Oncocytic Adrenal Cortical Carcinosarcoma With Pleomorphic Rhabdomyosarcomatous Metastases
Khin Thway, FRCPath, *; David Olmos, MBBS, PhD,1} Chirag Shah, FRCPath,* Rashpal Flora, FRCPath,* Janet Shipley, PhD,t and Cyril Fisher, MD, DSc, FRCPath*
Abstract: Adrenal cortical carcinosarcoma is a rare variant of adrenal cortical carcinoma. Sarcomatous change in adrenal cortical carcinomas is exceptionally rare, with only 9 cases pre- viously described. Adrenal cortical carcinosarcomas tend to be aggressive tumors, with locoregional recurrence and rapid meta- stases from the sarcomatoid component. We describe what seems to be the first case of sarcoma arising in oncocytic adrenal cortical carcinoma. The sarcomatous component here was pleomorphic rhabdomyosarcoma. This occurred in a 45-year-old man who had nodal and pulmonary metastases of the rhabdomyosarcom- atous component at presentation and who died of progressive disease 11 months later. Here, we discuss the clinical, radiologic, and pathologic findings and review the literature on adrenal cortical carcinosarcomas.
Key Words: adrenal sarcomatoid carcinoma, carcinosarcoma, metastasis, oncocytic, rhabdomyosarcoma, sarcoma
(Am J Surg Pathol 2012;36:470-477)
CASE REPORT
A 45-year-old Afro-Caribbean man with sickle cell trait presented with a 1-year history of abdominal bloating and recent-onset back pain. Clinical examination revealed a large abdominal mass. The patient had no clinical features of steroid hormone or catecholamine excess and no family history of note. Computed tomography scan showed a large 22 × 22 × 16 cm left retroperitoneal mass displacing the spleen superiorly and left kidney inferiorly, which was vascular with cystic lakes and areas of calcification. Enlarged retroperitoneal and abdominal nodal masses were present, as was a 1.9-cm-diameter solitary lesion in the mid zone of the left lung, all consistent with
metastatic deposits. At surgery (laparotomy), the mass lay be- tween the spleen and kidney and was lightly adherent to the pancreas and left colon. Lymph nodes were found in the splenic hilum and around superior mesenteric vessels. The tumor was excised along with the spleen, left kidney, and mass of left- sided retroperitoneal nodes. The separate 7-cm nodal mass at the root of the small bowel mesentery was closely related to the superior mesenteric vessels and was unresectable; hence, it was left in situ.
MATERIALS AND METHODS
Immunohistochemical staining (the streptavidin-biotin peroxidase complex method, with diaminobenzidine as the chromogen) was performed on formalin-fixed, paraffin- embedded tumor tissue using a panel of commercial anti- bodies (Table 1). Fluorescence in situ hybridization (FISH) was performed to assess for rearrangements of FOXO1 and PAX3 genes. Briefly, 1-um formalin-fixed, paraffin- embedded tissue sections were cut onto SuperFrostPlus glass slides (VWR International, Poole, UK). FOXO1 rearrange- ments were detected using Vysis LSI FOXO1 break-apart probes (Abbott Laboratories, Maidenhead, UK); PAX3 re- arrangements were detected using an in-house assay with probes flanking the PAX3 breakpoints [three 3’ centromeric and three 5’ telomeric (Fig. 1)]. FISH, labeling of bacterial artificial chromosomes including preparation of slides, probes, and washing were all carried out as previously de- scribed.38 Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to identify PAX3-FOXO1 and PAX7-FOXO1 fusion transcripts, according to standard methods.20,40
RESULTS
The excised tumor was a large, circumscribed, en- capsulated spherical mass measuring 24× 22.5× 16 cm and weighing 6.5 kg. The cut surface was firm and varied in color. The majority of the lesion was tan and bright yellow, but several paler cream nodules were scattered throughout and accounted for approximately 10% of the tumor area (Fig. 2A). Numerous foci of necrosis, ap- proximating to a further 10% of the tumor area, were also present. The kidney was uninvolved and the adrenal appeared intact and was stretched over the surface of the tumor (Fig. 2B). The splenic parenchyma appeared un- remarkable, but in the region of the splenic hilum were
From the *Sarcoma Unit, Department of Histopathology, The Royal Marsden NHS Foundation Trust, London; }Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research; and įSarcoma Unit, Drug Development and Medical Oncology Units, The Royal Mars- den NHS Foundation Trust, Sutton, Surrey, UK.
