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CASE REPORT  
Year : 2014  |  Volume : 57  |  Issue : 4  |  Page : 606-608
Cyclin D1 and p16INK4 positive endometrial stromal sarcoma: A case report with new insights


Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

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Date of Web Publication11-Oct-2014
 

   Abstract 

Endometrial stromal sarcoma (ESS) has a wide histopathological spectrum with CD10 as its diagnostic marker. Recently, few non-conventional ESSs have been identified that lack diffuse CD10 expression. A 46-year-old, perimenopausal lady referred to us with history of vaginal bleeding. On clinical examination and radiological imaging, a polypoid endometrial tumor was identified. Hysterectomy revealed a multinodular tumor in the myometrium. Microscopically, the tumor composed of rather banal oval to spindle-shaped cells in a fibromyxoid stroma. Focal areas displayed compact cellular arrangement, unassociated with significant mitoses and necrosis. Immunohistochemically, tumor cells were focally positive for CD10, estrogen receptor, progesterone receptor, p16INK4 and were diffusely positive for cyclinD1. Diagnosis of cyclinD1 and p16INK4 positive ESS was offered. This case highlights the value of additional IHC markers, especially cyclinD1 and p16INK4 in order to identify certain ESSs that lack diffuse CD10 immunoexpression; are invariably misdiagnosed as undifferentiated sarcomas, but actually form a relatively more aggressive subset of ESSs.

Keywords: CD10, cyclinD1, endometrial stromal sarcoma, endometrial stromal tumors, p16INK4

How to cite this article:
Rekhi B, Motghare P. Cyclin D1 and p16INK4 positive endometrial stromal sarcoma: A case report with new insights . Indian J Pathol Microbiol 2014;57:606-8

How to cite this URL:
Rekhi B, Motghare P. Cyclin D1 and p16INK4 positive endometrial stromal sarcoma: A case report with new insights . Indian J Pathol Microbiol [serial online] 2014 [cited 2020 Jun 2];57:606-8. Available from: http://www.ijpmonline.org/text.asp?2014/57/4/606/142689



   Introduction Top


Endometrial stromal sarcoma (ESS) is a tumor of endometrial stroma that invades into the myometrium; is known to exhibit a wide histopathological spectrum and expresses certain immunohistochemical markers, notably diffuse CD10 in most cases. [1],[2] Several cytogenetic abnormalities have been described in ESSs. [3] The most common is a recurrent translocation involving chromosomes 7 and 17[t(7; 17)(p15; q21)], leading to fusion of JAZF1/JJAZ1/SUZ12. [4] Initially this fusion was considered to be the genetic signature of ESS. Subsequently, it was observed that not all ESSs are characterized by this fusion. [4],[5] Similarly, not all ESSs exhibit diffuse CD10 immunostaining [1],[6] Recent studies have unraveled diffuse cyclin D1 expression as another diagnostic immunohistochemical result for confirming ESSs, especially those expressing low to absent CD10 expression and characterized by another underlying molecular signature that is YWHAE-FAM22 rearrangement. [7],[8] Very few such cases have been documented.


   Case report Top


A 46-year-old perimenopausal lady referred to us from another hospital with history of vaginal bleeding of 3 months duration.

Radiological findings

She underwent transvaginal and transabdominal ultrasonography that disclosed a 2.7 cm 2.4 cm 3.0 cm sized hypoechoic lesion with a central area of hyper echogenicity measuring 0.7 cm 0.7 cm in the area of cervix.

She underwent dilatation and curettage, followed by polypectomy and finally transvaginal hysterectomy. During intraoperative examination, a tumor protrusion of 1 cm was noted, through the cervical os.

Pathological findings

On histopathological examination, curettage specimen revealed proliferative changes in the endometrium.

Grossly, the hysterectomy specimen revealed an enlarged uterus with an irregular contour. On serial sectioning endometrial thickness varied from 0.1 to 0.2 cm and the myometrial thickness was 1.6 cm. Cut surface showed myometrial nodules, including a reddish pink nodule measuring 4.5 cm 3.0 cm 1.5 cm that was soft in consistency and exhibited whitish cut surface, unassociated with hemorrhage, necrosis or cystic degeneration.

Multiple sections of the myometrial nodules showed a multinodular, variegated, invasive endometrial stromal tumor composed of banal oval to spindly cells with, elongate nuclei and fibrillary cytoplasm, embedded in a fibromyxoid stroma. Tumor cells exhibited focal perivascular arrangement. Some areas showed compact, cellular arrangement of oval to round tumor nuclei. Mitotic figures were low. There were no areas of tumor necrosis. [Figure 1], [Figure 2]a-d.

