Uterine Leiomyoma with Massive Lymphoid Infiltrate in a Patient with History of Assisted In-Vitro Fertilization
Monia DI PRETE1, Matteo COLLAMARINI2, Claudio COLLAMARINI2, Francesco SESTI2, Alessandro MAURIELLO1, Giampiero PALMIERI1
1Department of Anatomic Pathology,University of Rome Tor Vergata, ROME, ITALY
2Department of Gynaecology and Obstetrics, University of Rome Tor Vergata, ROME, ITALY
Keywords: Leiomyoma, In-vitro fertilization, Uterine, Lymphoma
Uterine leiomyomas are the most common benign tumors of the gynecological tract. Massive lymphocytic infiltration has been reported rarely in
uterine leiomyomas and it has been described as a pathogenetic correlation with gonadotropin-releasing hormone agonists. Uterine leiomyomas
with massive lymphoid infiltration have to be differentiated from non-Hodgkin lymphomas. We report a case of a woman without a history
of gonadotropin-releasing hormone agonist treatment, who presented with a uterine leiomyoma that increased in size after the procedure of
assisted in-vitro fertilization, and associated with massive nodular lymphoid infiltrate simulating, morphologically, a non-Hodgkin lymphoma.
Uterine leiomyoma with massive lymphocytic infiltration is a very rare entity, probably of reactive significance, which has to be differentiated
from diseases that need a systemic therapeutic approach.
Uterine leiomyomas are the most common benign tumors
of the gynecological tract and occur in at least 20% of
women in their reproductive age 1
. Lymphoid infiltration
involving the uterus is generally confined to the cervix 2
but massive lymphocytic infiltration has also rarely been
reported in uterine leiomyomas 3-10
. A pathogenetic
correlation between lymphoid infiltration and treatment
with gonadotropin-releasing hormone (GnRH) agonists
has been described in literature, even if the mechanism is
still unclear 6,7
. GnRH agonists have been used in the
management of uterine leiomyomas, as a neoadjuvant
therapy before surgical excision, since the 1980s 11
The treatment produces size reduction, which results
in an easier and more conservative surgical approach
(myomectomy instead of hysterectomy, or vaginal rather
than abdominal hysterectomy). The underlying mechanism
is based on decreasing the production of luteinizing and
follicle-stimulating hormones from the pituitary gland,
which induces a subsequent hypoestrogenic status.
Uterine leiomyomas are estrogen-dependent tumors and
the decreased estrogenic stimulation leads to a reduction
in size 12
. Uterine leiomyomas with massive lymphoid
infiltration have to be differentiated from non-Hodgkin
lymphomas (NHL). We report a case of a thirty-sevenyear-
old woman, who had undergone assisted in-vitro fertilization, without using GnRH agonists, and who
presented a uterine leiomyoma with massive nodular
lymphoid infiltrate simulating NHL.
A 37-year-old Caucasian woman was referred to our
Gynecological Department for a slowly-growing leiomyoma
of the posterior wall of the uterus. She had no recent history
of uterine bleeding, abdominal pain or drug assumption.
A transvaginal ultrasound scan showed no evidence of
endometrial hyperplasia. Pap smear was negative for
malignancy and laboratory tests showed no significant
alterations. The patient had undergone two cycles of
assisted in-vitro fertilization, by intra-cytoplasmic sperm
injection (ICSI), three years ago, when a subserosal fibroid 1
cm in diameter was first described. During the fertilization
procedure, she took Cetrotide, a GnRH antagonist. She had
one pregnancy, with subsequent natural eutopic delivery.
The myoma grew in size rapidly after the fertilization
procedure and pregnancy was checked periodically
) until it was decided to perform a myomectomy.
The postoperative course was uneventful. Grossly, the
specimen consisted of a whitish ovoidal formation,
measuring 6 cm in greatest dimension, of firm consistency
and smooth surface. The cut surface showed a typical
aspect of interlacing bundles, with no areas of necrosis,
hemorrhage or softening (Figure 2A-C
). Microscopic examination revealed a well-circumscribed leiomyoma
composed of bland smooth-muscle spindle cells arranged
in fascicles, associated with a dense lymphoid infiltration
of small and mature lymphocytes organized in nodules
). These areas alternated with others where the infiltrate was diffuse but less dense. A few plasma cells were
identified . Occasional larger lymphocytes were present.
Neither tangible-body macrophages nor neutrophils were
detected. Vascularity was not prominent with thin-walled
blood vessels lined by flattened endothelium. Although the
density of the lymphoid infiltrate was sometimes greater
around the blood vessels, pathogens, fibrin deposits or
thrombi were absent in the tumor vessels. The massive
lymphoid infiltration imposed the differential diagnosis
with NHL. The nodular infiltrate consisted of lymphoid
follicles with germinal center consisting of CD20 + (with
a few small T lymphocytes CD3 + interspersed), bcl-2 -,
CD10 +, bcl-6 + associated with a meshwork of follicular
dendritic cells CD21 +. The Ki67 proliferation index was
high in reactive germinal centers. Small lymphocytes with
diffuse growth pattern were predominately CD3 + and CD4
+, with a CD4 + : CD8 + ratio of 3 : 1. Immunohistochemical
findings are shown in Figure 3. Only occasional scattered
lymphocytes were positive for granzyme B. Moreover, the
immunohistochemical staining for ALK-1 was negative,
excluding an inflammatory myofibroblastic tumor. This
finding, associated with the polymorphic composition of
the infiltrate, led to the conclusion of a leiomyoma with
massive lymphoid infiltration.
