Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, Italian Division

48 Pages·2016·7.41 MB·English

ISSN 0031-2983
Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS
Journal of the Italian Society of Anatomic Pathology
03
and Diagnostic Cytopathology,
Italian Division of the International Academy of Pathology
ORIGINAL ARTICLES
177 The potential of ki67 and p53 assessment in development of individualized targeted
therapy in breast cancer patients
C. Ormenisan, M. Kubik, S. Legrand, D. Kraemer, C. Smotherman, S. Masood –
181 Plexiform fibromyxoma of the gallbladder
M. Fassan, R. Salmaso, D. Saraggi, R. Alaggio, M. Guido, L. Balsamo, S. Carniato,
M. Gruppo, V. Ninfo, R. Bardini, M. Rugge
185 A population of 1136 HPV DNA-HR positive women: 04
expression of p16 INK4a / Ki67 Dual-Stain Cytology and cytological diagnosis.
Histological correlations and cytological follow up
P. Rossi, L. Borghi, R. Ferro, R. Mencarelli
CASE REPORTS
192 Solitary thyroid metastasis from colon cancer: fine-needle aspiration cytology
and molecular biology approach
M. Onorati, P. Uboldi, C.L. Bianchi, M. Nicola, G.M. Corradini, S. Veronese, A.I. Fascì,
DCB PISA 197 FT.u Dbie Nrouuosv soclerosis: histological analysis with confocal laser scanning microscope Vol. 107 September /
mma 1, oGf. Fgainvgiaiv, aAl. Taenmgipoefisbtaro, mL. aLtiomsoisngelli, E. Maiorano December 2015
D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, co 2 L2 A2ET000TT518IT EDAAAJIIR. I n. IM n .UC T eiEeOsnOwpeuc NTs tbicHidtGnueoeEgRtinnnu EtENtneaSDm,a lSIIlzT.ypO iOS ood eRrniala-acrIgNylue nk-p oC,dr oGsHeesl.I tEdBGaF otereuyp rpciataphzno,e c ZlIiet.oaSri l.dg iTa rutanrndoocip nedhgrio Psbyalsalteseotmipc:a tmtuomelosogsrai aign e( G htoyIPs tatheleere oItc)at loiamny pathologists
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mestrale – POSTE ITALIANE SPA - Spedizione in AbbonaGenova n. 75 del 22/06/1949
Periodico triAut. Trib. di SDoivciiseiotàn eIt aItlaialinaan ad id Aenllaat oInmteiran Pataiotonlaolg Aiccaa dee Cmityo poaf tPoalothgoialo Dgyiagnostica,
Cited in Index Medicus/MEDLINE, BIOSIS Previews, SCOPUS
Journal of the Italian Society of Anatomic Pathology
03
and Diagnostic Cytopathology,
Italian Division of the International Academy of Pathology
Editor-in-Chief A.G. Rizzo, Palermo Copyright
Marco Chilosi, Verona G. Rossi, Modena Società Italiana di Anatomia
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CONTENTS ki67-staining to classify CIN1 according to its risk of progression/
regression in order to plan a personalized follow-up.
Original articles Methods. Our analysis was in consecutive cases of 1136 women
aged 25-64 years, asymptomatic, HR-HPV DNA HC2 tested posi-
The potential of ki67 and p53 assessment in development
tive in a HPV-screening program, from February to December 2011.
of individualized targeted therapy in breast cancer patients
All the women had a cervical sample, in the Thin Prep, used for
C. Ormenisan, M. Kubik, S. Legrand, D. Kraemer,
cytological diagnosis and for p16/Ki67 dual- staining. Histological
C. Smotherman, S. Masood
correlations were 442. We studied the follow-up of two years of 387
Introduction. Despite the improvement of diagnostic methods and cases, especially the biological behaviour of 316 low-grade lesions.
