PostScript
CORRESPONDENCE
Sarcoma of the breast and chest wall after radiation treatment for bilateral breast carcinoma According to the recent National Comprehensive Cancer Network guidelines for breast cancer treatment, adjuvant radiation therapy is an important integral component of locoregional treatment of non-invasive and invasive breast carcinomas when lumpectomy is the surgery of choice.1 Despite its benefit in treating cancer, radiotherapy can cause a so-called ‘radiation-induced sarcoma’, a rare iatrogenic malignancy that comprises approximately 3% of all soft tissue sarcomas and is associated with poor outcome. Among
Table 1
radiation-induced sarcomas that occur after radiotherapy for breast carcinoma, angiosarcoma is the most common histological type whereas other types of sarcoma are less frequently encountered.2 We report an unusual case of metachronously occurring spindle cell sarcoma in the right breast and left chest wall of a 38-year-old women who had received radiation for bilateral breast carcinomas. Chronological details of pathological findings are summarised in table 1. The latest presentation was a 1.1 cm-sized nodule on the left chest wall ( post mastectomy) that was excised, showing a tumour within the subcutaneous soft tissue, with cut sections revealing a fleshy grey-white appearance. Microscopically, there were plump spindle cells with moderate to marked nuclear pleomorphism, arranged in long and short fascicles with focal storiform patterns. No residual breast tissue
A summary of the clinical history of breast lesions and the corresponding pathological findings
Disease onset
Laterality of the breast
Type of specimen
Pathological findings
11 years prior
Left
Wide excision
7 years prior
Right
Wide excision
3 years prior
Right
Wide excision
Main finding: IDC; 12 mm in greatest dimension; negative axillary lymph nodes (pT1c) Background: Tubular adenoma, DCIS, spindle cell proliferation in keeping with desmoplastic stromal reaction Main finding: High-grade DCIS with focal comedonecrosis Background: Tissue reaction consistent with previous biopsy site High-grade spindle cell neoplasm; No carcinomatous component identified
1 year prior
Left
Mastectomy
Right
Mastectomy and axillary dissection
Left chest wall
Wide excision
Present
was found. A similar histological appearance was observed in a 2.2 cm-sized lesion discovered 3 years earlier in the contralateral right breast ( post-wide excision). Both tumours were mitotically active (at least 20 mitoses per 10 high power fields) with several atypical mitotic figures and apoptotic bodies. Nuclei of the spindle cells were vesicular in appearance with some showing coarse-clumped chromatin, with the right breast spindle cell tumour disclosing more modest nuclear atypia than the latest left chest wall nodule. Cytoplasm was pale eosinophilic with illdefined borders. Tumour necrosis was not seen. An epithelial component was not identified in either tumour. Immunohistochemistry showed the right breast spindled tumour diagnosed 3 years ago to stain positively for calponin, CD10 and bcl-2 protein whereas desmin, h-caldesmon, p63, smooth muscle actin
Main finding: High-grade DCIS with comedonecrosis Background: Dense concentric fibrous tissue Spindle cell lesion with paucicellularity and mild nuclear atypia noted within a scar area, favouring reactive scar tissue; No evidence of carcinoma or overtly neoplastic spindle cell lesion; No evidence of metastasis in the axillary lymph nodes High-grade spindle cell neoplasm; No carcinomatous component identified
Important immunohistochemical findings
Treatment received
IDC: ER−, PR−, HER2 protein 3+ Reactive spindle cell proliferation: CKs−
Surgery; adjuvant chemotherapy; and localised radiation
High-grade DCIS: ER−, PR−
Surgery and postoperative radiation
Epithelial markers: AE1/AE3−, EMA−, 34βE12−, Cam5.2− Endothelial markers: CD34−, CD31− Others: Desmin−, h-caldesmon−, p63−, SMA−, S100−, CD10+, calponin+ (weak), bcl-2+ (patchy) High-grade DCIS: ER+ (ranging from 1+ to 2+ in intensity), PR−
Surgery
Epithelial markers: MNF116+ (subset), CAM5.2+ (subset), AE1/AE3+ (few cells), CK5/6−, CK7−, CK14−, CK19−, 34βE12− Endothelial markers: CD34−, CD31− Others: SMA+, desmin−, SMMHC−, h-caldesmon−, S100−, INI1+, p63−, Ki-67+ (up to 40%), ER−, PR−, HER2−
Surgery
Surgery
CKs, cytokeratins; DCIS, ductal carcinoma in situ; EMA, epithelial membrane antigen; ER, estrogen receptor; IDC, invasive ductal carcinoma; PR, progesterone receptor; SMA, smooth muscle actin; SMMHC, smooth muscle myosin heavy chain.