Click Here to Zoom
|Figure 1: Transvaginal ultrasound shows a well-defined, solid
subserosal mass, with variable echogenicity, that causes acoustic
shadowing, suggestive for leiomyoma.
Click Here to Zoom
|Figure 2: A) Whitish ovoidal
formation of firm consistency
and smooth surface. B-C)
The cut surface reveals typical
interlacing bundles, with no
areas of necrosis, hemorrhage or softening.
Click Here to Zoom
|Figure 3: A) Microscopic examination shows bland smooth-muscle spindle cells, arranged in fascicles, associated with a dense
lymphoid infiltration of small and mature lymphocytes, organized in nodules alternated with diffuse areas (H&E; 100). B-J) The
immunohistochemical study of a lymphoid follicle. C) CD20. D) CD3. E) CD10. F) CD21. G) Ki-67. H) bcl-2. I) CD4. J) CD8. (H&E;
x100) (IHC; x100).
Uterine leiomyoma with lymphoid infiltration is a very
rare condition. It is characterized by a small lymphocyte
infiltrate that can be focal to diffuse, moderate to brisk
in density, and associated with a few plasma cells, rare
eosinophils and occasional lymphoblasts 3,4
centers can be present but generally are not prominent. The
infiltrate is generally composed predominately by small and
mature CD8 + T-lymphocytes. The underlying causes are
not yet identified. The association with previous treatment
with GnRH agonists has been reported in the literature
. It was suggested that the pathogenic mechanism
derives from the immunological response elicited against
cell surface antigens altered by the therapy 13
. In our case,
the patient underwent an ICSI procedure, which took place
three years before the myomectomy. Fibroids’ dramatic
enlargement can be related to ICSI and pregnancy, as
reported in the literature 14
. Moreover, our patient took
Cetrotide, a GnRH antagonist, which was not previously
associated with uterine leiomyoma lymphoid infiltration,
during the procedure. GnRH antagonists, as the agonists,
are routinely used as a neoadjuvant treatment before
surgical removal of fibroids. These considerations lead to
the hypothesis that the lymphoid infiltrate, detected in our
case, may be connected with the therapy administered to
our patient 13
. The lymphocytic infiltration, composed
predominantly of small and mature lymphocytes and
organized in lymphoid follicles with a germinal center, is the
peculiar feature of our case. Massive lymphoid infiltration
in uterine leiomyomas has also been reported in association
with intrauterine contraceptive devices or autoimmune
diseases. The former may cause episodes of acute
inflammation within the myoma 3
. The latter may elicit
a direct cytotoxic effect 15
. A recent study on Hodgkin’s
disease and anaplastic large cell lymphoma reported that
tumor cells may aberrantly express TNF-α or thymus- and
activation-regulated chemokines (TARC), which might
attract a specific lymphocytic subset and CD4 + T-cell
with a Th2 phenotype in particular 16
we could not perform immunohistochemical staining for
TNF-α and TARC. Malignant tumors can be infiltrated
by T-lymphocytes (TILs: tumor-infiltrating lymphocytes)
due to a specific host response to the tumor itself 17
However, to our knowledge, TILs are described only
in association with malignant tumors. The differential
diagnosis of uterine leiomyoma with lymphoid infiltration
includes uterine malignant lymphomas and sarcomas,
such as an inflammatory myofibroblastic tumor, as well
as reactive conditions. Uterine leiomyoma with massive lymphoid infiltration cannot be distinguished from NHL
by clinical features; the latter may not have a systemic
presentation and can be confined to the uterus, even
involving preexistent fibroids 3,18
. The gross appearance
of leiomyomas with and without lymphoid infiltration is
similar, while malignant lymphoma is softer and fleshy. On
histologic examination, the uterus, including the cervix, is
generally involved by diffuse large B-cell lymphoma 18
In our case, the lymphoid infiltrate was composed by small
lymphocytes arranged in follicles, with a germinal center,
that was focally prominent, enforcing the differential
diagnosis with follicular lymphoma. This type of malignant
lymphoma is extremely rare in the uterus, and the cellular
composition (presence of plasma cells) associated with the
irregularity in size and shape of the lymphoid follicles, as
evidenced by immunohistochemistry, led to the diagnosis
of a leiomyoma with lymphoid infiltration. It was not
possible to evaluate the surrounding tissues, but the fibroid
was well-circumscribed and the lymphoid infiltration
appeared to be confined to the lesion, while malignant
lymphoma generally spreads to the adjacent myometrium.