chemotherapeutic regimens in breast cancer, overall 5-year survival Results. p16/Ki67 dual-staining increases the VPP CIN2+ and NPV
significantly depends on the stage of the disease. Over expression of CIN2+, especially in atrophy/dystrophy, in ASC-US and LSIL. In
tumor suppressor gene p53 and the marker for cellular proliferation follow-up of 387 cases, 71 CIN2+ and 316 CIN1, 69 CIN2+, after
Ki67 in breast cancer may have prognostic significance. surgical treatment, had a negative follow up; two cases of CIN2
Methods. We evaluated 675 patients diagnosed with breast cancer at (p16/ki67-) without invasive treatments, had a spontaneous regres-
UF Health Jacksonville between January 2000 and June 2007 with up sion. Among the 316 CIN1, progression was observed in 10 women
to 5-year follow up. The aim of the study was to determine whether (4 p16/Ki67 + and 6 p16/Ki67 -); regression in 260 women (64 p16/
immunohistochemical (IHC) assessment of Ki67 and p53 may predict Ki67 + and 196 p16/Ki67 -); 46 women had a persistent LSIL (9
outcome, the ‘hazard’ of dying. Cox’s proportional hazards models p16/Ki67 + and 37 p16/Ki67 -). It seems no significant differences
were used to control for age (< 50 vs. ≥ 50), race (white vs. other), in the biological behaviour in relation to the expression of the two
lymph node group (negative vs. positive), ER (estrogen receptor) biomarkers.
group (negative vs. positive), PR (progesterone receptor) group (nega- Conclusions. p16/Ki67 immunostaining increases sensitivity of
tive vs. positive), and tumor type. cytology in some diagnostic categories. After follow up of two years,
Results. When only p53 was considered in the model, the hazard of a personalized and adequate treatment does not seem still possible.
dying was significantly higher for p53 positive compared to p53 nega- Further studies and trials are required to improve the management of
tive (HR = 1.32, 95 % CI 1.02, 1.70, p = 0.036). When only ki67 was the cervical lesions in HPV-based screening strategies.
considered in the model, the hazard of dying was significantly higher
for ki67 positive compared to ki67 negative (Hazard ratio = 1.64, 95
% CI 1.08, 2.49, p = 0.021). Neither of the two markers, nor their Case reports
interaction was significant when all variables were considered in the
Solitary thyroid metastasis from colon cancer: fine-needle
model.
aspiration cytology and molecular biology approach
Discussion. This study confirms the expression of p53 and Ki67 as
M. Onorati, P. Uboldi, C.L. Bianchi, M. Nicola, G.M. Corradini,
strong individual indicators of patient outcome. However, when con-
S. Veronese, A.I. Fascì, F. Di Nuovo
trolling for the other variables, the two markers are not independent
Thyroid gland is one of the most vascularized organs of the body,
predictors. Future studies that will include these markers might help
nevertheless clinical and surgical series report an incidence of sec-
design targeted therapy.
ondary malignancies in this gland of only 3 %. Colorectal carci-
noma metastatic to the thyroid gland is not as uncommon as previ-
Plexiform fibromyxoma of the gallbladder
ously believed, infact the number of cases seems to be increased in
M. Fassan, R. Salmaso, D. Saraggi, R. Alaggio, M. Guido,
recent years due to the more frequent use of fine-needle aspiration
L. Balsamo, S. Carniato, M. Gruppo, V. Ninfo, R. Bardini, M. Rugge
cytology (FNAC) guided by ultrasonography. Although kidney,
We report the unusual case of a plexiform fibromyxoma, occasion-
breast and lung metastases to the thyroid are frequent, metastasis
ally assessed in a lithiasic gallbladder. The full thickness assessment
from colon cancer is clinically rare with 52 cases reported in the
of the gallbladder wall revealed an intra-mural, well demarked multi-
literature in the last 5 decades and three cases described as solitary
nodular tumor (1 cm), consisting of a plexiform growth of spindle
thyroid metastasis from the colon cancer without any other visceral
cells, included within a fibromyxoid stroma with a rich micro-
metastases.
