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\begin{document}

\title{Improvement of abnormal cervical cytology possibly due to a
graft-versus-tumor effect: A case report and literature review}



\author[1]{Natsuki Hayashi}%
\author[2]{Yasuhito Kato}%
\author[1]{Hiroe Miyakawa}%
\author[1]{Toshiyuki Nakata}%
\author[1]{Kenichi Tamate}%
\author[1]{Tomoki Kikuchi}%
\author[1]{Masahiko Obata}%
\affil[1]{Asahikawa Red Cross Hospital}%
\affil[2]{Asahikawa Medical University}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\textbf{Introduction}

Graft-versus-host disease (GVHD) is a potentially serious complication
of allogenic stem cell transplantation (allo-SCT), but patients who
develop GVHD also have a low incidence rate of leukemia recurrence,
suggesting a graft-versus-leukemia effect due to the donor
lymphocytes.\textsuperscript{1} This effect has also been suggested in
solid tumors. In the case here, cervical cytology transformed from
squamous cell carcinoma to negative for intraepithelial lesion or
malignancy (NILM), possibly due to a graft-versus-tumor (GVT) effect
following allo-SCT. The cervical cytology has continued changing,
although the dose of immunosuppressant likely also has an effect. Here
we describe our experience in this case and review the literature.

\textbf{Key words}

Cervical cancer, Cervical cytology, graft-versus-tumor effect, allogenic
stem cell transplantation

\textbf{Key Clinical Message}

In this case, the cervical cytology of our patient transformed from
squamous cell carcinoma to negative for intraepithelial lesion or
malignancy, possibly due to a graft-versus-tumor effect following
allogenic stem cell transplantation.

\textbf{Case History}

A 32-year-old woman (para 0) was referred to our hospital because of
abnormal vaginal bleeding. She had a history of sexually transmitted
infection at age 14 years and had been diagnosed with acute myeloid
leukemia at age 26 years, for which she had received allo-SCT. Cervical
cytology showed squamous cell carcinoma (Figure 1). We performed
cervical conization and the pathological diagnosis was cervical
intraepithelial neoplasia (Figure 2). The cervical margin was negative.
After conization, the cervical cytology persistently showed squamous
cell carcinoma or high-grade squamous intraepithelial lesion (HSIL).
Ideally, re-conization or hysterectomy would have been performed.
However, we could not perform these procedures as the patient had
pancytopenia caused by late marrow failure following allo-SCT. Hence,
transfusions were frequently performed for the pancytopenia. Because
there was no evidence of cervical tumor on MRI, she underwent a second
allo-SCT before gynecological treatment. She then developed acute GVHD,
with high fever, skin eruptions, and diarrhea. Although chronic GVHD
developed after acute GVHD, the dose of immunosuppressant was gradually
decreased and she was discharged 4 months after the second allo-SCT. The
patient still has chronic GVHD and requires regular adjustment of the
immunosuppressant dose.

Although the cervical cytology showed squamous cell carcinoma prior to
the second allo-SCT, it transformed to HSIL at 4 months (Figure 3),
atypical squamous cells of undetermined significance at 11 months
(Figure 4), and NILM at 16 months (Figure 5) after the second allo-SCT.
The cervical cytology remained NILM for 1 year, but again changed to
HSIL 33 months after the second allo-SCT. Since the abnormal cervical
cytology persisted, we performed abdominal total hysterectomy and
bilateral salpigo-oophorectomy 4 years after the second allo-SCT. The
pathological diagnosis was cervical intraepithelial neoplasia, grade
3/HSIL (Figure 6). The surgical margin was negative. Though the vaginal
stump cytology showed squamous cell carcinoma after the operation
(Figure 7), it improved to HSIL 5 months postoperatively (Figure 8).
Three years after the hysterectomy, the cytology had transformed from
HSIL to NILM without treatment (Figure 9).

\textbf{Discussion}

This case is unique because the cervical cytology changed in a short
time. The change in cervical and vaginal stump cytology without
treatment is rare, so we speculate that this change was associated with
allo-SCT.

GVHD is among the most potentially serious complications of allo-SCT,
but patients who develop GVHD also have a low incidence of leukemia
recurrence,\textsuperscript{1} suggesting a GVT effect due to the donor
lymphocytes in association with GVHD.

Eibl et al. reported a breast cancer patient with liver and bone
metastases who underwent allo-SCT and had complete resolution of the
liver metastases on CT 27 days later.\textsuperscript{2} On the same
day, the patient developed acute GVHD of the skin. Considering this
clinical course, Eibl et al. attributed the resolution of the metastases
to a GVT effect. Child et al. performed allo-SCT in 19 patients with
refractory metastatic renal-cell carcinoma, of whom 3 had complete
response and 7 had partial response. \textsuperscript{3} They noted that
regression of metastases occurred at a median of 129 days after
transplantation, often following withdrawal of cyclosporine and the
establishment of complete donor T cell chimerism. Cyclosporine
suppresses the increase of T cells and the production of cytokines. This
agrees with the previous study suggesting that the graft-versus-leukemia
and GVT effect is caused by donor T cells.\textsuperscript{4}

There are many reports of the GVT effect in patients with solid tumors.
To our knowledge, however, this is the first report showing a GVT effect
for only abnormal cytology. Some studies have reported that the cervical
cytology after allo-SCT was affected by immune status.

