ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК
Adenosquamous carcinoma and pure squamous cell carcinoma (SCC) of the rectum are extremely rare malignancies, accounting for approximately 0.15% of all colorectal cancers. Increasing attention has been paid to tumor phenotypic plasticity in the context of intensive anticancer therapy. We report the...
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| Date: | 2026 |
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| Issue: | 2 |
| Pages: | 172-180 |
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Experimental Oncology| _version_ | 1874183258290257920 |
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| author | Kovalyov, O. Zavhorodniy, S. Tolok, O. Anenko, A. Kubrak, M. Danilyuk, M. Kovalyov, K. |
| author_facet | Kovalyov, O. Zavhorodniy, S. Tolok, O. Anenko, A. Kubrak, M. Danilyuk, M. Kovalyov, K. |
| author_institution_txt_mv | [
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"author": "O. Tolok",
"institution": "YULIS Medical Oncology Center, Zaporizhzhia, Ukraine",
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"author": "A. Anenko",
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"author": "M. Kubrak",
"institution": "Zaporizhzhia State Medical and Pharmaceutical University, Zaporizhzhia, Ukraine",
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"author": "M. Danilyuk",
"institution": "Zaporizhzhia State Medical and Pharmaceutical University, Zaporizhzhia, Ukraine",
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"institution": "Zaporizhzhia State Medical and Pharmaceutical University, Zaporizhzhia, Ukraine",
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| author_sort | Kovalyov, O. |
| baseUrl_str | https://exp-oncology.com.ua/index.php/Exp/oai |
| collection | OJS |
| container_end_page | 180 |
| container_issue | 2 |
| container_start_page | 172 |
| container_title | Експериментальна онкологія |
| container_volume | 48 |
| datestamp_date | 2026-08-21T12:36:13Z |
| description | Adenosquamous carcinoma and pure squamous cell carcinoma (SCC) of the rectum are extremely rare malignancies, accounting for approximately 0.15% of all colorectal cancers. Increasing attention has been paid to tumor phenotypic plasticity in the context of intensive anticancer therapy. We report the case of a 45-year-old patient with locally advanced rectal adenocarcinoma (cT4bN2M0) who underwent total neoadjuvant therapy consisting of XELOX chemotherapy combined with pelvic radiotherapy. Baseline biopsy samples from multiple tumor areas showed moderately differentiated adenocarcinoma with an intestinal immunophenotype. After treatment, the resected tumor showed complete loss of intestinal differentiation markers (CK20, CDX2) and the emergence of a squamous immunophenotype with positive expression of p40 and p63. Histologically, the tumor was composed exclusively of poorly differentiated SCC. PCR analysis detected HPV16 DNA in the SCC component. Strong, diffuse p16INK4a expression was observed in both the primary adenocarcinoma and the post-treatment tumor. These findings indicate a marked therapy-associated phenotypic shift in tumor differentiation. However, the underlying biological mechanism remains uncertain. Possible explanations include therapy-associated tumor plasticity, clonal selection of a pre-existing squamous subclone, or an initially unrecognized mixed tumor phenotype. This case highlights the importance of careful pathological reassessment after neoadjuvant therapy in rectal cancer and illustrates the complexity of interpreting phenotypic changes in treated tumors. The potential role of HPV in such processes remains hypothetical and requires further investigation. |
| doi_str_mv | 10.15407/exp-oncology.2026.02.172 |
| first_indexed | 2026-08-22T01:00:37Z |
| format | Article |
| fulltext |
172 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
CASE REPORTS
C i t a t i o n: Kovalyov O, Zavhorodniy S, Tolok O, Anenko A, Kubrak M, Danilyuk M, Kovalyov K. Phenotypic shift of
adenocarcinoma to squamous cell carcinoma of the rectum after neoadjuvant chemoradiotherapy with detection of
HPV16: A clinical case. Exp Oncol. 2026; 48(2): 172-180. https://doi.org/10.15407/exp-oncology.2026.02.172
© PH “Akademperiodyka” of the NAS of Ukraine, 2026. This is an open access article under the CC BY-NC-ND license
(https://creativecommons.org/licenses/by-nc-nd/4.0/)
Rectal cancer is predominantly represented by ade-
nocarcinoma (AC), arising from the glandular cu-
boidal epithelium. Mixed adenosquamous carcino-
ma (ASC) or primary squamous cell carcinoma
(SCC) accounts for approximately 0.15% of all
colorectal malignancies [1, 2]. An even rarer phe-
nomenon is the emergence of a squamous pheno-
type in tumors initially diagnosed as AC, either dur-
ing tumor progression or after anticancer therapy.