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Figure 1 Representative sections of the right breast tumours. High-grade ductal carcinoma in situ (DCIS) with central comedonecrosis was initially identified (A) original magnification×100. Subsequently a spindle cell neoplasm consisting of neoplastic cells arranged in fascicles and vague storiform pattern was noted. The tumour cells showed a moderate degree of nuclear pleomorphism, nuclear hyperchromasia and mitotic figures (B) original magnification×200. The tumour cells were negative for MNF116 (C), p63 (D), CD34 (E) and S100 (F). (SMA), S100, epithelial markers (AE1/ AE3, EMA and 34βE12) and endothelial markers CD34 and CD31 were negative. No lineage-specific structures were identified by electron microscopic study. In the current left chest wall tumour, the majority of the spindle cells were positive for SMA with subplasmalemmal accentuation, whereas they were negative for desmin and other markers of smooth muscle differentiation (smooth muscle myosin heavy chain and h-caldesmon). Endothelial markers CD31 and CD34, and S100 also yielded negative results. Significantly, a subset of the neoplastic cells showed positive reactivity with MNF116 and CAM5.2, with AE1/ AE3 showing very focal reactivity. CK5/6, 34BE12, CK14, CK7, CK19 and p63 were negative. Retained INI-1 expression was demonstrated by positivity in the nuclei of the tumour cells. Proliferative index as measured by Ki-67 immunostaining was relatively high (up to 40%). Ultrastructurally, some features suggesting myofibroblastic differentiation such as 492
abundant rough endoplasmic reticulum, peripheral myofilament bundles with a fibronexus-like structure were identified. There was no electron microscopic evidence of epithelial or melanocytic differentiation. Pathological findings of both tumours were concluded as most consistent with undifferentiated sarcoma, although a differential diagnosis of a spindle cell carcinoma was strongly considered in the left chest wall tumour in view of the keratin positivity. However, contemplating the prior history of radiation exposure, absence of a metaplastic spindle cell component in the previous invasive ductal carcinoma diagnosed 11 years ago and the mastectomy that was performed a year ago for the in situ ductal carcinoma recurrence, the diagnosis of postradiation sarcoma was favoured. Histological features, immunohistochemical results and electron micrographs of both tumours are shown in figures 1–3. After the latest surgical wide excision for the left chest wall tumour, the patient declined further treatment. Twenty
weeks after surgery, she developed intra-abdominal sepsis with a new finding of a pancreatic tail mass. Liver lesions radiologically deemed consistent with metastases were also discovered, from which fine needle aspiration of a representative liver lesion showed adenocarcinoma, with an immunoprofile favouring a pancreaticobiliary origin. Radiation-induced sarcoma (also known as postradiation sarcoma) is an uncommon complication of radiotherapy. Generally, the criterion for making this diagnosis is a histologically confirmed sarcoma that arises in a prior irradiated field following a sufficient latency period. However, the time interval that is considered as ‘a sufficient latency period’ is different among studies, ranging from 6 months to 5 years.3–5 Sarcomas of various histological subtypes have been reported in the setting of radiation-induced sarcoma, with undifferentiated sarcoma comprising 25% or more.6 7 In most cases, a histological subtype of radiation-induced sarcoma J Clin Pathol June 2015 Vol 68 No 6
PostScript
Figure 2 Representative sections of the left breast and left-sided chest wall tumours. Invasive ductal carcinoma (A) and high-grade ductal carcinoma in situ (DCIS) (B) were initially identified (A and B) original magnification×100. Recurrent high-grade DCIS with focal comedonecrosis (C) and spindle cell neoplasm arising post mastectomy (D) were subsequently detected (C and D) original magnification×200. The postmastectomy tumour was mainly characterised by spindle cells arranged in long fascicles. Some tumour cells with hyperchromatic nuclei were identified among the majority of tumour cells with vesicular nuclei. Mitotic figures as well as apoptotic bodies were noted (D) original magnification×200. The spindle cells showed focal cytoplasmic staining for CAM5.2 (E) and MNF116 (F) whereas p63 (H) and high molecular weight keratins were negative. Positivity for smooth muscle actin (SMA) was demonstrated in a subplasmalemmal accentuation pattern (G).