David Olmos is supported by a Spanish Society of Medical Oncology (SEOM) translational research fellowship.
Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Khin Thway, FRCPath, Department of Histopathol- ogy, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK (e-mail: khin.thway@icr.ac.uk).
Copyright @ 2012 by Lippincott Williams & Wilkins
| Antibody | Source | Dilution |
|---|---|---|
| AE1/AE3 | Zymed Laboratories (CA) | 1:50 |
| MNF116 | Dako (Glostrop, Denmark) | 1:400 |
| EMA | Dako | 1:400 |
| CK7 | Dako | 1:50 |
| CK20 | Dako | 1:50 |
| Desmin | Dako | 1:50 |
| SMA | Dako | 1:200 |
| h-caldesmon | Dako | 1:50 |
| Myogenin | Dako | 1:100 |
| MyoD1 | Novocastra Laboratories (Newcastle-Upon-Tyne, UK) | 1:50 |
| CDK4 | Invitrogen Ltd (Paisley, UK) | 1:25 |
| MDM2 | Novocastra Laboratories | 1:100 |
| p16 | MTM Laboratories (Heidelberg, Germany) | Ready diluted (kit form) |
| S100 protein | Dako | 1:1500 |
| HMB45 | Dako | 1:100 |
| MelanA | Dako | 1:25 |
| Inhibin | Novocastra Laboratories | 1:50 |
| Calretinin | Invitrogen (Camarillo, CA) | 1:100 |
| CD10 | Novocastra Laboratories | 1:30 |
| CD30 | Novocastra Laboratories | 1:20 |
| CD34 | Novocastra Laboratories | 1:30 |
| CD45 | Dako | 1:20 |
| CD56 | Invitrogen | 1:50 |
| CD117 | Dako | 1:500 |
| DOG1 | Novocastra Laboratories | 1:50 |
| Chromogranin | Dako | 1:300 |
| Synaptophysin | Dako | 1:100 |
| AFP | Dako | 1:500 |
| Vimentin | Dako | 1:25 |
| MIB1 | Dako | 1:100 |
solid multinodular nodes containing tumor, measuring 6.5x 5× 4.5 cm. A separate 5.2 × 4 × 2.5 cm retroperitoneal mass of nodes containing tumor was also excised.
Histologically, the tumor comprised 2 discrete, mor- phologically and immunophenotypically distinct components that were well demarcated rather than intermingled. The majority of the mass, accounting for the tan and yellow areas described macroscopically, was composed of sheets and nests of polygonal, “oncocytic” cells with oval vesicular nuclei and frequently prominent nucleoli, occasional nuclear inclusions, and abundant eosinophilic cytoplasm (Fig. 2C). Nuclear atypia varied widely from minimal to focally marked (Fig. 2C). Clusters of vacuolated, foamy cells were present in areas (Fig. 2D) but constituted <5% of this portion of the tumor. Focally, cells were multinucleate. No glandular or squamous differentiation was identified. The mitotic index was variable but was focally up to 6/50 hpf, with occasional atypical forms, and there was focal necrosis and hyaliniza- tion. No definite capsular invasion was seen. Immunohisto- chemistry was positive in these areas for MelanA, CD56, and focally for MNF116 (Fig. 2E). It was negative for the other antibodies listed (Table 1), including S100 protein, HMB45, chromogranin, synaptophysin, AE1/AE3, CD10, inhibin, calretinin, MDM2, CDK4, p16, desmin, SMA, h-caldesmon, myogenin, and MyoD1. The proliferation fraction by MIB1 was low, at < 1%.
