Abstract
Introduction
The prognosis of pleomorphic carcinoma of the lung is poor with a propensity of metastasis and distant recurrence. The high intratumoral heterogeneity and variable morphologic composition of pleomorphic carcinomas lead to underdiagnosis in biopsy specimens from non-small cell carcinomas. This study aims to detail the p53 expression pattern in pleomorphic carcinoma and its role in biopsy assessment.
Methods
p53 immunostain was performed on a cohort of pleomorphic carcinoma resection and corresponding biopsy specimens, with TP53 sequencing performed on microdissected pleomorphic and non-pleomorphic components.
Results
A total of 30 cases were analyzed and non-pleomorphic components were identified in 11 cases. Aberrant p53 immunostain expression was seen in 24 (80%), consisting of 11 (36.7%) overexpression (≥ 90%) and 13 (43.3%) null patterns. The non-pleomorphic components showed concordant p53 expression with the pleomorphic components. All 11 corresponding biopsy specimens, and an additional adrenal metastatectomy, showed concordant aberrant p53 expression. Four cases were suitable for sequencing, and TP53 mutation was detected in all. In three cases, identical TP53 mutations (F134L, G245V and C227F) were found in the non-pleomorphic and pleomorphic components, with aberrant p53 staining. Concurrent EGFR mutation was seen in the case with C227F mutation. The remaining case showed different TP53 mutations in the non-pleomorphic (R342) and pleomorphic components (G245S with wild-typeimmunostain pattern.
Conclusion
TP53 mutation and aberrant p53 immunostain expression are consistently and concordantly observed in pleomorphic, non-pleomorphic components, metastatic and small biopsy specimens of pleomorphic carcinomas. There is value in performing p53 immunostain for diagnosing pleomorphic carcinoma in small specimens.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13000-025-01677-4.
Keywords: p53, Immunohistochemistry, Pleomorphic carcinoma, Biopsy
Introduction
The prognosis of pleomorphic carcinoma of the lung is among the poorest in non-small cell lung cancers (NSCLCs), with a propensity of metastasis and distant recurrence even in cases of complete resection and/or low disease stage [1]. Pleomorphic carcinomas display high intratumoral heterogeneity [2] and a variable composition of pleomorphic (spindled and/or giant) cells among typical adenocarcinoma, squamous cell carcinoma or other NSCLCs [3]. The diagnostic pleomorphic components are often not sampled or recognized in small specimens, leading to an underdiagnosis in biopsies [4]. TP53 mutation has been frequently reported in pleomorphic carcinomas [5–7]. Its surrogate immunostain p53 appears promising as a diagnostic adjunct of this entity in limited specimens. In this study, p53 immunostain was performed on a cohort of pleomorphic carcinomas and corresponding biopsy specimens, with TP53 sequencing performed on microdissected pleomorphic and non-pleomorphic components for confirmation, aiming to detail the p53 expression pattern in pleomorphic carcinomas and its role in small biopsies insufficient for confirming pleomorphic carcinoma.
Methods
Case selection
Pathology reports of lung resection specimens with a diagnosis of pleomorphic carcinoma were retrieved and slides were reviewed. Cases histologically confirmed as pleomorphic carcinoma, according to the World Health Organization classification of tumours of thoracic tumours (5th edition) [3], were included. Case notes and previous pathology reports of the included cases were reviewed, and all additional positive biopsy specimens (i.e. tumor cells present), including primary and lymph node, aspiration, core, and wedge biopsy specimens were retrieved and reviewed. Corresponding specimens with metastatic tumors were also retrieved and reviewed. At least representative one block per case in all included specimens was selected and sectioned for immunostaining and sequencing. All slides were reviewed by two pathologists. Discrepancies were resolved by reviewing the slides together until a consensus was reached.
p53 immunostain and assessment
p53 immunostaining was performed for all selected tissue blocks (Dako M7001, 1:40 concentration, citrate antigen retrieval at 37 °C for 23 min), except for cases where p53 immunostain already performed at the involved institute by the same protocol and available for review, with appropriate internal (if available) and external controls. p53 immunostain was assessed by two pathologists and classified as aberrant (diffuse overexpression (≥ 90%), null or cytoplasmic) or wild-type (supplementary Fig. 1). Discrepancies were resolved by reviewing the slides together until a consensus was reached.
p53 sequencing
In resection specimens with non-pleomorphic components that are distinct from the pleomorphic components and able to be microdissected, the non-pleomorphic and pleomorphic components were microdissected separately and submitted for sequencing. The DNA samples were extracted from the formalin-fixed paraffin-embedded tissue sections using KAPA Express Extract kit (Roche) after manual microdissection. The DNA was subjected to the library preparation using Illumina TruSight Tumor 15 library preparation kit (Illumina). The libraries were subsequently sequenced on the Illumina MiSeq sequencer at 150 bp pair-end (Illumina). The Fastq files were analyzed by TruSight Tumor 15 pipeline on BaseSpace (Illumina). Briefly, the sequencing reads were aligned to the reference human genome (hg19) and the single nucleotide variants and small insertion-deletion variants were called by Somatic Variant Caller (Illumina).