cannot be predicted by a site of a prior radiated field; however, in cases of the radiation-induced sarcoma that occur after treatment of breast cancer, angiosarcoma is the most common histological subtype whereas other subtypes of sarcoma are less frequently encountered.2 Our case of bilateral undifferentiated sarcomas metachronously developing in the left chest wall and right breast in a patient with a history of radiation treatment for invasive ductal carcinoma and high-grade ductal carcinoma in situ respectively, is therefore unique. Sarcoma following radiotherapy administered as treatment of breast carcinoma is a rare complication, with a cumulative incidence of 0.3–0.48% in 15 years.2 Its incidence is evidently associated with radiation dose.8 Other factors that might be related to its pathogenesis include having a deleterious BRCA-1 mutation, de novo J Clin Pathol June 2015 Vol 68 No 6
TP53 mutation and hereditary diseases such as Li-Fraumeni syndrome.9 10 According to the study by Kirova et al,2 reportedly the largest study in radiation-induced sarcomas following radiotherapy for breast carcinoma, this type of secondary sarcoma could develop in any site within the irradiated field (breast, chest wall, sternum, supraclavicular region, scapular region, axilla) and was usually seen in older patients whose median ages at diagnosis of breast carcinoma and radiation-induced sarcoma were 57 (range, 36–74) years and 63 (range, 47–82) years, respectively. The latency period between the time of breast carcinoma diagnosis and development of sarcoma ranged from 3 years to 20.3 years. However, the age of onset for breast carcinoma and radiation-induced sarcoma might be younger, and the latency period shorter, in patients with
genetic susceptibilities, such as those with BRCA-1 and TP53 mutations.9 11 In this particular case, although the latency period of the lesions in both breasts falls into the same time range as previously reported (4 years for the right breast and 11 years for the left postmastectomy chest wall), the patient’s age at the time of diagnosis for breast carcinoma (27 years for invasive ductal carcinoma of the left breast and 31 years for high-grade ductal carcinoma in situ of the right breast) and radiation-induced sarcoma (35 years for the right breast sarcoma and 38 years for the left postmastectomy chest wall sarcoma) is relatively younger than those previously described. Furthermore, to our knowledge, development of multifocal radiation-induced sarcomas following radiotherapy for breast carcinoma is uncommon. The question of whether this patient possesses any predisposing genetic 493
PostScript
Figure 3 Electron micrographs of the right breast spindle sarcoma (A) showed no lineage-specific structures whereas the neoplastic spindle cells of the left-sided chest wall nodule (B) demonstrated features suggesting myofibroblastic differentiation including presence of abundant rough endoplasmic reticulum with peripheral myofilament bundles (arrow) with a fibronexus-like structure (arrow head) and filaments resembling fibronectin (circle). abnormalities is therefore raised, particularly in light of the latest development of yet another primary tumour, this time from the pancreaticobiliary tract. According to the recent WHO Classification of tumours of soft tissue and bone,6 undifferentiated sarcoma is defined as a heterogeneous group that shows no evidence of lineage-specific differentiation in a realm of technology presently available; this also includes cases that were previously known as ‘malignant fibrous histiocytoma’. Regarding its morphology, it can be broadly divided into pleomorphic, spindle cell, round cell and epithelioid subsets. Exclusion of non-sarcomas (such as sarcomatoid carcinoma, malignant melanoma, mesothelioma and some haematolymphoid tumours) and dedifferentiated sarcoma is required before making the diagnosis. As defined, undifferentiated sarcoma shows no reproducible pattern of immunophenotypes; however, there is evidence that a subset shows immunohistochemical and ultrastructural features of myofibroblasts such as immunoreactivity for SMA, desmin, musclespecific actin and h-caldesmon and/or presence of abundant rough endoplasmic reticulum with peripheral myofilament bundles with dense bodies and, sometimes, pinocytotic vesicles and fragments of external lamina 13 in electron micrographs.12 Undifferentiated sarcoma that secondarily develops following radiotherapy of breast carcinoma is uncommon. To our best knowledge, only 16 cases have been reported in 494
the English literature so far.2 5 9 14–16 In our case, the tumour in the right breast tissue that occurred 3 years prior displayed histological features and immunophenotypical profiles as those described in undifferentiated pleomorphic sarcoma which could also be interpreted as atypical fibroxanthoma due to its superficial location (cutaneous undifferentiated pleomorphic sarcoma) and, hence, rendering excellent clinical outcome by adequate surgery. However, the present tumour that occurred in the left postmastectomy chest wall demonstrated relatively significant expression of cytokeratins, which raised a concern of recurrent carcinoma, particularly monophasic/sarcomatoidtype spindle metaplastic carcinoma that is believed to arise from the process of ‘dedifferentiation’ or ‘transformation’ from epithelial-type carcinoma.17–20 Supporting the diagnosis of radiation-induced sarcoma instead of metaplastic carcinoma includes absence of spindle cell metaplastic elements in the initial left breast tumour that could potentially account for a spindle cell metaplastic carcinoma recurrence in the left chest wall. Second, the time interval between the initially diagnosed breast carcinoma and the recently occurring spindle cell tumour in this case is much more remote (11 years) than that reported in previous studies of metaplastic carcinoma where earlier recurrences are encountered (up to 76 months).17–19 Third, in this case, there is a history of radiation therapy, which predisposes to the development of secondary
sarcoma. Additionally, mastectomy performed for the prior recurrence of ductal carcinoma in situ without any invasive elements also made it less likely for the latest tumour in the chest wall to be an invasive breast carcinoma recurrence. According to previous studies, most monophasic/ sarcomatoid-type metaplastic carcinomas may behave similarly to sarcomas.17–19 Of note, several sarcomas including primary and postradiation undifferentiated sarcomas can show cytokeratin expression, particularly low-molecular-weight types.21 22 In our case, the left chest wall tumour was negative for a series of high molecular weight keratins as well as p63, which are usually positively expressed in metaplastic carcinoma. In conclusion, radiation-induced sarcoma is an uncommon complication of radiotherapy of breast cancer, with histological subtypes other than angiosarcoma being very uncommon. To our best knowledge, this is the first described case of bilateral postradiation sarcoma with histological features of undifferentiated sarcoma that metachronously occurred in a woman previously diagnosed with bilateral breast carcinoma. Kanapon Pradniwat,1,2 Kong Wee Ong,3 Kesavan Sittampalam,1 Boon Huat Bay,4 Puay Hoon Tan1 1
Department of Pathology, Singapore General Hospital, Singapore Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 3 Department of Surgical Oncology, National Cancer Center, Singapore 4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2
Correspondence to Dr Puay Hoon Tan, Department of Pathology, Singapore General Hospital, 20 College Road, Diagnostics Tower, Level 7, Academia, Singapore 169856, Singapore; [email protected] Contributors KP wrote the manuscript. KWO was the managing surgeon who contributed to the content and obtained patient consent. KS reviewed the histology of the sarcomas and contributed to the manuscript. BHB provided input on the electron micrographs. PHT supervised the case study and manuscript. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; internally peer reviewed.