Although phenotypic plasticity is a fundamental
characteristic of malignant cells, the underlying bio-
logical mechanisms remain poorly understood [3, 4].
https://doi.org/10.15407/exp-oncology.2026.02.172
O. Kovalyov ¹, *, S. Zavhorodniy ¹, O. Tolok ²,
A. Anenko ², M. Kubrak ¹, M. Danilyuk ¹, K. Kovalyov ¹
1 Zaporizhzhia State Medical and Pharmaceutical University,
Zaporizhzhia, Ukraine
2 YULIS Medical Oncology Center, Zaporizhzhia, Ukraine
* Correspondence: E-mail: kovalev.onco@gmail.com
PHENOTYPIC SHIFT OF ADENOCARCINOMA
TO SQUAMOUS CELL CARCINOMA OF RECTUM
AFTER NEOADJUVANT CHEMORADIOTHERAPY
WITH DETECTION OF HPV16: A CLINICAL CASE
Adenosquamous carcinoma and pure squamous cell carcinoma (SCC) of the rectum are extremely rare malignancies,
accounting for approximately 0.15% of all colorectal cancers. Increasing attention has been paid to tumor phenotypic
plasticity in the context of intensive anticancer therapy. We report the case of a 45-year-old patient with locally advanced
rectal adenocarcinoma (cT4bN2M0) who underwent total neoadjuvant therapy consisting of XELOX chemotherapy
combined with pelvic radiotherapy. Baseline biopsy samples from multiple tumor areas showed moderately differenti-
ated adenocarcinoma with an intestinal immunophenotype. After treatment, the resected tumor showed complete loss
of intestinal differentiation markers (CK20, CDX2) and the emergence of a squamous immunophenotype with positive
expression of p40 and p63. Histologically, the tumor was composed exclusively of poorly differentiated SCC. PCR analy-
sis detected HPV16 DNA in the SCC component. Strong, diffuse p16INK4a expression was observed in both the primary
adenocarcinoma and the post-treatment tumor. These findings indicate a marked therapy-associated phenotypic shift in
tumor differentiation. However, the underlying biological mechanism remains uncertain. Possible explanations include
therapy-associated tumor plasticity, clonal selection of a pre-existing squamous subclone, or an initially unrecognized
mixed tumor phenotype. This case highlights the importance of careful pathological reassessment after neoadjuvant
therapy in rectal cancer and illustrates the complexity of interpreting phenotypic changes in treated tumors. The poten-
tial role of HPV in such processes remains hypothetical and requires further investigation.
Keywords: rectal adenocarcinoma, squamous transdifferentiation, HPV16, neoadjuvant chemoradiotherapy.
https://doi.org/10.15407/exp-oncology.2026.02.172
https://creativecommons.org/licenses/by-nc-nd/4.0/
https://doi.org/10.15407/exp-oncology.2026.02.172
mailto:kovalev.onco@gmail.com
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 173
Phenotypic Shift of Adenocarcinoma to Squamous Cell Carcinoma of Rectum after Neoadjuvant Chemoradiotherapy
The literature contains reports describing phenotypic
shifts of cancer cells occurring during antitumor
therapy [5]. In several tumor types, including cancers
of the esophagus, lung, and head and neck region,
therapy-associated changes toward squamous diffe
rentiation have been reported [6, 7]. Rare cases of
histological changes of colorectal AC into other ag-
gressive phenotypes, including choriocarcinoma, fol-
lowing chemotherapy, have also been described [8].
Total neoadjuvant therapy (TNT), combining ra-
diotherapy and systemic chemotherapy, is current-
ly the standard treatment approach for locally ad-
vanced rectal cancer. This strategy improves local
disease control, pathological complete response
rates, and overall survival [9].
However, TNT is associated with adverse effects
resulting from damage not only to tumor cells but
also to normal tissues, thereby increasing treat-
ment-related toxicity. At the molecular level, inten-
sive irradiation, combined with cytotoxic therapy,
induces profound biological stress, including DNA
damage, epigenetic remodeling, immune modula-
tion, and clonal selection [10, 11]. These processes
may contribute to tumor plasticity and shifts in the
dominant tumor phenotype.
The role of human papillomavirus (HPV) in the
development of gastrointestinal AC remains con-
troversial [12, 13]. Of particular interest is the po-
tential contribution of oncogenic viruses to cellular
phenotypic changes, possibly acting as co-factors
in carcinogenesis [14].
In this article, we report a case of a woman with
rectal AC that, after total neoadjuvant chemoradio-
therapy, demonstrated a marked shift in tumor
phenotype toward pure SCC, with detection of
HPV type 16 in the post-treatment tumor tissue.