vascular network. The tumor cells featured no nuclear atypia, nor To the best of our knowledge, we report the fourth case of soli-
mitotic activity. At the immunohistochemical profiling, the spindle tary, asymptomatic thyroid metastasis from colon cancer without
shaped cells unequivocally featured vimentin, SMA, HHF35, col- involvement of other organs. We discuss the importance of FNAC
lagen IV, and CD34; no cells expressed CD117, PDGFRA, CD10, to detect metastatazing process as a compulsory step of the diagnos-
desmin, GFAP, EMA, and S-100. Faint STAT6 nuclear expression tic and therapeutic management algorithm, combined with a molec-
was observed in isolated tumor cells. The molecular profiling did ular biology approach. A review of the last 5 decades literature, to
not revealed any CKIT and PDGFRA genes mutations. The uncom- update the number of cases described to date, is also included.
mon site of the tumor presentation and its aberrant CD34 expression
both confer to the reported case a unique place among the myxoid Tuberous sclerosis: histological analysis with confocal laser
tumors of the gastrointestinal tract. scanning microscope of gingival angiofibromatosis
G. Favia, A. Tempesta, L. Limongelli, E. Maiorano
A population of 1136 HPV DNA-HR positive women: expres-
Introduction. Tuberous sclerosis (TS) is an autosomal domi-
sion of p16 INK4a / Ki67 Dual-Stain Cytology and cytological
nant neuro-cutaneous syndrome characterized by multiple
diagnosis. Histological correlations and cytological follow up
hamartomas in various organs, especially on skin and central
P. Rossi, L. Borghi, R. Ferro, R. Mencarelli
nervous system. The most common features of TS include
Objective. The objectives of this study were to evaluate, in a facial angiofibromas, hypomelanotic cutaneous macules,
selected HR-HPV positive population, the clinical performance of shagreen patches in the lumbar area, cerebral cortical tubers,
the p16/ki67 immunostaining in all the cytological diagnoses, as a sub-ependymal nodules, sub-ependymal giant cell astrocyto-
reflex test of triage HPV-cytology, and assess the usefulness of p16/ mas, cardiac rhabdomyomas, and renal angiomyolipomas. Fre-
quently oral manifestations such as fibrous hyperplasia, angio- An incidentally diagnosed epithelioid trophoblastic tumor
fibromas and dental enamel pitting are also observed. in hysterectomy
The aim of this case report was to describe the histological A. Usubutun, I. Selcuk, G. Boyraz, Z.S. Tuncer
aspects of oral diffuse hyperplastic angiofibromatosis, never Epithelioid trophoblastic tumor is a rare non-molar gestational
reported in the English literature and analyzed by Confocal trophoblastic disease. A 40-year-old multiparous woman was
Laser Scanning Microscope (CLSM), and to highlight the sur- incidentally diagnosed with epithelioid trophoblastic tumor
gical implications of these aspects such as use of Diode Laser. after hysterectomy. Hysterectomy specimen revealed multiple
Case report. A 14-years-old female patient with TS diagnosis small, tan to yellow nodules measuring 0.3-0.8 cm just below
came to our attention for diffuse gingival hyperplasia on the the endometrium. In the microscopic examination uniform
mandible. Clinical examination highlighted epidermal hamar- neoplastic cells with varying cellularity were accompanied by
tomas on the whole body, especially on the face and scalp. necrotic zones and eosinophilic hyaline material. Immunohis-
Pathologic hyperplastic tissue was removed by pulsed diode tochemically neoplastic cells were diffusely stained with CK
laser at the power of 5-6W, and the surgical samples were sent 7, inhibin-alpha, p63, hPL, and CD146. There was no staining
for conventional and CLSM histopathological examination. After with beta-HCG, SMA, PLAP, or h-caldesmon. Ki-67 prolifera-
laser excision, wounds healed quickly without complications. At tive index was approximately 10 % and cyclin E was stained
CLSM examination collagen fibres, showing intense fluorescence in approximately 10 % of the neoplastic cells. Although immu-
and with variable spatial orientation, and variably sized blood nohistochemical studies are helpful in classifying gestational
vessels were noticed suggesting the diagnosis of gingival angiofi- trophoblastic lesions, borderline values can cause diagnostic
bromatosis, a still unreported finding in TS patients. confusion between neoplastic and reactive lesions, particularly
Conclusions. CLSM analysis allows to highlight some unusual in inadequate endometrial biopsies.
histopathological features of TS; diode laser is very effective
for the treatment of gingival angiofibromatosis.