To cite Pradniwat Kapon, Ong KW, Sittampalam K, et al. J Clin Pathol 2015;68:491–495. Received 16 February 2015 Revised 24 February 2015 Accepted 26 February 2015 Published Online First 18 March 2015 J Clin Pathol 2015;68:491–495. doi:10.1136/jclinpath-2015-202963 J Clin Pathol June 2015 Vol 68 No 6
PostScript REFERENCES 1
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National Comprehensive Cancer Network. Breast Cancer (Version 3.2014). Http://Www.Nccn.Org/ Professionals/Physician_Gls/Pdf/Breast.Pdf (accessed 25 Dec 2014). Kirova YM, Vilcoq JR, Asselain B, et al. Radiation-induced sarcomas after radiotherapy for breast carcinoma: a large-scale single-institution review. Cancer 2005;104:856–63. Cahan WG, Woodard HQ, Higinbotham NL, et al. Sarcoma arising in irradiated bone; report of 11 cases. Cancer 1948;1:3–29. Cha C, Antonescu CR, Quan ML, et al. Long-term results with resection of radiation-induced soft tissue sarcomas. Ann Surg 2004;239:903–9; discussion 909–10. Laskin WB, Silverman TA, Enzinger FM. Postradiation soft tissue sarcomas. an analysis of 53 cases. Cancer 1988;62:2330–40. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al. eds. Who classification of tumours of soft tissue and bone. Lyon: Iarc Press, 2013. Lagrange JL, Ramaioli A, Chateau MC, et al. Sarcoma after radiation therapy: retrospective multiinstitutional study of 80 histologically confirmed cases. Radiation Therapist and Pathologist Groups of the Federation Nationale des Centres de Lutte Contre le Cancer. Radiology 2000;216:197–205. Rubino C, Shamsaldin A, Le MG, et al. Radiation dose and risk of soft tissue and bone sarcoma after
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10
11
12
13
14
15
breast cancer treatment. Breast Cancer Res Treat 2005;89:277–88. Salmon A, Amikam D, Sodha N, et al. Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline ‘de-novo’ TP53 mutation. Clin Oncol (R Coll Radiol) 2007;19:490–3. Sheth GR, Cranmer LD, Smith BD, et al. Radiation-induced sarcoma of the breast: a systematic review. Oncologist 2012;17:405–18. De Bree E, Van Coevorden F, Peterse JL, et al. Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: genetic predisposition? Eur J Surg Oncol 2002;28:392–5. Hasegawa T, Hasegawa F, Hirose T, et al. Expression of smooth muscle markers in so called malignant fibrous histiocytomas. J Clin Pathol 2003;56:666–71. Montgomery E, Fisher C. Myofibroblastic differentiation in malignant fibrous histiocytoma ( pleomorphic myofibrosarcoma): a clinicopathological study. Histopathology 2001;38:499–509. Biswas S, Badiuddin F. Radiation induced malignant histiocytoma of the contralateral breast following treatment of breast cancer: a case report and review of the literature. Cases J 2008;1:313. Fang Z, Matsumoto S, Ae K, et al. Postradiation soft tissue sarcoma: a multiinstitutional analysis of 14 cases in Japan. J Orthop Sci 2004;9:242–6.
16
17
18
19
20
21
22
Kocer B, Gulbahar G, Erdogan B, et al. A case of radiation-induced sternal malignant fibrous histiocytoma treated with neoadjuvant chemotherapy and surgical resection. World J Surg Oncol 2008;6:138. Carter MR, Hornick JL, Lester S, et al. Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg Pathol 2006;30:300–9. Davis WG, Hennessy B, Babiera G, et al. Metaplastic sarcomatoid carcinoma of the breast with absent or minimal overt invasive carcinomatous component: a misnomer. Am J Surg Pathol 2005;29:1456–63. Tse GM, Tan PH, Putti TC, et al. Metaplastic carcinoma of the breast: a clinicopathological review. J Clin Pathol 2006;59:1079–83. Van Deurzen CH, Lee AH, Gill MS, et al. Metaplastic breast carcinoma: tumour histogenesis or dedifferentiation? J Pathol 2011;224:434–7. Miettinen M. Immunohistochemistry of soft tissue tumours—review with emphasis on 10 markers. Histopathology 2014;64:101–18. Weiss SW, Bratthauer GL, Morris PA. Postirradiation malignant fibrous histiocytoma expressing cytokeratin. Implications for the immunodiagnosis of sarcomas. Am J Surg Pathol 1988;12:554–8.