This case raises important questions regarding
therapy-associated tumor plasticity, clonal selec-
tion, and the possible involvement of HPV in epi-
thelial lineage changes under treatment-induced
selective pressure.
Case presentation
In a 45-year-old woman, locally advanced rectal
cancer staged as cT4bN2M0 was diagnosed in July
2024, based on clinical, radiological, and histopa
thological evaluation.
The tumor originated above the dentate line and
anorectal junction and was located predominantly in
the mid-rectum. The distal tumor margin was ap-
proximately 5 cm from the anal verge, with a longitu-
dinal extent of about 10 cm (proximal margin ~15 cm
from the anal verge), corresponding to a mid-to-low
rectal tumor with predominant involvement of the
mid-rectal segment. There was no involvement of the
anal canal or the anorectal transitional zone.
Baseline biopsy samples obtained from five diffe
rent tumor areas confirmed the moderately differen-
tiated AC. Given the locally advanced nature of the
disease, TNT was initiated, consisting of 4 cycles of
XELOX chemotherapy combined with pelvic radio-
therapy at a total dose of 40 + 20 Gy. Treatment was
completed in March 2025.
No objective clinical response to TNT was ob-
served, as tumor dimensions remained unchanged.
However, radiotherapy was complicated by severe
local toxicity, including radiation proctitis and the
development of a pararectal abscess. Following sur-
gical drainage and sanitation, a prolonged period
of delayed wound healing and persistent inflamma-
tory changes in the perineal region was noted. Due
to these complications, definitive surgical treat-
ment was postponed.
Subsequently, 5 months after completion of TNT
and 11 months after the initial diagnosis, the patient
underwent forced salvage surgery. Cytoreductive ab-
dominoperineal extralevator excision of the rectum
according to Holm was performed, together with
hysterectomy with bilateral adnexectomy and resec-
tion of the posterior vaginal wall (en bloc AD resec-
tion), as well as D2 lymph node dissection.
The surgical specimen (pathology report No.
13790/25) consisted of 21 histological blocks
(21 slides). Gross examination and sampling were
performed according to the College of American Pa-
thologists (CAP) protocol for colorectal AC, which
focuses on TNM staging and does not require com-
plete tumor bed mapping in routine practice.
The sampled blocks included the primary tumor
areas, resection margins, mesorectal tissue, adja-
cent organs (vaginal wall, cervix, adnexa), stoma
site, regional lymph nodes, and clinically suspected
metastatic sites.
A total of 11 regional lymph nodes were exam-
ined, all of which were negative for metastatic in-
volvement (ypN0, 0/11). The lymph nodes were
small and preserved in architecture, with no evi-
dence of metastases or therapy-induced regression
changes (such as fibrosis, necrosis, or mucin pools).
174 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
O. Kovalyov, S. Zavhorodniy, O. Tolok, A. Anenko, M. Kubrak, M. Danilyuk, K. Kovalyov
Postoperatively, the patient received additional
systemic chemotherapy with carboplatin + pacli-
taxel (3 cycles) and cisplatin + 5-fluorouracil
(2 cycles), which proved ineffective. Despite mul-
timodal treatment, rapid disease progression oc-
curred, manifested by local recurrence and peri-
toneal metastases.
Histopathological examination demonstrated a
lack of tumor response to therapy, corresponding
to grade III therapeutic pathomorphosis according
to the Ryan classification. The residual tumor was
composed exclusively of poorly differentiated SCC
with strong p16INK4a expression. Despite thorough
morphological examination of the entire surgical
specimen, no glandular structures or residual AC
components were identified.
Given the marked morphological differences ob-
served at various stages of tumor progression, addi-
tional immunohistochemical (IHC) and molecular
analyses were performed on all archived tumor ma-
terial, including assessment of HPV involvement.
The following markers were evaluated: cytokera-
tin 7 (DAKO, clone OV-TL 12/30), cytokeratin 20
(DAKO, clone Ks 20.8), cytokeratin 5/6 (DAKO,
clone D5/16 B4), CDX-2 (DAKO, clone DAK-
CDX2), p40 (Diagnostic BioSystems, polyclonal),
p63 (Diagnostic BioSystems, clone DBR 16.1),
p16INK4a, (clone JC2), HPV16 (capsid protein L1,
clone CAMVIR-1), E-cadherin (Diagnostic BioSys-
tems, clone SPM471), vimentin (DAKO, clone V9),
and mismatch repair proteins for MSI assessment
(MLH-1 clone G168-15, MSH6 clone 44, PMS2
clone A16-4, and MSH2 clone FE11).
IHC evaluation was performed using a semi-
quantitative approach, taking into account the type
of staining, expression pattern, staining intensity,
and the percentage of positive tumor cells.