Pathologica 2015;107(02):103
Atti Congresso AnnuAle di AnAtomiA pAtologiCA siApeC-iAp 2015
errAtA
The pathologist in the diagnostic and therapeutic path: a new role for a before hidden profession
D. Bellis1,2, A. Abbona1, D. Antonini1, S. Guzzetti1, P. Riella1
1 S.C. di Anatomia Patologica, Ospedale Martini - ASLTO1, Torino; 2 Patologo in Staff alla Rete Oncologica del Pie-
monte e della Valle d’Aosta, Delegato Regionale SIAPEC Piemonte
Corrige
The pathologist in the diagnostic and therapeutic path: a new role for a before hidden profession
D. Bellis1,2, g. Abbona1, D. Antonini1, S. Guzzetti1, P. Riella1
1 S.C. di Anatomia Patologica, Ospedale Martini - ASLTO1, Torino; 2 Patologo in Staff alla Rete Oncologica del Pie-
monte e della Valle d’Aosta, Delegato Regionale SIAPEC Piemonte
pathologica 2015;107:177-180
Original article
The potential of ki67 and p53 assessment
in development of individualized targeted therapy
in breast cancer patients
C. Ormenisan1, m. KubiK1, s. Legrand1, d. Kraemer2, 3, C. smOtherman2, s. masOOd1
1 department of Pathology, university of Florida College of medicine, Jacksonville, usa; 2 Center for health equity and Quality
research, university of Florida, Jacksonville, usa; 3 department of neurology, university of Florida, Jacksonville, usa
Key words
Breast cancer • P53 • Ki67
Summary
Introduction. despite the improvement of diagnostic methods and Results. When only p53 was considered in the model, the hazard
chemotherapeutic regimens in breast cancer, overall 5-year survival of dying was significantly higher for p53 positive compared to
significantly depends on the stage of the disease. Over expression p53 negative (HR = 1.32, 95 % CI 1.02, 1.70, p = 0.036). When
of tumor suppressor gene p53 and the marker for cellular prolifera- only ki67 was considered in the model, the hazard of dying was
tion Ki67 in breast cancer may have prognostic significance.
significantly higher for ki67 positive compared to ki67 negative
Methods. We evaluated 675 patients diagnosed with breast cancer
(Hazard ratio = 1.64, 95 % CI 1.08, 2.49, p = 0.021). Neither of
at UF Health Jacksonville between January 2000 and June 2007
the two markers, nor their interaction was significant when all
with up to 5-year follow up. The aim of the study was to determine
variables were considered in the model.
whether immunohistochemical (IHC) assessment of Ki67 and p53
Discussion. This study confirms the expression of p53 and Ki67
may predict outcome, the ‘hazard’ of dying. Cox’s proportional
hazards models were used to control for age (< 50 vs. ≥ 50), race as strong individual indicators of patient outcome. However,
(white vs. other), lymph node group (negative vs. positive), ER when controlling for the other variables, the two markers are
(estrogen receptor) group (negative vs. positive), PR (progesterone not independent predictors. Future studies that will include these
receptor) group (negative vs. positive), and tumor type. markers might help design targeted therapy.
Introduction spectively. However, within the group of hormone re-
ceptor positive patients, a subgroup of patients appeared
Breast cancer is a major public health problem for wom- to respond poorer to this somewhat targeted therapy,
en across the globe, being the most common type of can- with early relapses and poorer survival 2. Studies have
cer in women. Despite the improvement of diagnostic shown that Ki-67 can be used for subtyping and dis-
methods and chemotherapeutic regimens, overall 5-year tinguishing breast cancer and is therefore of greatest
survival of patients significantly depends on the stage of importance, considering the implications for treatment
the disease. However, over the last decades, understand- protocols, especially when combined with other markers
ing of the tumor biology has been greatly improved by such as p53 2 3. In addition, utilizing immunohistochem-
molecular research that allows application of a tumor’s istry as surrogate marker for molecular testing (gene
molecular features for selection of personalized therapy profiling) to sub-classify breast cancer is an important
and prediction of short and long term therapy 1. factor in terms of cost containment.