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CORRESPONDENCE
Sarcoma of the breast and chest wall after radiation treatment for bilateral breast carcinoma According to the recent National Comprehensive Cancer Network guidelines for breast cancer treatment, adjuvant radiation therapy is an important integral component of locoregional treatment of non-invasive and invasive breast carcinomas when lumpectomy is the surgery of choice.1 Despite its benefit in treating cancer, radiotherapy can cause a so-called ‘radiation-induced sarcoma’, a rare iatrogenic malignancy that comprises approximately 3% of all soft tissue sarcomas and is associated with poor outcome. Among
Table 1
radiation-induced sarcomas that occur after radiotherapy for breast carcinoma, angiosarcoma is the most common histological type whereas other types of sarcoma are less frequently encountered.2 We report an unusual case of metachronously occurring spindle cell sarcoma in the right breast and left chest wall of a 38-year-old women who had received radiation for bilateral breast carcinomas. Chronological details of pathological findings are summarised in table 1. The latest presentation was a 1.1 cm-sized nodule on the left chest wall ( post mastectomy) that was excised, showing a tumour within the subcutaneous soft tissue, with cut sections revealing a fleshy grey-white appearance. Microscopically, there were plump spindle cells with moderate to marked nuclear pleomorphism, arranged in long and short fascicles with focal storiform patterns. No residual breast tissue
A summary of the clinical history of breast lesions and the corresponding pathological findings
Disease onset
Laterality of the breast
Type of specimen
Pathological findings
11 years prior
Left
Wide excision
7 years prior
Right
Wide excision
3 years prior
Right
Wide excision
Main finding: IDC; 12 mm in greatest dimension; negative axillary lymph nodes (pT1c) Background: Tubular adenoma, DCIS, spindle cell proliferation in keeping with desmoplastic stromal reaction Main finding: High-grade DCIS with focal comedonecrosis Background: Tissue reaction consistent with previous biopsy site High-grade spindle cell neoplasm; No carcinomatous component identified
1 year prior
Left
Mastectomy
Right
Mastectomy and axillary dissection
Left chest wall
Wide excision
Present
was found. A similar histological appearance was observed in a 2.2 cm-sized lesion discovered 3 years earlier in the contralateral right breast ( post-wide excision). Both tumours were mitotically active (at least 20 mitoses per 10 high power fields) with several atypical mitotic figures and apoptotic bodies. Nuclei of the spindle cells were vesicular in appearance with some showing coarse-clumped chromatin, with the right breast spindle cell tumour disclosing more modest nuclear atypia than the latest left chest wall nodule. Cytoplasm was pale eosinophilic with illdefined borders. Tumour necrosis was not seen. An epithelial component was not identified in either tumour. Immunohistochemistry showed the right breast spindled tumour diagnosed 3 years ago to stain positively for calponin, CD10 and bcl-2 protein whereas desmin, h-caldesmon, p63, smooth muscle actin
Main finding: High-grade DCIS with comedonecrosis Background: Dense concentric fibrous tissue Spindle cell lesion with paucicellularity and mild nuclear atypia noted within a scar area, favouring reactive scar tissue; No evidence of carcinoma or overtly neoplastic spindle cell lesion; No evidence of metastasis in the axillary lymph nodes High-grade spindle cell neoplasm; No carcinomatous component identified
Important immunohistochemical findings
Treatment received
IDC: ER−, PR−, HER2 protein 3+ Reactive spindle cell proliferation: CKs−
Surgery; adjuvant chemotherapy; and localised radiation
High-grade DCIS: ER−, PR−
Surgery and postoperative radiation
Epithelial markers: AE1/AE3−, EMA−, 34βE12−, Cam5.2− Endothelial markers: CD34−, CD31− Others: Desmin−, h-caldesmon−, p63−, SMA−, S100−, CD10+, calponin+ (weak), bcl-2+ (patchy) High-grade DCIS: ER+ (ranging from 1+ to 2+ in intensity), PR−
Surgery
Epithelial markers: MNF116+ (subset), CAM5.2+ (subset), AE1/AE3+ (few cells), CK5/6−, CK7−, CK14−, CK19−, 34βE12− Endothelial markers: CD34−, CD31− Others: SMA+, desmin−, SMMHC−, h-caldesmon−, S100−, INI1+, p63−, Ki-67+ (up to 40%), ER−, PR−, HER2−
Surgery
Surgery
CKs, cytokeratins; DCIS, ductal carcinoma in situ; EMA, epithelial membrane antigen; ER, estrogen receptor; IDC, invasive ductal carcinoma; PR, progesterone receptor; SMA, smooth muscle actin; SMMHC, smooth muscle myosin heavy chain.