For p16, only block-type staining was considered
positive, defined as strong, diffuse nuclear and cy-
toplasmic expression in ≥70% of tumor cells. Focal
or heterogeneous staining involving <70% of cells
was considered non–block-type and interpreted as
negative or non-specific.
For p63 and p40, nuclear staining was evaluated.
Expression was categorized based on the propor-
tion of positive tumor cells (<10% negative, 10%—
50% focal, >50% diffuse for p63; <5%—10% nega-
tive, ≥10% positive for p40). The diffuse nuclear
expression of p63 and p40 was interpreted as sup-
porting squamous differentiation.
Staining intensity for all markers was graded as
0 (absent), 1+ (weak), 2+ (moderate), or 3+ (strong).
IHC findings were interpreted in the context of
tumor morphology and clinical data. p16 expres-
sion was interpreted with caution, as it is not spe-
cific for HPV-driven carcinogenesis in the absence
of molecular confirmation.
HPV DNA status was assessed by PCR analysis of
vaginal swab specimens as well as tumor tissue from
SCC components using an IVD-certified test system
(Seegene, South Korea) and a CFX96 real-time ther-
mocycler (Bio-Rad, USA), with a sensitivity of
Immunohistochemical and molecular profile of the tumor
at different stages of evolution
Marker Primary tumor (AC) Residual tumor after
TNT (SCC) Metastasis (SCC)
Hematoxylin & eosin staining Glandular architecture,
adenocarcinoma morphology
Squamous cell
morphology
Squamous cell
morphology
CK20 + — —
CDX2 + — —
p40 — + +
p63 Not performed + +
p16INK4a + + +
Capsid protein L1 Not performed — —
E-cadherin + + Not performed
Vimentin — — Not performed
MSI Microsatellite stable Microsatellite stable Microsatellite stable
HPV16 DNA in the tumor Not performed + Not performed
HPV DNA in the vaginal swab Not performed — —
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 175
Phenotypic Shift of Adenocarcinoma to Squamous Cell Carcinoma of Rectum after Neoadjuvant Chemoradiotherapy
50 copies per reaction. HPV types 6, 11, 16, 18, 26,
31, 33, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58,
59, 61, 66, 68, 69, 70, 73, and 82 were analyzed.
The obtained results are summarized in the Ta-
ble. Histopathological and IHC features are shown
in Figs 1—6.
Due to the nature of the biopsy (core needle
biopsy), only tumor tissue was available, and no
adjacent normal mucosa was present to serve as an
internal positive control.
IHC staining quality was verified using appro-
priate external positive controls in accordance with
standard laboratory protocols.
In our case, the IHC profile of the primary tu-
mor was consistent with rectal adenocarcinoma
with typical intestinal differentiation, demonstra
Fig. 1. Rectal adenocarcinoma (cT4bN2M0) before treat-
ment. Hematoxylin and eosin staining, ×200
Fig. 2. Rectal adenocarcinoma (cT4bN2M0) before treat-
ment. Diffuse cytoplasmic expression of cytokeratin 20
(CK20) (DAKO, clone Ks 20.8), ×200
Fig. 4. Squamous cell carcinoma of the rectum in the same
patient after total neoadjuvant therapy. Hematoxylin and
eosin staining, ×200
Fig. 3. Rectal adenocarcinoma (cT4bN2M0) before treat-
ment. Strong diffuse nuclear and cytoplasmic expression
of p16INK4a (clone JC2), ×200
176 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
O. Kovalyov, S. Zavhorodniy, O. Tolok, A. Anenko, M. Kubrak, M. Danilyuk, K. Kovalyov
ted by positive expression of CK20 and CDX2 and
the absence of squamous marker p40.
In tumor tissue obtained after TNT, loss of in-
testinal differentiation markers was observed
(CK20−, CDX2−), accompanied by the emergence
of a distinct squamous immunophenotype with
positive expression of p40 and p63, consistent
with SCC morphology.
E-cadherin expression was preserved, while vi-
mentin expression was absent in all examined tu-
mor specimens.
Notably, the primary AC showed strong diffuse
expression of p16INK4a, which is uncommon for
most colorectal adenocarcinomas. The tumor also
showed persistent strong expression of p16INK4a af-
ter treatment. HPV16 DNA was identified only in
the SCC components.
Microsatellite status remained stable (microsat-
ellite stable, MSS) throughout all stages of tumor
progression. No differences in mismatch repair
protein expression were observed between pre-
treatment and post-treatment samples.
NRAS mutation analysis was not performed, as
it is not routinely recommended for primary rectal
AC and would not have altered neoadjuvant treat-
ment decisions. Likewise, NRAS testing is not stan-
dard in SCC, where RAS pathway alterations are
uncommon, and its absence does not affect the in-
terpretation of this case.