Traditionally, there has been a division of breast cancer Ki67 is an immunohistochemical marker of proliferat-
into hormone receptor positive and negative groups to ing cells which is widely used in various types of ma-
guide treatment with endocrine and chemotherapy, re- lignancy to assess proliferation rate. It is a fairly large
Correspondence
Claudia Ormenisan, university Of Florida, College of medicine,
Jacksonville - 655 West 8th Street, Box C-505, 32209 Jacksonville,
FL, United States of America - Tel. [phone] - Fax 001
904 244 4060 - E-mail: [email protected]
178 C. Ormenisan et al.
nuclear protein (395kD) that is present during all active other, and other tumors vs. DCIS+Lobular carcinoma +
cell cycle phases, except for G0 4. Naturally, prolifera- Infiltrating ductal carcinoma). The best subset selection
tion status correlates tightly with tumor aggressiveness, method was performed to assess the best predictive model
and therefore, Ki67 labeling index is a commonly used using all the other variables. The criterion used to deter-
prognostic indicator in breast cancer. In DCIS (Ductal mine the “best” subset is based on the global score chi-
Carcinoma in Situ), Ki67 positivity is associated with square statistic. For two different models, each having the
a higher risk of developing DCIS local recurrence after same number of explanatory variables, the model with the
breast conserving therapy. higher score chi-square statistic is considered to be better.
P53 is a tumor suppressor gene which regulates cell cy- Then, each of the markers p53 and ki67 were added in the
cle progression in response to various stimuli; alteration best model previously found.
of p53 function is seen in tumor development and pro-
gression in various organ systems. Positivity for these
markers generally infers a worse prognosis, greater Results
probability of failure with endocrine therapy in hormone
receptor positive patients and poorer survival 5 6. Patients’ demographic and baseline characteristics are
An Iranian study suggested that Ki67 may have more listed on Table I. Seventy percent of the patients were
significant prognostic strength in terms of survival than 50 years or older, and 53 % were white (53 % ). P53 was
p53; however, this study was fairly small, and a larger negative for 74 % of the sample, and Ki67 was negative
scale study is needed to substantiate these findings 7. for 43 % of the patients. Assessment of positive results
There is also an urgent need to improve prognostic clas- was based on the standard of practice (for p53 scoring
sifiers in breast cancer. Most recent decisions for breast
>10 % nuclear staining was considered positive, for
cancer patients are made on the basis of prognostic and
Ki67 > 20 % is positive, 10 to 20 % borderline and 1 to
predictive factors. Molecular studies of breast cancer
9 % negative) 8 9. Figure 1 presents patterns of staining
continue to unveil the biological heterogeneity of the
for Ki67 and p53.
disease which has opened new perspectives for per-
First, the joint effect of p53, ki67, and the interaction
sonalized therapy. Overexpression of tumor suppressor
between p53 and ki67 on the probability of survival was
gene p53 and the marker for cellular proliferation Ki67
assessed. The reference level for both markers was cho-
in breast cancer may have prognostic significance.
sen to be the “negative” level. None of the two mark-
The aim of our study was to investigate the correlation
ers, nor their interaction was significant (p = 0.050,
between Ki67 and p53 positivity with patient outcome
p = 0.242, and p = 0.252, respectively). When only p53
in a large retrospective study of 675 patients with 5 year
was considered in the model, the hazard of dying was
follow up, to potentially predict patient outcome and
significantly higher for p53 positive compared to p53
open new horizons in the development of individualized
negative (HR = 1.32, 95 % CI 1.02, 1.70, p = 0.036).
targeted therapy.