Results
A total of 30 cases of pleomorphic carcinoma confirmed on resection were identified. There were 11 (37%) with a non-pleomorphic component (adenocarcinoma in all cases) present. Aberrant p53 immunostain expression was seen in 24 cases (80%), with 11 (36.7%) displaying diffuse overexpression and 13 (43.3%) displaying null pattern (Table 1). The non-pleomorphic components in the cases present showed concordant p53 expression with the pleomorphic components (Fig. 1), including cases with wild-type staining pattern. There were 11 biopsy specimens available for review and p53 immunostaining, consisting of six lung (four core biopsies, one wedge biopsy and one aspiration biopsy) and five lymph node (four excisional biopsies and one aspiration biopsy) specimens. Pleomorphic carcinoma was not diagnosed in the original reports of the six lung biopsies. Aberrant p53 expression was seen in all 11 biopsy specimens, and with concordant expression patterns compared to the resection specimen (Fig. 2), even in small volume specimens without a pleomorphic component (Fig. 3a). There was one case (case 10) with a matched adrenalectomy specimen with tumor metastasis and p53 immunostain showed concordant overexpression referenced to the primary tumor (Table 2).
Table 1.
Clinicopathological features of the cohort
| Number of cases | 30 |
| Non-pleomorphic component | |
| Present | 11 |
| Absent | 19 |
| p53 immunostain pattern | |
| Aberrant | |
| Diffuse overexpression | 11 |
| Null | 13 |
| Wild-type | 6 |
Fig. 1.
Concordant p53 overexpression in pleomorphic and non-pleomorphic components. (a) p53, 40x magnification. (b) Reference H&E section showing spindled tumor cells (top) and adenocarcinoma (bottom), 40x magnification
Fig. 2.
Concordant p53 loss in primary lung tumor and lung aspiration biopsy. (a) p53 (primary lung tumor), 100x magnification. (b) Reference H&E section, 100x magnification. (c) p53 (lung aspiration biopsy), 100x magnification. (d) Reference H&E section, 100x magnification
Fig. 3.
Consistent high level p53 overexpression in pleomorphic carcinomas of the lung. (a) Lung resection, 40x magnification. (b) Lung core biopsy, 100x magnification
Table 2.
Comparison of p53 Immunostain pattern in biopsy and matched specimens
| Case no. | p53 immunostain (resection) | Biopsy specimen | p53 immunostain (biopsy) | Concordant |
|---|---|---|---|---|
| 1 | Aberrant– diffuse overexpression | Lung wedge biopsy | Aberrant– diffuse overexpression | Yes |
| 2 | Aberrant– null | Lung core biopsy | Aberrant– null | Yes |
| 3 | Aberrant– null | Lymph node excisional biopsy | Aberrant– null | Yes |
| 4 | Aberrant– diffuse overexpression | Lymph node aspiration | Aberrant– diffuse overexpression | Yes |
| 5 | Aberrant– diffuse overexpression | Lymph node excisional biopsy | Aberrant– diffuse overexpression | Yes |
| 6 | Aberrant– null | Lymph node excisional biopsy | Aberrant– null | Yes |
| 7 | Aberrant– null | Lung aspiration | Aberrant– null | Yes |
| 8 | Aberrant– diffuse overexpression | Lung core biopsy | Aberrant– diffuse overexpression | Yes |
| 9 | Aberrant– null | Lung core biopsy | Aberrant– null | Yes |
| 10 | Aberrant– diffuse overexpression | Lung core biopsy | Aberrant– diffuse overexpression | Yes |
| Lymph node excisional biopsy | Aberrant– diffuse overexpression | Yes | ||
| Adrenalectomy | Aberrant– diffuse overexpression | Yes |
In the 11 cases with a non-pleomorphic component present, there were five cases suitable for paired sequencing of non-pleomorphic and pleomorphic components. One of the five case was subsequently rejected due to low DNA quality. TP53 mutation was detected in all four cases. In three cases, identical TP53 mutations (F134L, G245V and C227F) were found in the non-pleomorphic and pleomorphic components of the tumor, and p53 immunostain displayed aberrant staining patterns. Concurrent EGFR mutation (p.L747_A750delinsP**) was detected in the case (case 8) with C227F mutation, in both pleomorphic and non-pleomorphic components. Interestingly, one case (case 11) showed different TP53 mutations in the non-pleomorphic (R342*) and pleomorphic components (G245S). p53 immunostain did not demonstrate aberrant expression for this case (Table 3).