Extensive histopathological examination of the
entire resection specimen revealed no residual
glandular structures or mixed adenosquamous
components.
A total of 21 histological blocks (21 slides) were
examined from the tumor bed and surrounding tis-
sues to exclude the presence of residual AC or
mixed adenosquamous components.
Standard tumor regression grading (TRG) sys-
tems (e.g., the Ryan and Mandard systems) were
considered; however, their application was limited
in this case due to the marked change in tumor
phenotype after neoadjuvant therapy.
No classical morphological features of regression
(such as fibrosis, necrosis, or mucin pools) were
identified in the tumor bed. Therefore, treatment
response was assessed descriptively, based on the
proportion of viable tumor tissue and the absence
of histological signs of regression.
This limitation reflects the lack of established
criteria for evaluating regression in cases with the
rapy-associated phenotypic shift.
Discussion
Rectal AC accounts for approximately 90% of
malignant tumors of the rectum. Other histolo
gical types, including neuroendocrine tumors,
lymphomas, gastrointestinal stromal tumors, and
sarcomas, are distinctly uncommon. ASC is an
exceptionally rare entity, accounting for approxi
mately 0.15% of colorectal malignancies, while
Fig. 5. Post-therapy rectal squamous cell carcinoma. Posi-
tive nuclear expression of p40 (Diagnostic BioSystems,
polyclonal), ×200
Fig. 6. Post-therapy rectal squamous cell carcinoma. Dif-
fuse overexpression of p16INK4a (clone JC2), ×200
ISSN 1812-9269. Experimental Oncology 48 (2). 2026 177
Phenotypic Shift of Adenocarcinoma to Squamous Cell Carcinoma of Rectum after Neoadjuvant Chemoradiotherapy
pure SCC of the rectum remains a pathological
rarity [15—17].
Histologically, ASC is defined by the coexistence
of glandular and squamous components, each com-
prising at least 10%—20% of the tumor volume,
according to the 2019 WHO Classification of Di-
gestive System Tumours [18]. In contrast, pure rec-
tal SCC without any glandular component has been
reported only sporadically, with fewer than 150 do
cumented cases over several decades and no stan-
dardized treatment recommendations [1].
Several pathogenetic hypotheses have been pro-
posed to explain the presence of squamous diffe
rentiation in the rectum. One of them is based on
squamous metaplasia of the rectal mucosa, in
which chronic inflammation or carcinogenic stim-
uli induce transformation of columnar epithelium
into squamous epithelium. This phenomenon has
been described in inflammatory bowel disease and
in association with HPV infection, with subsequent
progression from metaplasia to dysplasia and car-
cinoma [19—21].
An alternative explanation involves the presence
of multipotent basal or stem-like cells at the ano-
rectal junction capable of divergent differentiation.
Experimental data and histological evidence sug-
gest that these cells may serve as a reservoir for
squamous differentiation under inflammatory, vi-
ral, or therapeutic pressure [22].
Tumor phenotypic plasticity is increasingly reco
gnized as a hallmark of cancer, particularly under
strong genotoxic and inflammatory stress. Current
data indicate that such plasticity is more frequently
driven by epigenetic reprogramming rather than by
the acquisition of new driver mutations [3, 23]. In
this context, neoadjuvant chemoradiotherapy rep-
resents a potent selective force, inducing DNA
damage, oxidative stress, immune modulation, and
clonal selection [24].
Radiotherapy, in particular, promotes chronic in-
flammation and tissue remodeling, potentially favo
ring survival of tumor cell populations with en-
hanced resistance to hypoxia and DNA damage [25].
In some tumor types, squamous differentiation
has been associated with altered responses to radio-
therapy and chemotherapy, suggesting that lineage
plasticity may influence tumor adaptation under
therapeutic pressure [26].
In the present case, the marked change in tumor
phenotype observed after neoadjuvant therapy
raises the possibility of therapy-associated tumor
plasticity. However, the precise biological mecha-
nism underlying this shift cannot be definitively
established in a single case report.
Several alternative explanations should be consi
dered. One possibility is clonal selection of a pre-
existing squamous subclone that was not detected in
the initial biopsy samples due to limited tissue sam-
pling. Another potential explanation is the presence
of an initially mixed adenosquamous tumor in
which the squamous component became dominant
after treatment. Tumors arising in the anorectal
transitional zone may exhibit complex patterns of
epithelial differentiation, which can complicate in-
terpretation of tumor lineage. In this context, the ob-
served findings most likely reflect therapy-associa
ted changes in the dominant tumor phenotype ra
ther than definitive proof of transdifferentiation.