The mitotic index (focally > 5/50 hpf) and the pres- ence of atypical mitotic figures were 2 of the major criteria for malignancy in the proposed system for separating benign from malignant oncocytic adrenocortical neo- plasms (OAN),7 in which the presence of any of the 3 major criteria (the third being venous invasion) is con- sidered malignant. This part of the lesion was interpreted as oncocytic adrenal cortical carcinoma (ACC).
The other component of tumor comprised large nodules (corresponding to the firm cream foci macro- scopically), interspersed within the first element. These
5’ PAX3 Telomeric probes (BACs)
3’ PAX3 Centromeric probes (BACs)
FISH interpretation
3’ FOXO1
5’ FOXO1
-650 Kb
-600 Kb
centromeric probe
telomeric probe
Telomeric probes Vysis Assay
-720 Kb
-650 Kb
Centromerio probes Vysis Assay
RP11.4518
RP11-120F9
RP11.16PG
RP11-790H12
Gene rearrangement
Normal (no break)
FOXO1
ELF1
RP41-41206
RPIE-T1/24
13q14
Telomere 3’
Centromere 5’
- Telomere 5’ 2q35
- Centromere J’
Cell Nucleus
T
Breakpoint distribution
Oncocytic ACC
PAX3 dual-color break apart assay
Rhabdomyosarcoma
FOXO1 dual-color break apart assay
A
B
C
D
F
consisted of sheets of ovoid to focally spindle cells with moderately to markedly pleomorphic ovoid vesicular nuclei (Fig. 2F), including multinucleate forms (Fig. 3A). Large, polygonal rhabdomyoblasts with prominent cross- striations were abundant (Fig. 2F). The mitotic index was up to 25/10 hpf, with atypical forms. There was strong, diffuse desmin expression (Fig. 3B) and strong nuclear myogenin (Fig. 3C) (in approximately 30% of cells) and none for the other markers (Table 1), including SMA, h- caldesmon, AE1/AE3, MelanA, HMB45, MDM2, p16, and CDK4.
Although the morphology did not suggest it, in view of the unusual clinical context of the tumor, FISH and RT-PCR were performed to fully exclude alveolar rhab- domyosarcoma (ARMS). PAX3|7-FOXO1 fusion tran- scripts of ARMS were not detected by RT-PCR. No rearrangements of PAX3 or FOXO1 were detected by FISH (Fig. 1), confirming the RT-PCR findings and ruling out the presence of other (atypical) translocations involving rearrangements of PAX3 or FOXO1. Occasional increases in PAX3 and/or FOXO1 copy number were observed in the rhabdomyosarcomatous component but not in the onco- cytic ACC or in normal cells. The tumor was characterized as pleomorphic rhabdomyosarcoma.
The main tumor mass was completely excised, with both components separated from the surgical margin by a fibrous capsule. The adrenal gland appeared intact, but is- lands of adrenal cortical tissue were found within the tumor capsule, including in areas well away from the adrenal gland. Lymphovascular invasion of the rhabdomyosarco- matous component was present (Fig. 3D). The tumor abutted the renal capsule but was not seen to directly invade renal parenchyma, which was unremarkable. The tumor did not invade the spleen, which also showed unremarkable parenchyma.
The splenic hilar and para-aortic lymph node groups both showed extensive partially necrotic metastatic pleo- morphic rhabdomyosarcoma, with numerous large, round rhabdomyoblasts and strap cells with cross-striations essen- tially similar in morphology to that in the main tumor mass but with more pronounced skeletal muscle differentiation (Fig. 3E). There was extranodal extension into the perinodal fat. No adrenal cortical carcinomatous component was present. A separate core biopsy from the lung mass showed metastatic rhabdomyosarcoma (Fig. 3F), but no metastatic adrenocortical tumor component was identified.