Figure 2 is the survival plot that contains two curves,
one for p53 positive and one for p53 negative. It can be
seen that, overall, the probability of survival is higher
Materials and methods
for p53 negative compared to p53 positive. When only
ki67 was considered in the model, the hazard of dying
We evaluated 675 patients diagnosed with breast cancer
with 5 year follow up at UF Health Jacksonville between
January 2000 and June 2007. The expression of Ki67
and stability of p53 were determined by immunohisto- Tab. I. patients’ demographic and characteristics (N = 675).
chemistry. The aim of the study was to determine wheth- Variable Category Count (%)
er immunohistochemical (IHC) assessment of Ki67 and age 50 years or older 515 (76)
p53 may predict outcome. Race White 355 (53)
The primary outcome variable was the ‘hazard’ of dying. hispanic Yes 18 (3)
Hazard is the instantaneous probability of dying given p53 positive 175 (26)
that patients have survived up to a given point in time Ki67 Negative 292 (43)
or the risk for death at that moment. First, three Cox’s Borderline 90 (14)
proportional hazards models were fit: one with p53, ki67, positive 293 (43)
and interaction p53*ki67 as predictors, one with only p53 tumor DciS 86 (13)
predictor, and one with only ki67 as predictor. Second, iDc 533 (79)
models were fit to determine the joint effects of p53 group lobular carcinoma 34 (5)
and ki67 group of patients, controlling for age (< 50 vs. other 22 (3)
≥ 50), race (white vs. other), lymph node group (negative Non-emergent 211 (33)
vs. positive), ER (estrogen receptor) group (negative vs. ER Negative 166 (30)
positive), PR (progesterone receptor) group (negative vs. pR Negative 213 (39)
positive), and tumor type (DCIS group vs. other, Lobu- ER and pR Negative 163 (30)
lar carcinoma vs. other, Infiltrating ductal carcinoma vs. DciS = Ductal carcinoma in Situ, iDc = invasive Ductal carcinoma
The poTenTial of ki67 and p53 assessmenT in developmenT of individualized TargeTed Therapy in breasT cancer paTienTs 179
Fig. 1. immunohistochemistry Ki67 and p53 staining pattern in negative and positive breast cancer.
Fig. 2. Survival curves for p53 group. Fig. 3. Survival curves for ki67 group.
was significantly higher for ki67 positive compared to Using the best subset selection method, the “best” model
ki67 negative (Hazard ratio = 1.64, 95 % CI 1.08, 2.49, selected was the model including race (p = 0.14), lymph
p = 0.21). There was no difference between ki67 bor- node group (p = 0.013), PR group (p = 0.18), DCIS
derline compared to ki67 negative (Hazard ratio = 0.82, group (p = 0.06), and LC group (p = 0.22) as significant
95 % CI 0.53, 1.26). Figure 3 presents the survival predictors. When entered in the model described above,
curves for ki67 groups. p53 (p = 9.65) and ki67 (p = 5.77) are no longer signifi-
180 C. Ormenisan et al.
cant. The hazard ratio of dying was 1.00 (95 % CI 0.72, indicating that they should be evaluated separately when
1.41) for p53 positive compared to p53 negative, and assessing a panel of immunohistochemical stains as sur-
1.22 (95 % CI 0.76, 1.96) for ki67 positive compared to rogate markers for tumor biology.
ki67 negative.
Conclusions
Discussion
This study confirms the expression of p53 and Ki67 as
Several studies have shown the cumulative value of in- strong single predictors of patient outcome and survival.
cluding p53 and Ki67 immunohistochemical staining This in the future might help to design studies for tar-
when assessing breast cancer prognosis and risk-strat- geted therapy development and improving patient care.
ifying patients. Positivity for these markers generally
infers a worse prognosis (e.g. greater probability of fail-
ure with endocrine therapy in hormone receptor positive References
patients) 2 10. Sarode et al. reported high Ki67 and p53
overexpression were characteristic of HER2 and triple 1 U.S. Cancer Statistics Working Group. United States Cancer Sta-
tistics: 1999–2011 Incidence and Mortality Web-based Report.
negative subtypes of breast cancer 11. While Ki67 has
Atlanta (GA): Department of Health and Human Services, Centers
been established as an important prognostic indicator, for Disease Control and Prevention, and National Cancer Institute;
there seems to be a lack of uniformity in reporting Ki67 2014.