Several biological mechanisms may potentially
contribute to the observed phenotypic shift. Inten-
sive chemoradiotherapy represents a strong selec-
tive pressure capable of inducing epigenetic remo
deling, clonal selection, and adaptive reprogram-
ming of tumor cells. Experimental and clinical
studies increasingly suggest that therapy-induced
plasticity may allow tumor cells to adopt alternative
differentiation states that confer survival advanta
ges under cytotoxic stress. In this context, squa-
mous differentiation has been associated with rela-
tive resistance to radiation and chemotherapy in
several tumor types.
A particularly notable feature of this case is the
emergence of HPV16 in the SCC after treatment.
While HPV is a well-established etiological fac-
tor in SCC of the cervix, oropharynx, and anal ca-
nal, its role in colorectal carcinogenesis remains
controversial [27, 28]. Reported HPV prevalence in
colorectal AC varies widely, partly due to method-
ological differences in detection [29].
Viral infection may act as a co-factor facilitating
epigenetic instability and altered differentiation
programs.
The detection of HPV16 DNA in the post-treat-
ment tumor raises the suggestion that viral infec-
tion may have contributed to the observed pheno-
type. However, since HPV status was not assessed
in the primary tumor, the role of HPV in this pro-
cess remains hypothetical.
Clinically, this case underscores the importance
of thorough pathological reassessment following
178 ISSN 1812-9269. Experimental Oncology 48 (2). 2026
O. Kovalyov, S. Zavhorodniy, O. Tolok, A. Anenko, M. Kubrak, M. Danilyuk, K. Kovalyov
neoadjuvant therapy, as tumor biology and pheno-
type may change substantially during treatment.
HPV testing by PCR may be considered in p16-pos-
itive colorectal carcinomas or in tumors demonstra
ting unexpected phenotypic shifts, particularly when
therapeutic resistance is observed [30, 31].
An important feature of this case is the clear tem
poral and morphological sequence documented by
multiple baseline biopsies and subsequent exami-
nation of the entire resection specimen. The pri-
mary tumor demonstrated a conventional intesti-
nal AC phenotype, whereas the post-treatment tu-
mor consisted exclusively of poorly differentiated
SCC without residual glandular structures. This
striking shift in dominant lineage strongly supports
the concept of therapy-associated phenotypic plas-
ticity rather than simple sampling variation.
This study has several limitations. HPV testing
of the primary tumor was not performed due to
the lack of residual biopsy material, precluding
retrospective molecular analysis. In addition, no
clonal or genomic profiling was conducted. These
limitations restrict the ability to fully elucidate the
mechanisms underlying the observed phenotypic
transformation. Therefore, these results should be
interpreted with caution, as the available clinico
pathological data do not allow a definitive distinc-
tion between true transdifferentiation and thera-
py-related clonal selection of a pre-existing squa-
mous subclone.
To sum up, this case illustrates a rare phenotypic
shift from rectal AC to HPV16-positive SCC fol-
lowing total neoadjuvant chemoradiotherapy. The
findings support the concept of therapy-associated
tumor plasticity and suggest a potential, yet un-
proven, role of HPV in lineage reprogramming un-
der treatment-induced selective pressure. Careful
pathological reassessment after neoadjuvant the
rapy is essential in rectal cancer, particularly in tu-
mors with atypical differentiation. Further molecu-
lar and genomic studies are required to clarify the
biological mechanisms and clinical implications of
therapy-associated phenotypic shifts in colorectal
malignancies.
Conflict of interest statement
The authors declare no competing interests.
Consent
Written informed consent for publication of this
clinical case and accompanying images was ob-
tained from the patient. A copy of the signed con-
sent form is available to the journal’s Editor-in-
Chief upon request.
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Submitted: February 02, 2026
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O. Kovalyov, S. Zavhorodniy, O. Tolok, A. Anenko, M. Kubrak, M. Danilyuk, K. Kovalyov
О. Ковальов ¹, С. Завгородній ¹, О. Толок ², А. Аненко ²,
М. Кубрак ¹, М. Данилюк ¹, К. Ковальов ¹
¹ Запорізький державний медико-фармацевтичний
університет, Запоріжжя, Україна
² Медичний онкологічний центр ЮЛІС, Запоріжжя, Україна
ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ
РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ
ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК
Аденосквамозний рак та істинно плоскоклітинний рак прямої кишки є надзвичайно рідкісними злоякісними
новоутвореннями, що становлять приблизно 0,15% усіх випадків колоректального раку. У поодиноких випад-
ках неоад’ювантна хіміопроменева терапія може супроводжуватися істотними змінами в диференціюванні пух-
линних клітин, однак біологічні механізми таких змін з’ясовані недостатньо. У повідомленні наведено випадок
місцево поширеної аденокарциноми прямої кишки (cT4bN2M0) у жінки, яка отримала тотальну неоад’ювантну
терапію, що включала хіміотерапію за схемою XELOX у поєднанні з променевою терапією малого таза. Первин-
ні біопсійні зразки, отримані з кількох ділянок пухлини, підтвердили наявність помірно диференційованої аде-
нокарциноми з типовим кишковим імунофенотипом. Після лікування в резектованій пухлині відзначено по-
вну втрату маркерів CK20, CDX2 та появу плоскоклітинного імунофенотипу з позитивною експресією p40 і p63.