Table 3.
TP53 sequencing results
| Case no. | Non-pleomorphic component | Pleomorphic component | Other mutations | ||
|---|---|---|---|---|---|
| p53 mutation | p53 immunostain | p53 mutation | p53 immunostain | ||
| 5 | G245V | Aberrant– diffuse overexpression | G245V | Aberrant– diffuse overexpression | |
| 8 | C277F | Aberrant– diffuse overexpression | C277F | Aberrant– diffuse overexpression | EGFR p.L747_A750delinsP## |
| 11 | R342* | Wild-type | G245S | Wild-type | |
| 12 | F134L | Aberrant– diffuse overexpression | F134L | Aberrant– diffuse overexpression | |
# An additional specimen (case 6) was also subjected to sequencing but rejected due to low DNA quality
## EGFR mutation detected in both pleomorphic and non-pleomorphic components
Discussion
NSCLC is a heterogenous disease with high intra- and inter-tumoral heterogeneity [8], evidenced by morphologic and molecular findings [9]. Pleomorphic carcinoma of the lung is rare and only accounts for less than 1% of NSCLC cases [10]. However, the prognosis of pleomorphic carcinomas is poor and is often associated with aggressive features such as lymphovascular invasion [11]. The reported median survival for patients with pleomorphic carcinomas was only 19 months [1]. Even in stage I disease, the 5-year survival rate was only 16.3%, significantly lower than other NSCLCs [12]. The difference in outcomes may be attributable to the propensity for pleomorphic carcinomas to metastasize, as distant recurrence is frequently observed even in completely resected early stage disease [1].
The diagnosis of pleomorphic carcinoma is based on histology, and requires only the presence of a spindle and/or giant cell component of at least 10%, with the remaining tumor components comprising adenocarcinoma, squamous cell carcinoma and/or large cell carcinoma [3, 13]. With the limitations in sampling for small biopsies, in particular core biopsies and cytology specimens [14, 15], diagnosis of pleomorphic carcinoma by morphology alone may be difficult in view of its intratumoral heterogeneity. A diagnosis of pleomorphic carcinoma is not possible when only non-pleomorphic components are sampled, and even when pleomorphic components are present, differentials such as solid pattern adenocarcinoma, and the 10% volume criteria has to be considered. Oikawa et al. reviewed 126 lung biopsy and/or bronchial cytology specimens with resection as reference standard, and all five cases of pleomorphic carcinoma were not diagnosable on biopsy/cytology [4]. In such situations, if an accurate immunohistochemical or molecular marker is available, the diagnostic accuracy for pleomorphic carcinoma can be greatly improved. Molecular analysis of pleomorphic carcinomas from multiple cohorts [5–7] has independently identified TP53 mutation as the most frequent genetic alteration. In addition to DNA sequencing, p53 immunostain can indicate abnormal loss or accumulation of p53 protein, and correlates with TP53 mutational status [16]. Considering the cost and turnaround time for TP53 testing, p53 immunostain appears to be a suitable candidate as a diagnostic adjunct for identifying pleomorphic carcinomas.
The rate of aberrant p53 expression in NSCLC has been reported at 37–68% [17–19]. However, the cut offs taken for varies significantly in each study, with some studies taking cut offs as low as 5–10% [17, 18]. At a higher threshold of 50%, the rate of p53 aberrant expression decreases to 8% and 24% in adenocarcinoma and squamous cell carcinoma of the lung respectively [17]. This contrasts with the more stringent cut offs of 80% and up to 90% adopted in p53 immunostain assessment of gynecological cancers [20]. In this cohort, using a stringent cut off of ≥ 90% expression for overexpression, found a significantly higher rate of aberrant expression at 80% (n = 24/30). Regardless of the cut off, the cases with p53 overexpression of this cohort displayed even higher levels of diffuse and complete positivity (Fig. 3), which were distinctively recognizable at low power magnification. For the diagnostic purpose of identifying pleomorphic carcinoma, a strict cut off for p53 overexpression is recommended. The complete concordance of 100% (n = 14/14) of the p53 immunostaining pattern between biopsy specimens, specimens from metastatic lesions and lung resection specimens confirms the accuracy of p53 immunostain.