values, with different reasons, such as different tech- 2 Jacquemier J, Charafe-Jauffret E, Monville F, et al. Association of
niques, cut off values, etc 12. In addition, intratumoral GATA3, P53, Ki67 status and vascular peritumoral invasion are
heterogeneity of proliferation can make it very difficult strongly prognostic in luminal breast cancer. Breast Cancer Res
2009;11:R23.
to assess an accurate Ki67 proliferation rate, depending
on adequate tissue sampling 12. Standardization of Ki67 3 Laurinavicius A, Laurinaviciene A, Ostapenko V, et al. Immuno-
histochemistry profiles of breast ductal carcinoma: factor analysis
reporting values may help strengthen the value of Ki67
of digital image analysis data. Diagn Pathol 2012;7:27.
as a prognostic factor.
4 Kobayashi T, Iwaya K, Matsubara O. A simple immunohistochemi-
An Iranian study suggested that Ki67 may have a more
cal panel comprising 2 conventional markers, Ki67 and p53, is a
significant prognostic strength in terms of survival than powerful tool for predicting patient outcome in luminal-type breast
p53 6; however, this study was fairly small, and a larger cancer. BMC Clin Pathol 2013;13:5.
scale study would be indicated to substantiate these find- 5 Iwaya K, Tsuda H, Hiraide H, et al. Nuclear p53 immunoreaction
ings. Other studies demonstrated that the combination of associated with poor prognosis of breast cancer. Jpn J Cancer Res
p53 and Ki67 is more accurate than Ki67 alone in pre- 1991;82:835-40.
dicting the prognosis for patients with hormone receptor 6 Shapochka DO, Zaletok SP, Gnidyuk MI. Relationship between
NF-KB, ER, PR, HER2/neu, Ki67, P53 expression in human breast
positive and Her2-negative breast cancer 4.
cancer. Exp Oncol 2012;34:358-63.
Our results confirm that both Ki67 and p53 are sig-
7 Golmohammadi R, Pejhan A. The prognostic value of the P53 pro-
nificantly associated with an adverse clinical outcome
tein and the Ki67 marker in breast cancer patients. J Pak Med
in terms of reduced overall survival. When adjusting
Assoc 2012;62:871-5.
for clinic-pathological parameters such as race, lymph
8 Tashima R, Nishimur R, et al. Evaluation of an optimal cut-off
node status, ER and PR status, the association between point for the Ki-67 index as a prognostic factor in primary breast
outcome and p53 /Ki-67 status is no longer significant, cancer. PLoS One 2015 15;10:e0119565.
indicating that these variables are confounders. This cor- 9 Coates AS, Millar EK, O’Toole SA, et al. Prognostic interaction
relates with a study from Cheang et al. reporting that between expression of p53 and estrogen receptor in patients with
Ki67 was an independent prognostic factor for luminal node-negative breast cancer: results from IBCSG Trials VIII and
IX. Breast Cancer Res 2012,14:R143.
B type of breast carcinoma, advocating the use of a sur-
rogate IHC panel including ER/PR/HER2 and Ki67 for 10 Millar EKA, Graham PH, McNeil CM, et al. Prediction of outcome
of early er+ breast cancer is improved using a biomarker panel,
biological subtyping, independently of standard clinic-
which includes ki-67 and p53. Br J Cancer 2011;105:272-80.
pathologic parameters such as age, lymph node status,
11 Sarode VR, Han JS, Morris DH, et al. A comparative analysis of
tumor size and grade 13. Our results indicate that both
biomarker expression and molecular subtypes of pure ductal car-
Ki67 and p53 are single prognostic indicators that may cinoma in situ and invasive breast carcinoma by image analysis:
be evaluated separately from other clinic-pathological relationship of the subtypes with histologic grade, ki67, p53 over-
parameters. expression, and dna ploidy. Int J Breast Cancer 2011;2011:217060.
