Phylloides Tumor With Numerous Thanatosomes

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tumor to be composed of large cells with pleomorphic nuclei (Figure 1). ... resembled a “juvenile fibroadenoma” with a proliferative glandular component and ...
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IJSXXX10.1177/1066896913482728Internati

Case Report

Phylloides Tumor With Numerous Thanatosomes (“Death Bodies”): A Report of Two Cases and a Study of Thanatosomes in Breast Tumors

International Journal of Surgical Pathology 2014, V   ol. 22(4) 337­–342 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896913482728 ijs.sagepub.com

Timothy M. D’Alfonso, MD1, Paula S. Ginter, MD1, Steven P. Salvatore, MD1, Lilian B. Antonio, BS, MPH1, and Syed A. Hoda, MD1

Abstract Thanatosomes, a form of degenerative intracellular hyaline globules, have been described in various neoplastic and nonneoplastic disease processes in several organs. These structures are indicative of apoptotic cell death. Herein, we report 2 cases of malignant phylloides tumor, both of which showed numerous thanatosomes—to the point of dominating the histological appearance and masking the stromal element. Our subsequently conducted study showed that thanatosomes were present in 14 of 86 (16.3%) high-grade malignant breast tumors. The structures were identified in 5/25 (20%) malignant phylloides tumors, 4/19 (21.1%) metaplastic spindle cell carcinomas, 3/21 (14.3%) invasive carcinomas s/p neoadjuvant chemotherapy, and 2/21 (9.5%) poorly differentiated invasive ductal carcinomas. When present, thanatosomes were typically a rare and focal finding in most types of cases. In malignant phylloides tumors, the structures were relatively more numerous when present. Our study shows that although thanatosomes can be present in several types of malignant breast tumors, they are more common in malignant phylloides tumor. Only rarely, as evident from our 2 index cases, do thanatosomes cause diagnostic difficulty. Keywords hyaline globules, thanatosomes, phylloides

Introduction

Materials and Methods

Thanatosomes (“death bodies”), a form of intracellular hyaline globules, are observed in a variety of neoplastic and nonneoplastic disease processes in multiple organ systems.1 The formation of thanatosomes is a function of cell turnover and apoptotic cell death brought about via autophagic and/or heterophagic processes. In most instances, the presence of these terminal cytoplasmic structures is a nonspecific morphological finding and is merely indicative of potentially irreversible cell injury. Several studies have documented the presence of thanatosomes in multiple organs,1-6 and one report focused on its incidence in the gastrointestinal tract.7 However, the presence (and significance) of thanatosomes in the breast remains largely uncharacterized. Herein, we report our encounter with 2 cases of malignant phylloides tumor (MPT), which were both extraordinarily rich in thanatosomes—to the point of causing diagnostic uncertainty in each. In addition, we report our findings of a subsequently conducted study of thanatosomes in a limited series of malignant breast tumors.

Hematoxylin and eosin stained slides for the 2 index cases and a variety of routinely performed immunostains (as listed in the description of Case 1, please see below) were reviewed. Cases of high-grade malignant breast tumors, in which slides were available for review, were randomly identified and retrieved from our pathology files. These included 25 high-grade MPT, 19 high-grade metaplastic spindle cell carcinomas (MSCCs), 21 cases of residual invasive carcinoma status-post neoadjuvant chemotherapy (ICs/pNAC; all of which showed at least 0.5 cm of residual invasive carcinoma in the tumor bed), and 21 cases of poorly differentiated ductal carcinoma, NOS (PDDC). Slides from 1

Weill Cornell Medical College, New York, NY, USA

Corresponding Author: Timothy M. D’Alfonso, Department of Pathology & Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, 525 East 68th Street, Starr 1031E, New York, NY 10065, USA. Email: [email protected]

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Figure 1. Case 1. (A) Low-power magnification shows a circumscribed tumor with prominent lymphoid stroma. (B) Higher magnification of tumor focus within solid-line box in A demonstrates elongated epithelial-lined clefts characteristic of fibroepithelial tumors. (C) Higher magnification of tumor focus within dotted-line box in “A” shows pleomorphic cells containing thanatosomes in “sinusoidal-like” areas. (D) Intracytoplasmic thanatosomes are evident at higher magnification. All hematoxylin and eosin.

each case containing lesional tissue were reviewed. The presence, frequency, and distribution of thanatosomes, if present, were recorded. One case, rich in thanatosomes, was selected for histochemical studies. Periodic acid–Schiff (PAS) with diastase, Masson’s trichrome, and phosphotungstic acid haematoxylin (PTAH) stains were performed on 5-µm sections cut from the selected paraffin block.