The differential diagnoses offered at the referring laboratory were smooth muscle tumor with uncertain malignant potential (STUMP), endometrial stromal sarcoma and inflammatory myofibroblastic tumor (IMFT).
Figure 1: (a) Endometrial epithelium overlying variably cellular neoplasm composed of spindly cells in a fibromyxoid stroma. Hematoxylin and Eosin (H and E), ×100

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Figure 2: Endometrial stromal sarcoma. (a) Infiltrating tumor composed of fibromyxoid stroma with interspersed blood vessels. H and E, ×100. (b) Moderately cellular tumor areas composed of rather banal appearing spindly cells. H and E ×100. (c) Higher magnification displaying fibroblastic type of cells arranged around blood vessels. H and E, ×200. (d) Focal areas displaying compactly arranged oval to round cells. H and E, ×200

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Immunohistochemically, tumor cells were mostly negative for CD10, but highlighted focal tumor areas. In additional, tumor cells were negative for desmin, smooth muscle actin (SMA), C-Kit/CD117, DOG1 and Alk1. Tumor cells exhibited diffuse nuclear staining for cyclin D1 and focal positivity for estrogen receptor (ER) (in 5-10% tumor areas); significant positivity for progesterone receptor (PR) (in 50% tumor areas), along with moderate to diffuse positivity with p16INK4 [Figure 3]a-g.
Figure 3: Immunohistochemical results. (a) Focal CD10 positivity within tumor cells. Diaminobenzidine (DAB), ×200. (b) SMA negativity in tumor cells. DAB, ×200. (c) Desmin negativity in tumor cells. DAB, ×200. (d) ER positivity in tumor cells. DAB ×200. (e). PR positivity in tumor cells. DAB, ×200. (f) Distinctly p16INK4 positive tumor cells. DAB, ×400. (g) Diffuse cyclin D1 positive tumor cells. DAB, ×200

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Diagnosis of cyclin D1 and p16INK4 positive ESS was finally offered.


   Discussion Top


ESSs account for nearly 0.2% of all malignant uterine tumors and 10-15% of uterine sarcomas. These tumors occur in women between 40 and 55 years of age, as noted in the present case. [1],[2]

Histopathologically, ESSs are invariably defined as low-grade sarcomas. The higher grade tumors, based on higher mitotic counts are considered as undifferentiated endometrial sarcomas (UESs). While the classical histopathological pattern of ESSs includes oval cells resembling endometrial stroma, arranged compactly and periarteriolar arrangement of cells infiltrating the myometrium, with limited mitotic figures; variable features include the presence of eosinophilic hyaline material; sex-cord stromal elements, along with fibroblastic/myofibroblastic variant of ESS. [1] The latter two, uncommon patterns were noted in the present tumor that led to consideration of various differential diagnoses. In view of lack of mitosis, but the presence of myxoid areas composed of elongate spindly cells with eosinophilic cytoplasm, diagnosis of STUMP was considered. Negative expression for desmin and SMA ruled out this tumor. Lack of these markers, along with Alk negativity made diagnosis of IMFT, less likely. ESS remained the closest diagnosis. However, the tumor was predominantly CD10 negative, except in focal areas. Focal tumor areas of compact cell arrangement, along with periarteriolar arrangement of tumor cells led us to consider usage of an extended IHC panel of markers in the present case. These included ER, PR, p16, and cyclinD1, all that were positive. ER and PR are also expressed in smooth muscle tumors.