Individually, Ki-67 and p53 are valuable prognostic fac- 12 Bhargava R, Striebel J, Beriwal S et al. Prevalence, morphologic
features and proliferation indices of breast carcinoma molecular
tors in the setting of breast cancer that can also aid in
classes using immunohistochemical surrogate markers. Int J Clin
subtyping different types of breast cancer. However, in
Exp Pathol 2009;2:444-55.
our study, they are no longer significant predictors when
13 Cheang MCU, Chia SK, Voduc D, et al. Ki67 index, her2 status,
both markers were entered in the same model, empha-
and prognosis of patients with luminal b breast cancer. J Natl Can-
sizing their independence as prognostic indicators and cer Inst 2009;101:736-50.
pathologica 2015;107:181-184
Original article
Plexiform fibromyxoma of the gallbladder
M. FASSAN1*, R. SALMASO1*, D. SARAGGI1, R. ALAGGIO1, M. GUIDO1, L. BALSAMO1, S. CARNIATO2, M. GRUPPO2,
V. NINFO1, R. BARDINI2, M. RUGGE1
1 Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy;
2 Department of Surgery, Oncology and Gastroenterology; General Surgery, University of Padua, Padua, Italy
* The first two authors contributed equally
Key words
Plexiform angiomyxoid myofibroblastic tumor • Gallbladder • CKIT • GIST
Summary
We report the unusual case of a plexiform fibromyxoma, occa- tin, SMA, HHF35, collagen IV, and CD34; no cells expressed
sionally assessed in a lithiasic gallbladder. The full thickness CD117, PDGFRA, CD10, desmin, GFAP, EMA, and S-100. Faint
assessment of the gallbladder wall revealed an intra-mural, well STAT6 nuclear expression was observed in isolated tumor cells.
demarked multi-nodular tumor (1 cm), consisting of a plexiform The molecular profiling did not revealed any CKIT and PDGFRA
growth of spindle cells, included within a fibromyxoid stroma genes mutations. The uncommon site of the tumor presentation
with a rich micro-vascular network. The tumor cells featured no and its aberrant CD34 expression both confer to the reported case
nuclear atypia, nor mitotic activity. At the immunohistochemical a unique place among the myxoid tumors of the gastrointestinal
profiling, the spindle shaped cells unequivocally featured vimen- tract.
Introduction for a previously established diagnosis of cholelithiasis.
At the admission, no significant past medical history
Myxoid non-GIST tumors of the gastrointestinal tract en- was recorded, and both the physical examination and
compass a heterogeneous group of uncommon non-epithe- laboratory tests were unremarkable. The pre-surgical ab-
lial lesions 1, and the different definitions applied to such dominal ultrasound did not reveal any mural thickening.
tumors (e.g. myxoma, fibromyxoma, plexiform fibromyx- Laparoscopic cholecystectomy was performed, with no
oma) reflect both the complex phenotype of the lesions and post-surgical complications.
their controversial nosology 1. In 2007, Takahashi and col-
leagues defined as “plexiform angio-myxoid myofibroblas-
tic tumor (PAMT)” a multi-nodular benign tumor, mostly Materials and methods
arising in the gastro-duodenal district, but also occasionally
described in the small and large bowel 2-5. Pathology
We report the unique case of a benign myxoid, plexi- The gross examination of the surgical specimen con-
form, spindle shaped cell tumor of the gallbladder wall, firmed the pre-surgical diagnosis of cholelitiasis; the
featuring the histological and immunohistochemical gallbladder’s wall was irregularly increased in thick-
phenotype of the plexiform fibro-myxoid tumor, with ness, with no grossly evident nodular lesions. Multiple
aberrant expression of CD34 endothelial marker. tissue specimens were obtained for routine histology ex-
amination, including a coronal section of the cystic duct.
The tissue specimens were fixed in formalin, embedded
Clinical history in paraffin, and cut in 4 micrometer thick histology sec-
tions, which were stained with hematoxylin and eosin.
A 55-year-old Caucasian female was referred to the Because of one the specimens obtained from the corpus
General Surgery Unit of the Padova teaching Hospital wall showed a marginal myxoid area, the whole gall-
Correspondence
Matteo Fassan, Department of Medicine DIMED, Surgical
Pathology and Cytopathology Unit, University of Padova, via
Gabelli 61, 35121 Padova, Italy - Tel. [phone] - Fax +39
049 8272277 - E-mail: [email protected]