The four cases submitted for p53 sequencing and successfully sequenced all harbored TP53 mutations. Concordant pathogenic TP53 mutations (F134L, G245V and C277F) were seen in three cases [21–23]. The remaining case displayed wild-type expression pattern on p53 immunostaining, R342* was detected in the non-pleomorphic component while G245S was detected in the pleomorphic component (Table 3). TP53 R342* mutation has been described in a case of adenocarcinoma [24], and a case of squamous cell carcinoma reportedly transforming to small cell carcinoma after pembrolizumab therapy with TP53 R342* detected in the transformed specimen [25]. Unfortunately, p53 immunostaining was not included in these case reports. Although TP53 G245S mutation is known to be pathogenic, literature regarding its prevalence in lung cancers is lacking [26]. Nagano et al. performed DNA sequencing and detected mutations that are associated with epithelial-mesenchymal transition (ARID2, NF1, and PIK3CG) in the pleomorphic component of pleomorphic carcinomas, evidencing a transition of the non-pleomorphic component into a pleomorphic phenotype during tumor progression [2]. As TP53 mutations likely represent early events in lung cancer tumorigenesis [27], the case with two discordant TP53 mutations suggests that a minority of biphasic pleomorphic carcinomas may be collision or synchronous lesions.
The current study is limited by its single arm design and is only capable of demonstrating the sensitivity of p53 immunostain for diagnosing pleomorphic carcinomas in small biopsy specimens. The specificity of p53 immunostain for such purpose is affected by the p53 expression in other NSCLCs [17]. This can be overcome by setting a high cut off when interpreting p53 immunostain for this context. Olivares-Hernández et al. reported low level p53 expression (≥ 5%) in 66.7% and 58.8% of adenocarcinomas and squamous cell carcinomas of the lung, which decreased to 8.3% and 23.5% at the highest cutoff of ≥ 50% reported in their study [17]. Similarly, Mitsudomi et al. reported p53 expression rates of < 20% in adenocarcinomas and squamous cell carcinomas at a cutoff of ≥ 70% [20]. Unfortunately, unlike endometrial cancers in which an accepted and stringent of at least 80% nuclear expression is considered as overexpression [20], the interpretation of p53 immunostaining in lung carcinomas is not standardized, with relevant studies adopting loose cutoffs of 5–10%, resulting in reported overexpression rates of over 50% [28, 29]. It should also be noted that other aberrant p53 expression patterns, namely the null (complete negative staining) and cytoplasmic patterns [20]. These patterns are relatively uncommon and were not encountered in the current cohort.
Rare nonsense mutations give rise to “false wild-type” (false negative) p53 expression pattern [16], which is also observed in one case from this cohort. Such cases require TP53 sequencing, but taking cost and tissue economy into consideration, the priority of TP53 sequencing compared to less costly immunostains such as TTF1, p40, ALK and ROS1 [30], and theragnostic tests such as EGFR testing [31] has to be adjusted according to the clinical context.
Conclusion
Pleomorphic carcinoma is difficult to diagnose on biopsy due to high intratumoral heterogeneity. TP53 mutation is common and aberrant p53 immunostain expression is consistently and concordantly observed in pleomorphic, non-pleomorphic, metastatic and small biopsy specimens of pleomorphic carcinomas. At strict cutoff of ≥ 90% expression for overexpression, p53 overexpression suggests the possibility of pleomorphic carcinomas even the absence of non-pleomorphic components in a biopsy specimen. In cases with widespread disease despite a small primary lung lesion, or when resection is not feasible, there is value in performing p53 immunostain for the diagnosis of pleomorphic carcinoma of the lung in a small specimen.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Author contributions
JJXL and JKMN conceptualized the project. JJXL and JKMN collected clinical data. CC performed the experiments. JJXL and CC analyzed the data. JJXL, CC, KPC and MSCL interpreted and validated the findings. JJXL drafted the manuscript and KFT critically revised the manuscript. All authors reviewed the manuscript.
Funding
The authors have no funding to declare.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Statement of ethics
The study was approved by the Joint Chinese University of Hong Kong and New Territories East Cluster clinical research ethics committee (2022.061).
Footnotes
Publisher’s note
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Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.