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PostScript
Figure 1 Representative sections of the right breast tumours. High-grade ductal carcinoma in situ (DCIS) with central comedonecrosis was initially identified (A) original magnification×100. Subsequently a spindle cell neoplasm consisting of neoplastic cells arranged in fascicles and vague storiform pattern was noted. The tumour cells showed a moderate degree of nuclear pleomorphism, nuclear hyperchromasia and mitotic figures (B) original magnification×200. The tumour cells were negative for MNF116 (C), p63 (D), CD34 (E) and S100 (F). (SMA), S100, epithelial markers (AE1/ AE3, EMA and 34βE12) and endothelial markers CD34 and CD31 were negative. No lineage-specific structures were identified by electron microscopic study. In the current left chest wall tumour, the majority of the spindle cells were positive for SMA with subplasmalemmal accentuation, whereas they were negative for desmin and other markers of smooth muscle differentiation (smooth muscle myosin heavy chain and h-caldesmon). Endothelial markers CD31 and CD34, and S100 also yielded negative results. Significantly, a subset of the neoplastic cells showed positive reactivity with MNF116 and CAM5.2, with AE1/ AE3 showing very focal reactivity. CK5/6, 34BE12, CK14, CK7, CK19 and p63 were negative. Retained INI-1 expression was demonstrated by positivity in the nuclei of the tumour cells. Proliferative index as measured by Ki-67 immunostaining was relatively high (up to 40%). Ultrastructurally, some features suggesting myofibroblastic differentiation such as 492
abundant rough endoplasmic reticulum, peripheral myofilament bundles with a fibronexus-like structure were identified. There was no electron microscopic evidence of epithelial or melanocytic differentiation. Pathological findings of both tumours were concluded as most consistent with undifferentiated sarcoma, although a differential diagnosis of a spindle cell carcinoma was strongly considered in the left chest wall tumour in view of the keratin positivity. However, contemplating the prior history of radiation exposure, absence of a metaplastic spindle cell component in the previous invasive ductal carcinoma diagnosed 11 years ago and the mastectomy that was performed a year ago for the in situ ductal carcinoma recurrence, the diagnosis of postradiation sarcoma was favoured. Histological features, immunohistochemical results and electron micrographs of both tumours are shown in figures 1–3. After the latest surgical wide excision for the left chest wall tumour, the patient declined further treatment. Twenty
weeks after surgery, she developed intra-abdominal sepsis with a new finding of a pancreatic tail mass. Liver lesions radiologically deemed consistent with metastases were also discovered, from which fine needle aspiration of a representative liver lesion showed adenocarcinoma, with an immunoprofile favouring a pancreaticobiliary origin. Radiation-induced sarcoma (also known as postradiation sarcoma) is an uncommon complication of radiotherapy. Generally, the criterion for making this diagnosis is a histologically confirmed sarcoma that arises in a prior irradiated field following a sufficient latency period. However, the time interval that is considered as ‘a sufficient latency period’ is different among studies, ranging from 6 months to 5 years.3–5 Sarcomas of various histological subtypes have been reported in the setting of radiation-induced sarcoma, with undifferentiated sarcoma comprising 25% or more.6 7 In most cases, a histological subtype of radiation-induced sarcoma J Clin Pathol June 2015 Vol 68 No 6
PostScript
Figure 2 Representative sections of the left breast and left-sided chest wall tumours. Invasive ductal carcinoma (A) and high-grade ductal carcinoma in situ (DCIS) (B) were initially identified (A and B) original magnification×100. Recurrent high-grade DCIS with focal comedonecrosis (C) and spindle cell neoplasm arising post mastectomy (D) were subsequently detected (C and D) original magnification×200. The postmastectomy tumour was mainly characterised by spindle cells arranged in long fascicles. Some tumour cells with hyperchromatic nuclei were identified among the majority of tumour cells with vesicular nuclei. Mitotic figures as well as apoptotic bodies were noted (D) original magnification×200. The spindle cells showed focal cytoplasmic staining for CAM5.2 (E) and MNF116 (F) whereas p63 (H) and high molecular weight keratins were negative. Positivity for smooth muscle actin (SMA) was demonstrated in a subplasmalemmal accentuation pattern (G).
cannot be predicted by a site of a prior radiated field; however, in cases of the radiation-induced sarcoma that occur after treatment of breast cancer, angiosarcoma is the most common histological subtype whereas other subtypes of sarcoma are less frequently encountered.2 Our case of bilateral undifferentiated sarcomas metachronously developing in the left chest wall and right breast in a patient with a history of radiation treatment for invasive ductal carcinoma and high-grade ductal carcinoma in situ respectively, is therefore unique. Sarcoma following radiotherapy administered as treatment of breast carcinoma is a rare complication, with a cumulative incidence of 0.3–0.48% in 15 years.2 Its incidence is evidently associated with radiation dose.8 Other factors that might be related to its pathogenesis include having a deleterious BRCA-1 mutation, de novo J Clin Pathol June 2015 Vol 68 No 6
TP53 mutation and hereditary diseases such as Li-Fraumeni syndrome.9 10 According to the study by Kirova et al,2 reportedly the largest study in radiation-induced sarcomas following radiotherapy for breast carcinoma, this type of secondary sarcoma could develop in any site within the irradiated field (breast, chest wall, sternum, supraclavicular region, scapular region, axilla) and was usually seen in older patients whose median ages at diagnosis of breast carcinoma and radiation-induced sarcoma were 57 (range, 36–74) years and 63 (range, 47–82) years, respectively. The latency period between the time of breast carcinoma diagnosis and development of sarcoma ranged from 3 years to 20.3 years. However, the age of onset for breast carcinoma and radiation-induced sarcoma might be younger, and the latency period shorter, in patients with