Lately, p16 (INK4a) and higher expression of cyclin D1, p21 (cip1), and p53 have been observed in UESs. [9] In the preceding year, Lee et al., [7] observed diffuse cyclin D1 expression in a subset of ESSs with YWHAE-FAM22 rearrangement, with a sensitivity of 100% and specificity of 99% in these tumors, including an occasional leiomyosarcoma and few undifferentiated endometrial sarcomas (UESs) with nuclear uniformity, the latter that were ER and PR negative. Among 12 ESS, with YWHAE-FAM22 rearrangement, 4 tumors contained low-grade fibrous/fibromyxoid component, as noted in our case. They proposed that ESSs characterized by YWHAE-FAM22 genetic fusion are histologically higher-grade tumors and clinically more aggressive than ESSs with JAZF1-SUZ12 or equivalent genetic rearrangements; hence it is clinically important to recognize this subset of ESSs. It has also been observed that fibrous, myxoid or epithelioid variants of ESS do not show conventional JAZF1/JJAZ1 fusion. [5] This was in contrast to study results of Iwasaki et al., [9] who concluded that cyclinD1 and p16INK4 immunostaining was associated with UESs. Recently, in another study [10] the authors identified diffuse cyclin D1 immunoexpression in monomorphic UESs. However, in both these studies, the authors did not identify ER, PR expression in those cases, unlike Lee et al., [7] and in the present case. We believe that histopathologically appearing low-grade ESSs exist that are diffusely positive for cyclinD1 and p16INK4 and might be associated with an aggressive clinical course. Such cases should be designated as ESSs rather than UES and should be ideally tested for genetic analysis with clinical outcomes. We could not perform the genetic analysis in view of lack of the probes for these specific rearrangements, at the moment, in our molecular pathology laboratory. The patient has been recommended close follow-up. This case was unique in terms of being a ESS with variable morphology; of lower grade, displaying reduced CD10 expression, yet diffuse cyclin D1 and distinct p16INK4 immunoexpression.

To conclude: In suspect cases of ESSs, including fibroblastic or myxoid variants, revealing reduced to absent CD10 immunoexpression, an extended panel of IHC markers, especially cyclin D1 and p16INK4, along with ER and PR should be added to identify a subset of relatively aggressive ESSs that might not show higher mitotic counts. The nosological status of such cases is unclear. Documentation of additional such cases with follow-up would enhance our understanding on the expanding spectrum of ESSs, especially in terms of their prognostic variants.

 
   References Top

1.
Zaloudek CJ, Hendrickson M, Soslow RA. Mesenchymal tumors of the uterus. In: Blaustein's pathology of the female genital tract. In: Kurman RJ, Ellenson LH, Ronnett BM, editors. 6 th ed. Berlin, New York: Springer-Verlag Heidelberg; 2011. p. 470-516.   Back to cited text no. 1
    
2.
McCluggage WG, Sumathi VP, Maxwell P. CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. Histopathology 2001;39:273-8.  Back to cited text no. 2
    
3.
Sandberg AA. The cytogenetics and molecular biology of endometrial stromal sarcoma. Cytogenet Genome Res 2007;118:182-9.  Back to cited text no. 3
[PUBMED]    
4.
Koontz JI, Soreng AL, Nucci M, Koontz JI, Soreng AL, Nucci M, et al. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A 2001;98:6348-53.  Back to cited text no. 4
    
5.
Huang HY, Ladanyi M, Soslow RA. Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: Evidence for genetic heterogeneity. Am J Surg Pathol 2004;28:224-32.  Back to cited text no. 5
    
6.
Lee CH, Mariño-Enriquez A, Ou W, Zhu M, Ali RH, Chiang S, et al. The clinicopathologic features of YWHAE-FAM22 endometrial stromal sarcomas: A histologically high-grade and clinically aggressive tumor. Am J Surg Pathol 2012;36:641-53.  Back to cited text no. 6
    
7.
Lee CH, Ali RH, Rouzbahman M, Marino-Enriquez A, Zhu M, Guo X, et al. Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement. Am J Surg Pathol 2012;36:1562-70.  Back to cited text no. 7
    
8.
Kurihara S, Oda Y, Ohishi Y, Kaneki E, Kobayashi H, Wake N, et al. Coincident expression of beta-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas. Mod Pathol 2010;23:225-34.  Back to cited text no. 8
    
9.
Iwasaki S, Sudo T, Miwa M, Ukita M, Morimoto A, Tamada M, et al. Endometrial stromal sarcoma: Clinicopathological and immunophenotypic study of 16 cases. Arch Gynecol Obstet 2013;288:385-91.  Back to cited text no. 9
    
10.
Stewart CJ, Leung YC, Murch A, Peverall J. Evaluation of fluorescence in-situ hybridization in monomorphic endometrial stromal neoplasms and their histological mimics: A review of 49 cases. Histopathology 2014 [In Press].  Back to cited text no. 10
    

Top
Correspondence Address:
Bharat Rekhi
Professor/Pathologist, Department of Pathology, 8th Floor, Annex Building, Tata Memorial Hospital, Dr. E.B. Road, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.142689

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    Figures

  [Figure 1], [Figure 2], [Figure 3]

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