ependymoma, a diffuse glioneuronal tum... |
The practical implication is that the phrase “oligodendroglioma-like” should be used as a morphological descriptor and diagnostic prompt and that it should not be allowed to function as a substitute for integrated classification. |
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