genetic susceptibilities, such as those with BRCA-1 and TP53 mutations.9 11 In this particular case, although the latency period of the lesions in both breasts falls into the same time range as previously reported (4 years for the right breast and 11 years for the left postmastectomy chest wall), the patient’s age at the time of diagnosis for breast carcinoma (27 years for invasive ductal carcinoma of the left breast and 31 years for high-grade ductal carcinoma in situ of the right breast) and radiation-induced sarcoma (35 years for the right breast sarcoma and 38 years for the left postmastectomy chest wall sarcoma) is relatively younger than those previously described. Furthermore, to our knowledge, development of multifocal radiation-induced sarcomas following radiotherapy for breast carcinoma is uncommon. The question of whether this patient possesses any predisposing genetic 493
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Figure 3 Electron micrographs of the right breast spindle sarcoma (A) showed no lineage-specific structures whereas the neoplastic spindle cells of the left-sided chest wall nodule (B) demonstrated features suggesting myofibroblastic differentiation including presence of abundant rough endoplasmic reticulum with peripheral myofilament bundles (arrow) with a fibronexus-like structure (arrow head) and filaments resembling fibronectin (circle). abnormalities is therefore raised, particularly in light of the latest development of yet another primary tumour, this time from the pancreaticobiliary tract. According to the recent WHO Classification of tumours of soft tissue and bone,6 undifferentiated sarcoma is defined as a heterogeneous group that shows no evidence of lineage-specific differentiation in a realm of technology presently available; this also includes cases that were previously known as ‘malignant fibrous histiocytoma’. Regarding its morphology, it can be broadly divided into pleomorphic, spindle cell, round cell and epithelioid subsets. Exclusion of non-sarcomas (such as sarcomatoid carcinoma, malignant melanoma, mesothelioma and some haematolymphoid tumours) and dedifferentiated sarcoma is required before making the diagnosis. As defined, undifferentiated sarcoma shows no reproducible pattern of immunophenotypes; however, there is evidence that a subset shows immunohistochemical and ultrastructural features of myofibroblasts such as immunoreactivity for SMA, desmin, musclespecific actin and h-caldesmon and/or presence of abundant rough endoplasmic reticulum with peripheral myofilament bundles with dense bodies and, sometimes, pinocytotic vesicles and fragments of external lamina 13 in electron micrographs.12 Undifferentiated sarcoma that secondarily develops following radiotherapy of breast carcinoma is uncommon. To our best knowledge, only 16 cases have been reported in 494
the English literature so far.2 5 9 14–16 In our case, the tumour in the right breast tissue that occurred 3 years prior displayed histological features and immunophenotypical profiles as those described in undifferentiated pleomorphic sarcoma which could also be interpreted as atypical fibroxanthoma due to its superficial location (cutaneous undifferentiated pleomorphic sarcoma) and, hence, rendering excellent clinical outcome by adequate surgery. However, the present tumour that occurred in the left postmastectomy chest wall demonstrated relatively significant expression of cytokeratins, which raised a concern of recurrent carcinoma, particularly monophasic/sarcomatoidtype spindle metaplastic carcinoma that is believed to arise from the process of ‘dedifferentiation’ or ‘transformation’ from epithelial-type carcinoma.17–20 Supporting the diagnosis of radiation-induced sarcoma instead of metaplastic carcinoma includes absence of spindle cell metaplastic elements in the initial left breast tumour that could potentially account for a spindle cell metaplastic carcinoma recurrence in the left chest wall. Second, the time interval between the initially diagnosed breast carcinoma and the recently occurring spindle cell tumour in this case is much more remote (11 years) than that reported in previous studies of metaplastic carcinoma where earlier recurrences are encountered (up to 76 months).17–19 Third, in this case, there is a history of radiation therapy, which predisposes to the development of secondary
sarcoma. Additionally, mastectomy performed for the prior recurrence of ductal carcinoma in situ without any invasive elements also made it less likely for the latest tumour in the chest wall to be an invasive breast carcinoma recurrence. According to previous studies, most monophasic/ sarcomatoid-type metaplastic carcinomas may behave similarly to sarcomas.17–19 Of note, several sarcomas including primary and postradiation undifferentiated sarcomas can show cytokeratin expression, particularly low-molecular-weight types.21 22 In our case, the left chest wall tumour was negative for a series of high molecular weight keratins as well as p63, which are usually positively expressed in metaplastic carcinoma. In conclusion, radiation-induced sarcoma is an uncommon complication of radiotherapy of breast cancer, with histological subtypes other than angiosarcoma being very uncommon. To our best knowledge, this is the first described case of bilateral postradiation sarcoma with histological features of undifferentiated sarcoma that metachronously occurred in a woman previously diagnosed with bilateral breast carcinoma. Kanapon Pradniwat,1,2 Kong Wee Ong,3 Kesavan Sittampalam,1 Boon Huat Bay,4 Puay Hoon Tan1 1
Department of Pathology, Singapore General Hospital, Singapore Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 3 Department of Surgical Oncology, National Cancer Center, Singapore 4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2
Correspondence to Dr Puay Hoon Tan, Department of Pathology, Singapore General Hospital, 20 College Road, Diagnostics Tower, Level 7, Academia, Singapore 169856, Singapore; [email protected] Contributors KP wrote the manuscript. KWO was the managing surgeon who contributed to the content and obtained patient consent. KS reviewed the histology of the sarcomas and contributed to the manuscript. BHB provided input on the electron micrographs. PHT supervised the case study and manuscript. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; internally peer reviewed.