Results Case 1 Clinical Summary. A 52-year-old woman with no history of breast disease presented with a 2.0 cm palpable mass in the right breast. Excisional biopsy was performed.

Pathological Findings. Grossly, a circumscribed 2.0 × 2.0 × 2.0 cm firm tumor was present within the 3.0 cm excisional biopsy. Microscopic examination showed the tumor to be composed of large cells with pleomorphic nuclei (Figure 1). These cells were mainly present in intratumoral “sinusoidal-like” areas. Although the tumor was reminiscent of a lymph node at low-power examination, no true lymph node capsule or lymphoid follicles were identified. Numerous intracytoplasmic, refractile, round, eosinophilc globules of varying sizes were identified in the majority of lesional cells. To a much lesser degree, intranuclear and extracellular globules were also present. Rare tumor cells contained nuclear pseudoinclusions. Focally, at the periphery of the lesion, epithelial-lined clefts, representing residual portions of a fibroepithelial tumor, were identified. The adjacent breast

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D’Alfonso et al parenchyma was inactive. The aforementioned globules were PAS-positive. Immunohistochemically, the structures were reactive for immunoglobulin G (IgG) and lysozyme and were nonreactive for cytokeratin AE1/3, vimentin, and a wide array of epithelial, melanocytic, lymphoid, histiocytic, mesenchymal, and other tissuespecific markers. Cells containing globules showed high proliferation index (approximately 15%, per Ki-67). The lymphoid component of the tumor was polytypic by immunohistochemistry. Based on histological and immunohistochemical findings, as well as the opinion of Dr Juan Rosai, whose expert opinion was sought on the case, a diagnosis of “anaplastic malignant tumor containing hyaline globules (thanatosomes), arising from phylloides tumor” was rendered. Follow-Up Information. There was no evidence of metastatic disease at 1-year follow-up.

Case 2 Clinical Summary. A 17-year-old woman presented with enlargement of the left breast. Mammography and ultrasound showed an 11 cm round circumscribed mass occupying almost the entirety of the breast. Needle core biopsy was diagnosed as “fibroepithelial tumor with cellular stroma.” Thereafter, an excisional biopsy was performed. Pathological Findings. Grossly, the excisional biopsy was entirely composed of a lobulated, somewhat polypoid, mass measuring 13.0 × 11.0 × 7.0 cm. Microscopic examination revealed a largely circumscribed tumor with a heterogeneous appearance. Some areas of the tumor resembled a “juvenile fibroadenoma” with a proliferative glandular component and pericanilucular growth pattern. Other areas showed the classic leaf-like pattern of phylloides tumor (Figure 2). In most areas, the stromal component of the tumor showed pleomorphic cells with intracytoplasmic globules, similar to those seen in Case 1. The cells containing the globules were mitotically active (greater than 5 per 10 high-power fields) and were clustered in the subepithelial stroma of the clefted areas within the tumor. The globules were focally associated with apoptotic nuclear debris. The epithelial component of the lesion was quiescent and showed no significant atypia. A diagnosis of “malignant phylloides tumor with degenerative hyaline globules (thanatosomes)” was rendered. Follow-Up Information. Subsequent mastectomy revealed microscopic foci of residual phylloides tumor around the biopsy cavity. There was no evidence of metastatic disease at a 6-month follow-up evaluation.

Study of T  hanatosomes in Malignant Breast Tumors Histological review of 86 high-grade breast tumors showed thanatosomes to be present in 14 (16.3%) cases (Table 1). Of the 25 additionally studied cases of MPT, thanatosomes were identified in 5 (20%) cases, including 3 cases with heterologous differentiation (liposarcoma, 2; chondrosarcoma, 1). In 1 case of MPT, thanatosomes were clustered in the subepithelial stroma, similar to the pattern seen in Case 2 (Figure 3A). Thanatosomes were identified in 4/19 (21.1%) cases of MSCC (Figure 3B), including 2/4 cases with chondroid differentiation. In 1 MSCC, thanatosomes were present in the intraductal carcinoma but not in the invasive carcinoma. Thanatosomes were identified in 3/21 (14.3%) cases of ICs/pNAC. These 3 cases showed thanatosomes in either residual invasive (2 cases) or intraductal carcinoma (1 case; Figure 3C). Thanatosomes were identified in 2/21 (9.5%) cases of PDDC, albeit as a rare and focal finding in each.