Гістологічно пухлина була представлена виключно низькодиференційованою плоскоклітинною карциномою.
За результатами ПЛР-аналізу в плоскоклітинному компоненті пухлини виявлено ДНК вірусу папіломи людини
16-го типу (ВПЛ16). Виражена дифузна експресія p16INK4a спостерігалась як у первинній аденокарциномі, так і в
пухлині після лікування. Отримані результати свідчать про виражений асоційований з терапією фенотиповий
зсув у диференціації пухлини. Водночас точний біологічний механізм цього явища залишається невизначе-
ним. Серед можливих пояснень розглядаються індукована терапією пухлинна пластичність, клональна селек-
ція раніше існуючого плоскоклітинного субклону або первинно нерозпізнаний змішаний пухлинний фенотип.
Представлений випадок підкреслює важливість ретельної патоморфологічної повторної оцінки пухлин після
неоад’ювантної терапії при раку прямої кишки та демонструє складність інтерпретації фенотипових змін у
пухлинах після лікування. Потенційна роль ВПЛ в таких процесах залишається гіпотетичною і потребує по-
дальших досліджень.
Ключові слова: аденокарцинома прямої кишки, плоскоклітинна трансдиференціація, ВПЛ16, неоад’ювантна
хіміопроменева терапія.
|
| id | oai:ojs2.ex.aqua-time.com.ua:article-652 |
| institution | Experimental Oncology |
| issn | 2312-8852 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-22T01:00:37Z |
| publishDate | 2026 |
| publisher | PH Akademperiodyka |
| record_format | ojs |
| resource_txt_mv | exp-oncologycomua/17/75c0e7f278b6f9c8b0ac1cdbd60f5417.pdf |
| spelling | oai:ojs2.ex.aqua-time.com.ua:article-6522026-08-21T12:36:13Z PHENOTYPIC SHIFT OF ADENOCARCINOMA TO SQUAMOUS CELL CARCINOMA OF RECTUM AFTER NEOADJUVANT CHEMORADIOTHERAPY WITH DETECTION OF HPV16: A CLINICAL CASE ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК Kovalyov, O. Zavhorodniy, S. Tolok, O. Anenko, A. Kubrak, M. Danilyuk, M. Kovalyov, K. аденокарцинома прямої кишки, плоскоклітинна трансдиференціація, ВПЛ16, неоад’ювантна хіміопроменева терапія rectal adenocarcinoma, squamous transdifferentiation, HPV16, neoadjuvant chemoradiotherapy Adenosquamous carcinoma and pure squamous cell carcinoma (SCC) of the rectum are extremely rare malignancies, accounting for approximately 0.15% of all colorectal cancers. Increasing attention has been paid to tumor phenotypic plasticity in the context of intensive anticancer therapy. We report the case of a 45-year-old patient with locally advanced rectal adenocarcinoma (cT4bN2M0) who underwent total neoadjuvant therapy consisting of XELOX chemotherapy combined with pelvic radiotherapy. Baseline biopsy samples from multiple tumor areas showed moderately differentiated adenocarcinoma with an intestinal immunophenotype. After treatment, the resected tumor showed complete loss of intestinal differentiation markers (CK20, CDX2) and the emergence of a squamous immunophenotype with positive expression of p40 and p63. Histologically, the tumor was composed exclusively of poorly differentiated SCC. PCR analysis detected HPV16 DNA in the SCC component. Strong, diffuse p16INK4a expression was observed in both the primary adenocarcinoma and the post-treatment tumor. These findings indicate a marked therapy-associated phenotypic shift in tumor differentiation. However, the underlying biological mechanism remains uncertain. Possible explanations include therapy-associated tumor plasticity, clonal selection of a pre-existing squamous subclone, or an initially unrecognized mixed tumor phenotype. This case highlights the importance of careful pathological reassessment after neoadjuvant therapy in rectal cancer and illustrates the complexity of interpreting phenotypic changes in treated tumors. The potential role of HPV in such processes remains hypothetical and requires further investigation. Аденосквамозний рак та істинно плоскоклітинний рак прямої кишки є надзвичайно рідкісними злоякісними новоутвореннями, що