To cite Pradniwat Kapon, Ong KW, Sittampalam K, et al. J Clin Pathol 2015;68:491–495. Received 16 February 2015 Revised 24 February 2015 Accepted 26 February 2015 Published Online First 18 March 2015 J Clin Pathol 2015;68:491–495. doi:10.1136/jclinpath-2015-202963 J Clin Pathol June 2015 Vol 68 No 6
PostScript REFERENCES 1
2
3
4
5
6
7
8
National Comprehensive Cancer Network. Breast Cancer (Version 3.2014). Http://Www.Nccn.Org/ Professionals/Physician_Gls/Pdf/Breast.Pdf (accessed 25 Dec 2014). Kirova YM, Vilcoq JR, Asselain B, et al. Radiation-induced sarcomas after radiotherapy for breast carcinoma: a large-scale single-institution review. Cancer 2005;104:856–63. Cahan WG, Woodard HQ, Higinbotham NL, et al. Sarcoma arising in irradiated bone; report of 11 cases. Cancer 1948;1:3–29. Cha C, Antonescu CR, Quan ML, et al. Long-term results with resection of radiation-induced soft tissue sarcomas. Ann Surg 2004;239:903–9; discussion 909–10. Laskin WB, Silverman TA, Enzinger FM. Postradiation soft tissue sarcomas. an analysis of 53 cases. Cancer 1988;62:2330–40. Fletcher CDM, Bridge JA, Hogendoorn PCW, et al. eds. Who classification of tumours of soft tissue and bone. Lyon: Iarc Press, 2013. Lagrange JL, Ramaioli A, Chateau MC, et al. Sarcoma after radiation therapy: retrospective multiinstitutional study of 80 histologically confirmed cases. Radiation Therapist and Pathologist Groups of the Federation Nationale des Centres de Lutte Contre le Cancer. Radiology 2000;216:197–205. Rubino C, Shamsaldin A, Le MG, et al. Radiation dose and risk of soft tissue and bone sarcoma after
J Clin Pathol June 2015 Vol 68 No 6
9
10
11
12
13
14
15
breast cancer treatment. Breast Cancer Res Treat 2005;89:277–88. Salmon A, Amikam D, Sodha N, et al. Rapid development of post-radiotherapy sarcoma and breast cancer in a patient with a novel germline ‘de-novo’ TP53 mutation. Clin Oncol (R Coll Radiol) 2007;19:490–3. Sheth GR, Cranmer LD, Smith BD, et al. Radiation-induced sarcoma of the breast: a systematic review. Oncologist 2012;17:405–18. De Bree E, Van Coevorden F, Peterse JL, et al. Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: genetic predisposition? Eur J Surg Oncol 2002;28:392–5. Hasegawa T, Hasegawa F, Hirose T, et al. Expression of smooth muscle markers in so called malignant fibrous histiocytomas. J Clin Pathol 2003;56:666–71. Montgomery E, Fisher C. Myofibroblastic differentiation in malignant fibrous histiocytoma ( pleomorphic myofibrosarcoma): a clinicopathological study. Histopathology 2001;38:499–509. Biswas S, Badiuddin F. Radiation induced malignant histiocytoma of the contralateral breast following treatment of breast cancer: a case report and review of the literature. Cases J 2008;1:313. Fang Z, Matsumoto S, Ae K, et al. Postradiation soft tissue sarcoma: a multiinstitutional analysis of 14 cases in Japan. J Orthop Sci 2004;9:242–6.
16
17
18
19
20
21
22
Kocer B, Gulbahar G, Erdogan B, et al. A case of radiation-induced sternal malignant fibrous histiocytoma treated with neoadjuvant chemotherapy and surgical resection. World J Surg Oncol 2008;6:138. Carter MR, Hornick JL, Lester S, et al. Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg Pathol 2006;30:300–9. Davis WG, Hennessy B, Babiera G, et al. Metaplastic sarcomatoid carcinoma of the breast with absent or minimal overt invasive carcinomatous component: a misnomer. Am J Surg Pathol 2005;29:1456–63. Tse GM, Tan PH, Putti TC, et al. Metaplastic carcinoma of the breast: a clinicopathological review. J Clin Pathol 2006;59:1079–83. Van Deurzen CH, Lee AH, Gill MS, et al. Metaplastic breast carcinoma: tumour histogenesis or dedifferentiation? J Pathol 2011;224:434–7. Miettinen M. Immunohistochemistry of soft tissue tumours—review with emphasis on 10 markers. Histopathology 2014;64:101–18. Weiss SW, Bratthauer GL, Morris PA. Postirradiation malignant fibrous histiocytoma expressing cytokeratin. Implications for the immunodiagnosis of sarcomas. Am J Surg Pathol 1988;12:554–8.
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