Another differential diagnosis that has to be considered is
inflammatory myofibroblastic tumor, which is generally
positive for ALK-1 19
. In our case, the immunostaining
was negative and the background cells did not express a
In conclusion, uterine leiomyoma with massive lymphocytic
infiltration is a very rare entity, probably of reactive
significance, and has distinct morphological features,
which allow the differential diagnosis from diseases that
need a systemic therapeutic approach such as NHL.
CONFLICT of INTEREST
The authors declare no conflict of interest nor funding
1) Buttram VC, Reiter RC. Uterine leiomyomata: Etiology,
symptomatology and management. Fertil Steril. 1981;36:433-45.
2) Young RH, Harris NL, Scully RE. Lymphoma-like lesions of the
female genital tract: A report of 16 cases. Int J Gynecol Pathol.
3) Ferry JA, Harris NL, Scully RE. Uterine leiomyomas with
lymphoid infiltration simulating lymphoma. A report of seven
cases. Int J Gynecol Pathol. 1989;8:263-70.
4) Botsis D, Trakakis E, Kondis-Pafitis A, Kontoravdis A, Kassanos
D, Chryssikopoulos A, Creatsas G. Leiomyoma of the uterus
with massive lymphoid infiltration simulating lymphoma. A case
report. Eur J Gynaecol Oncol. 1999;20:61-2.
5) Chuang SS, Lin CN, Li CY, Wu CH. Uterine leiomyoma
with massive lymphocytic infiltration simulating malignant
lymphoma. A case report with immunohistochemical study
showing that the infiltrating lymphocytes are cytotoxic T cells.
Pathol Res Pract. 2001;197:135-8.
6) Ohmori T, Wakamoto R, Lu LM, Okada K, Nose M.
Immunohistochemical study of a case of uterine leiomyoma
showing massive lymphoid infiltration and localized vasculitis
after LH-RH derivant treatment. Histopathology. 2002;41:276-7.
7) McClean G, McCluggage WG. Unusual morphologic features
of uterine leiomyomas treated with gonadotropin-releasing
hormone agonists: Massive lymphoid infiltration and vasculitis.
Int J Surg Pathol. 2003;11:339-44.
8) Paik SS, Oh YH, Jamg KS, Han HX, Cho SH. Uterine leiomyoma
with massive lymphoid infiltration: Case report and review of the
literature. Pathol Int. 2004;54:343-8.
9) Saðlam A, Güler G, Taþkin M, Ayhan A, Üner AH. Uterine
leiomyoma with prominent lymphoid infiltrate. Int J Gynecol
10) Botsis D, Koliopoulos C, Kondi-Pafitis A, Creatsas G. Frequency,
histological, and immunohistochemical properties of massive
inflammatory lymphocytic infiltration of leiomyomas of the
uterus: An entity causing diagnostic difficulties. Int J Gynecol
11) Filicori M, Hall DA, Loughlin JS, Rivier J, Vale W, Crowley
WF Jr. A conservative approach to the management of uterine
leiomyoma: Pituitary desensitization by a luteinizing hormonereleasing
hormone analogue. Am J Obstet Gynecol. 1983;147:726-7.
12) Wilson EA, Yang F, Rees ED. Estradiol and progesterone binding
in uterine leiomyomata and in normal uterine tissues. Obstet
13) Crow J, Gardner RL, McSweeney G, Shaw RW. Morphological
changes in uterine leiomyomas treated by GnRH agonist
goserelin. Int J Gynecol Pathol. 1995;14:235-42.
14) Benaglia L, Cardellicchio L, Filippi F, Paffoni A, Vercellini P,
Somigliana E, Fedele L. The rapid growth of fibroids during early
pregnancy. PLoS One. 2014;9:e85933.
15) Laforga JB, Aranda FI. Uterine leiomyomas with T-cell infiltration
associated with GnRH agonist goserelin. Histopathology.
16) Vermeer MH, Dukers DF, ten Berge RL, Bloemena E, Wu L, Vos
W, de Vries E, Tensen CP, Meijer CJ, Willemze R. Differential
expression of thymus and activation regulated chemokine and
its receptor CCR4 in nodal and cutaneous anaplastic large-cell
lymphomas and Hodgkin’s disease. Mod Pathol. 2002;15:838-44.
17) Whiteside TL, Parmiani G. Tumor-infiltrating lymphocytes:
Their phenotype, functions and clinical use. Cancer Immunol
18) Harris NL, Scully RE. Malignant lymphoma and granulocytic
sarcoma of the uterus and vagina: A clinicopathologic analysis of
27 cases. Cancer. 1984; 53:2530-45.
19) Parra-Herran C, Quick CM, Howitt BE, Dal Cin P, Quade BJ,
Nucci MR. Inflammatory myofibroblastic tumor of the uterus:
Clinical and pathologic review of 10 cases including a subset with
aggressive clinical course. Am J Surg Pathol. 2015;39:157-68.