Shanis et al. studied 82 women who underwent allo-SCT and found the
cumulative incidence rate of any genital HPV infection at 20 years after
transplantation to be 40.1\%.\textsuperscript{5} Women who developed
extensive and genital chronic GVHD had a cumulative HPV infection rate
of 67.1\%, compared with 18.4\% in women without chronic GVHD. They also
reported that the cumulative rate of severe dysplasia reached 19\% at 20
years after transplantation, and the rate was significantly different
between women with and without chronic GVHD (41.2\% versus 2.5\%). In
contrast, there was no association between acute GVHD and the rate of
HPV infection. Shanis et al. suggested that, since sexual activity after
allo-SCT is generally decreased, the increased HPV infection rate was
due to reactivation of HPV rather than new infection. Moreover, viral
reactivation may have been influenced by chronic GVHD and/or
immunosuppression. Similarly, Bipin et al. reported that genital HPV
disease occurred in one-third of 38 patients.\textsuperscript{6} All of
them were long-term survivors of allo-SCT on prolonged immunosuppressive
therapy. Bipin et al. suggested that prolonged systemic
immunosuppressive treatment for chronic GVHD was associated with a
higher risk of developing genital HPV disease.

Our patient may have already been infected with HPV before she underwent
the first allo-SCT considering her history of sexually transmitted
infection. The abnormal cervical cytology may represent HPV reactivation
due to prolonged immunosuppression.

We suggest that our patient developed a GVT effect associated with GVHD,
which resulted in transient improvement of the cervical cytology after
the second allo-SCT. This GVT effect may have been suppressed later by
immunosuppressive therapy, resulting in worsening of her cervical
cytology. As shown in Figure 10, the cervical cytology changed from NILM
to HSIL. When GVHD recurred and the immunosuppressant dose was
increased, the cervical cytology improved. When the immunosuppressant
dose was again decreased because of improvement of GVHD, the cervical
cytology worsened. Although we speculate that the cervical cytology was
affected by a GVT effect mediated by the immunosuppressant dose, there
is no direct evidence that the cervical cytology improved because of a
GVT effect. However, transformation of the cervical cytology from NILM
to HSIL without treatment is rare. Although the possibility of sampling
error cannot be excluded, if it were to occur, then there would be no
correlation between cytology, GVHD and the immunosuppressant dose.

The cervical cytology of patients after allo-SCT is likely to change
depending on their immune status. Regular gynecologic follow-up is
needed even after improvement of the cervical cytology to monitor for
changes.

\textbf{Author contribution}

Yasuhito Kato: Supervision. Hiroe Miyakawa: Conceptualization. Toshiyuki
Nakata: Conceptualization. Kenichi Tamate: Project administration.
Tomoki Kikuchi: Resources, Writing-review \& editing. Masahiko Obata:
Resources.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Sullivan KM, Storb R, Buckner CD, et al. Graft-versus-host disease as
  adoptive immunotherapy in patients with advanced hematologic
  neoplasms. N Engl J Med 1989;320(13):828-834.
\item
  Eibl B, Schwaighofer H, Nachbaur D, et al. Evidence for a
  graft-versus-tumor effect in a patient treated with marrow ablative
  chemotherapy and allogeneic bone marrow transplantation for breast
  cancer. Blood 1996;88(4):1501-1508.
\item
  Childs R, Chernoff A, Contentin N, et al. Regression of metastatic
  renal-cell carcinoma after nonmyeloablative allogeneic
  peripheral-blood stem-cell transplantation. N Engl J Med
  2000;343(11):750-758.
\item
  J.H.F Falkenburg, I. Jedema Allo-reactive T cells for the treatment of
  hematological malignancies. Mol Oncol 2015;9(10):1894-903.
\item
  Shanis D, Anandi P, Grant C, et al. Risks factors and timing of
  genital human papillomavirus (HPV) infection in female stem cell
  transplant survivors: a longitudinal study. Bone Marrow Transplant
  2018;53(1):78-83.
\item
  Bipin N, Pamela S, Aarthi S, et al. Increased risk of cervical
  dysplasia in long-term survivors of allogeneic stem cell
  transplantation-implications for screening and HPV vaccination. Biol
  Blood Marrow Transplant 2008;14(9):1072-1075.
\end{enumerate}

\textbf{List of figure legends}

Figure 1. First cervical cytology: squamous cell carcinoma (\selectlanguage{ngerman}×40 Pap
smear).

Figure 2. Pathological specimen from conization: carcinoma in situ (×20
hematoxylin and eosin stain).

Figure 3. Cervical cytology 4 months after the second allogenic stem
cell transplantation: high-grade squamous intraepithelial lesion (×40
Pap smear).

Figure 4. Cervical cytology 11 months after the second allogenic stem
cell transplantation: atypical squamous cells of undetermined
significance (×40 Pap smear).

Figure 5. Cervical cytology 16 months after the second allogenic stem
cell transplantation: negative for intraepithelial lesion or malignancy
(×40 Pap smear).

Figure 6. Pathological specimen from hysterectomy: cervical
intraepithelial neoplasia, grade 3/HSIL (×20 hematoxylin and eosin
stain).

Figure 7. Cervical cytology 2 months after hysterectomy: squamous cell
carcinoma (×40 Pap smear).

Figure 8. Cervical cytology 5 months later after hysterectomy:
high-grade squamous intraepithelial lesion (×40 Pap stain).

Figure 9. Cervical cytology 3 years after hysterectomy: negative for
intraepithelial lesion or malignancy (×40 Pap stain).

Figure 10. Course of cervical cytology and dose of immunosuppressant.
ASC-H, atypical squamous cells cannot exclude HSIL; ASC-US, atypical
squamous cells of undetermined significance; ATH+BSO, abdominal total
hysterectomy and bilateral salpingo-oophorectomy; HSIL, high-grade
squamous intraepithelial lesion; NILM, negative for intraepithelial
lesion or malignancy; SCC, squamous cell carcinoma.

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