Histological, Histochemical, and Immunohistochemical Properties of Thanatosomes In all cases in which thanatosomes were identified, the structures appeared as spherical, brightly eosinophilic, glassy, refractile globules. Most thanatosomes were intracytoplasmic. Extracellular thanatosomes were rare. Thanatosomes were highly variable in size, which in combination with their predominantly intracellular location, aided in their distinction from red blood cells. Frequently, thanatosomes occupied cells admixed with apoptotic nuclear debris. Thanatosomes were PAS+ and diastaseresistant, showed deep fuchsinophilic (bluish-red) staining with Masson’s trichrome, and stained dark blue to black with PTAH (Figure 3D-F).

Discussion Thanatosomes, a term derived from the Greek words “thanatos” meaning death and “soma” meaning body, are intracellular globular structures that are formed as a consequence of cell turnover.1 These “bodies of death” represent either an autophagic or heterophagic process and form as a consequence of apoptotic cell death. Thanatosomes have been described in a variety of neoplastic as well as nonneoplastic disease processes in several organs. It is rather unfortunate that the term thanatosomes has been used synonymously with various other intracytoplasmic structures such as reabsorption droplets, immunoglobulin deposits (Russell bodies), Mallory’s hyaline, alpha-1-antitrypsin, alpha-fetoprotein deposits,

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Figure 2. Case 2. (A) Low-power magnification shows a circumscribed tumor with polypoid leaf-like architecture. (B) Intracytoplasmic thanatosomes are present in stromal cells with a vacuolated appearance. (C) Cells containing thanatosomes are clustered in the subepithelial stroma. (D) Thanatosomes show variation in size, which distinguish them from red blood cells (arrow). All hematoxylin and eosin. Table 1. Frequency of Thanatosomes in Various Types of Breast Malignancies. Type of Malignancy Malignant phylloides tumor Metaplastic spindle cell carcinoma Invasive carcinoma (s/p neoadjuvant chemotherapy) Invasive ductal carcinoma, poorly differentiated Total

Number of Cases with Thanatosomes (%) 5/25 (20.0) 4/19 (21.1) 3/21 (14.3) 2/21 (9.5) 14/86 (16.3)

and others. Such imprecise usage has been advanced by a unifying morphogenetic concept for such intracytoplasmic

structures, which has the obvious merit of simplifying the nomenclature at the expense of oversimplifying the recognition of specific types of structures in a wide group.1 “Thanatosomes” in the breast have been described in 2 reports. Dekker and Krause2 described the presence of abundant “thanatosomes” in a 49-year-old woman who died of widely metastatic breast carcinoma. At autopsy, “thanatosomes” were identified in metastatic tumor deposits in the brain and adrenals. Jensen et al8 described the presence of “hyaline globules” in a mammary ductal adenoma. The globoid structures described in these 2 reports most likely did not represent true “thanatosomes.” True thanatosomes need to be differentiated from the morphologically similar group of structures generically referred to as hyaline globules. The latter are usually a nonspecific

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Figure 3. Thanatosomes in a variety of malignant breast tumors. (A) Thanatosomes clustered in subepithelial stroma of malignant phylloides tumor. (B) Thanatosomes in metaplastic spindle cell carcinoma. (C-F) Thanatosomes in high-grade ductal carcinoma in situ (DCIS): (C) hematoxylin and eosin, (D) PAS with diastase highlights the structures. (E) Masson’s trichrome shows fuchsinophilia of thanatosomes, and (F) PTAH stains the structures black.

finding, but specific forms thereof can be a diagnostic aid in tumors such as yolk sac tumor.9 On hematoxylin and eosin stained preparations, true thanatosomes typically appear as intracytoplasmic round structures of varying size. Thanatosomes stain brilliant red

with PAS and appear fuchsinophilic with Masson’s trichrome preparation. The aforementioned histological and staining properties are consistent with those of structures that have been formed from products of cytoplasmic dissolution and nuclear disintegration followed by either