становлять приблизно 0,15% усіх випадків колоректального раку. У поодиноких випадках неоад’ювантна хіміопроменева терапія може супроводжуватися істотними змінами в диференціюванні пухлинних клітин, однак біологічні механізми таких змін з’ясовані недостатньо. У повідомленні наведено випадок місцево поширеної аденокарциноми прямої кишки (cT4bN2M0) у жінки, яка отримала тотальну неоад’ювантну терапію, що включала хіміотерапію за схемою XELOX у поєднанні з променевою терапією малого таза. Первинні біопсійні зразки, отримані з кількох ділянок пухлини, підтвердили наявність помірно диференційованої аденокарциноми з типовим кишковим імунофенотипом. Після лікування в резектованій пухлині відзначено повну втрату маркерів CK20, CDX2 та появу плоскоклітинного імунофенотипу з позитивною експресією p40 і p63. Гістологічно пухлина була представлена виключно низькодиференційованою плоскоклітинною карциномою. За результатами ПЛР-аналізу в плоскоклітинному компоненті пухлини виявлено ДНК вірусу папіломи людини 16-го типу (ВПЛ16). Виражена дифузна експресія p16INK4a спостерігалась як у первинній аденокарциномі, так і в пухлині після лікування. Отримані результати свідчать про виражений асоційований з терапією фенотиповий зсув у диференціації пухлини. Водночас точний біологічний механізм цього явища залишається невизначеним. Серед можливих пояснень розглядаються індукована терапією пухлинна пластичність, клональна селекція раніше існуючого плоскоклітинного субклону або первинно нерозпізнаний змішаний пухлинний фенотип. Представлений випадок підкреслює важливість ретельної патоморфологічної повторної оцінки пухлин після неоад’ювантної терапії при раку прямої кишки та демонструє складність інтерпретації фенотипових змін у пухлинах після лікування. Потенційна роль ВПЛ в таких процесах залишається гіпотетичною і потребує подальших досліджень. PH Akademperiodyka 2026-08-21 Article Article application/pdf https://exp-oncology.com.ua/index.php/Exp/article/view/652 10.15407/exp-oncology.2026.02.172 Experimental Oncology; Vol. 48 No. 2 (2026): Experimental Oncology; 172-180 Експериментальна онкологія; Том 48 № 2 (2026): Експериментальна онкологія; 172-180 2312-8852 1812-9269 10.15407/exp-oncology.2026.02 en https://exp-oncology.com.ua/index.php/Exp/article/view/652/478 Copyright (c) 2026 Experimental Oncology https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| spellingShingle | аденокарцинома прямої кишки плоскоклітинна трансдиференціація ВПЛ16 неоад’ювантна хіміопроменева терапія Kovalyov, O. Zavhorodniy, S. Tolok, O. Anenko, A. Kubrak, M. Danilyuk, M. Kovalyov, K. ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК |
| title | ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК |
| title_alt | PHENOTYPIC SHIFT OF ADENOCARCINOMA TO SQUAMOUS CELL CARCINOMA OF RECTUM AFTER NEOADJUVANT CHEMORADIOTHERAPY WITH DETECTION OF HPV16: A CLINICAL CASE |
| title_full | ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК |
| title_fullStr | ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК |
| title_full_unstemmed | ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК |
| title_short | ФЕНОТИПОВИЙ ЗСУВ АДЕНОКАРЦИНОМИ В ПЛОСКОКЛІТИННИЙ РАК ПРЯМОЇ КИШКИ ПІСЛЯ НЕОАД’ЮВАНТНОЇ ХІМІОПРОМЕНЕВОЇ ТЕРАПІЇ З ВИЯВЛЕННЯМ ВПЛ16: КЛІНІЧНИЙ ВИПАДОК |
| title_sort | фенотиповий зсув аденокарциноми в плоскоклітинний рак прямої кишки після неоад’ювантної хіміопроменевої терапії з виявленням впл16: клінічний випадок |
| topic | аденокарцинома прямої кишки плоскоклітинна трансдиференціація ВПЛ16 неоад’ювантна хіміопроменева терапія |
| topic_facet | аденокарцинома прямої кишки плоскоклітинна трансдиференціація ВПЛ16 неоад’ювантна хіміопроменева терапія rectal adenocarcinoma squamous transdifferentiation HPV16 neoadjuvant chemoradiotherapy |
| url | https://exp-oncology.com.ua/index.php/Exp/article/view/652 |
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