342 autophagocytosis or heterophagocytosis, with the deposition of plasma proteins onto the resultant cellular debris. Immunohistochemical stains are generally unhelpful in confirming the presence of thanatosomes; however, hyaline globular deposits due to immunoglobulins, alpha-1-antitrypsin, alpha fetoprotein, and others, can be excluded via appropriate immunostains. In 2012, we encountered 2 cases of MPT in each of which thanatosomes were the predominant histopathological finding. These structures largely eclipsed the fundamental fibroepithelial features of the 2 tumors, much more so in the first case. In Case 1, giant stromal cells with thanatosomes associated with prominent lymphoid stroma were dominant; thus, the possibility of either a lymphoproliferative neoplasm or Rosai–Dorfman disease was entertained. In Case 2, thanatosomes in the stromal component of a fibroepithelial tumor simulated lipoblasts, and as such phylloides tumor with a liposarcomatous component was a consideration in the differential diagnosis. In each case, the presence of numerous thanatosomes led to diagnostic difficulty. Our encounter with the 2 cases, both of which were cases submitted for consultation opinion, prompted us to undertake a pilot study of thanatosomes in a broad array of mammary tumors. Since thanatosomes occur in cells undergoing rapid turnover, we reviewed a set of highgrade malignant mammary tumors, including malignant fibroepithelial (phylloides) tumors and poorly differentiated carcinomas. We also studied carcinomas status-post neoadjuvant chemotherapy—another tumoral condition in which abundant thanatosomes have been described in other organs.1 In our limited study, thanatosomes were identified in 16.3% (14/86) of tumors reviewed. In each “positive” case, thanatosomes were present in isolated rare cells within the tumor and would likely have been neither identified nor reported in routine practice. Only in 8% (2/25) cases of MPTs were thanatosomes a conspicuous morphological feature. We observed clustering of thanatosomes in the subepithelial stroma in 2 cases of MPT—a finding in keeping with the increased proliferative activity that is typically encountered in this location.10 No other pattern of distribution of thanatosomes was discerned among the other tumors. Thanatosomes were uncommon in both the untreated and the treated groups of breast carcinoma. In summary, our study (which to our knowledge is the first to study thanatosomes in breast tumors) suggests that thanatosomes can be found, albeit rarely and only focally, in a variety of high-grade malignant breast tumors. Thanatosomes can be more readily encountered in MPTs. Only rarely, as evidenced in our 2 index cases, does the

International Journal of Surgical Pathology 22(4) presence of numerous thanatosomes hinder the diagnosis of phylloides tumors. Acknowledgment The authors would like to thank Dr. Steven Smith and Dr. Daniel Boudreaux for providing case material and follow-up information.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

References   1. Papadimitriou JC, Drachenberg CB, Brenner DS, Newkirk C, Trump BF, Silverberg SG. “Thanatosomes”: a unifying morphogenetic concept for tumor hyaline globules related to apoptosis. Hum Pathol. 2000;31:1455-1465.   2. Dekker A, Krause JR. Hyaline globules in human neoplasms. A report of three autopsy cases. Arch Pathol. 1973;95:178181.   3. Dikov D, Roland J, Chatelet FP, Cywiner-Golenzer C, Dimitrakov J. Hyaline globules (thanatosomes) in prostate disease. Am J Surg Pathol. 2003;27:700-702.  4. Beranek JT. Thanatosomes and cardiomyocyte apoptotic bodies. Hum Pathol. 2001;32:894-895.   5. Giner F, Compan A, Monteagudo C. Uterine glomeruloid hemangioma in a patient without POEMS syndrome. Int J Surg Pathol. 2012;20:407-410.   6. Lee H, Meier FA, Ma CK, Ormsby AH, Lee MW. Eosinophilic globules in 3 cases of glomeruloid hemangioma of the head and neck: a characteristic offering more evidence for thanatosomes with or without POEMS. Am J Dermatopathol. 2008;30:539-544.   7. Dikov DI, Auriault ML, Boivin JF, Sarafian VS, Papadimitriou JC. Hyaline globules (thanatosomes) in gastrointestinal epithelium: pathophysiologic correlations. Am J Clin Pathol. 2007;127:792-799.  8. Jensen ML, Johansen P, Noer H, Sorensen IM. Ductal adenoma of the breast: the cytological features of six cases. Diagn Cytopathol. 1994;10:143-145.   9. Ulbright TM, Roth LM, Brodhecker CA. Yolk sac differentiation in germ cell tumors. A morphologic study of 50 cases with emphasis on hepatic, enteric, and parietal yolk sac features. Am J Surg Pathol. 1986;10:151-164. 10. Tse GM, Tsang AK, Putti TC, et al. Stromal CD10 expression in mammary fibroadenomas and phyllodes tumours. J Clin Pathol. 2005;58:185-189.