The appearances were therefore consistent with onco- cytic adrenal cortical carcinosarcoma (with the sarcomatous component comprising pleomorphic rhabdomyosarcoma), with metastatic pleomorphic rhabdomyosarcoma in the lymph nodes and lung.
The patient recovered well from surgery and was treated with combination high-dose palliative chemo- therapy of vincristine, ifosfamide, doxorubicin, and eto- poside, alternating with ifosfamide, carboplatin, and etoposide. Three months later, after 4 cycles of treatment, the abdominal nodal disease was seen to be stable, but the pulmonary disease had progressed on computed tomog- raphy. Treatment was changed to single-agent ifosfamide,
but 8 months after diagnosis the patient re-presented with headache and left inferior quadrantanopia. Computed tomography demonstrated a large, solitary right posterior occipital lobe metastasis with mass effect but without midline shift or ventricular involvement. The patient was treated with high-dose dexamethasone and palliative whole-brain radiotherapy but died of progressive disease 11 months after initial diagnosis.
DISCUSSION
Sarcomatous change within ACC (referred to var- iably as adrenal carcinosarcoma and sarcomatoid ACC) is exceptionally rare, and only 9 cases have been previously reported in the English literature (Table 2). 6,11-13,16,27,33,35,37 We describe the first case in which oncocytic ACC, a rare ACC variant, gave rise to sarcoma. The sarcomatous components of most adrenal cortical carcinosarcomas have been described as spindle cell sarcomas without specific differentiation, with 1 report describing osteogenic and chondroid features,6 3 manifesting with prominent rhab- domyosarcomatous differentiation,13,16,35 and another de- scribing expression of smooth and skeletal muscle markers.11 Adrenal cortical carcinosarcomas tend to be aggressive tumors, with locoregional recurrence and rapid metastases from the sarcomatoid component. The 8 pre- viously reported patients for which there was clinical fol- low-up survived for 3 to 12 months after tumor resection, and the aggressive nature of the neoplasm is echoed by the survival of the patient we describe, who had metastases at presentation and died 11 months postoperatively.
Oncocytic adrenal cortical carcinomas (OACs) are rare. Although 45 cases have been reported in the English literature to date, a 1-3,7,14,15,17,19,21,23,24,26,31,32,34,36,39,46 study by Wong et al46 applied modified criteria for ma- lignancy of OANs7 (described below) to all published cases with sufficient information. Added to their own previously unpublished cases, this classified 24 of 110 OANs as malignant. This, coupled with a recent study of OAN with 12 malignant tumors,14 brings the total num- ber of OACs to 36. OACs consist exclusively or pre- dominantly of oncocytes (epithelial cells with abundant granular eosinophilic cytoplasm), with tumors showing diffuse, nested, or trabecular patterns of large, neoplastic polygonal oncocytic cells with round nuclei, prominent nucleoli, and abundant granular and eosinophilic cyto- plasm. Most OANs are nonfunctioning, as in this case, and the patient had no features of hormone excess such as stigmata of glucocorticoid or mineralocorticoid over- secretion. The immunoprofile of OAC is similar to that of conventional ACC, which is generally negative or only weakly positive for cytokeratins and negative for EMA; this case expressed neither. Alpha-inhibin and MelanA expressions are sensitive but not specific for ACC,8,30 and this case expressed MelanA but lacked inhibin expression. The latter was found focally in 1/4 cases of OAC in 1 study19 but was expressed in all 4 OACs of another.36 The antimitochondrial antibody mES-13 has been found to be
DA
C
D
E
F
| Case No. | References | Age | Sex | Clinical Presentation | Size With/ Without Weight | Sarcomatous Component | Postoperative Survival |
|---|---|---|---|---|---|---|---|
| 1 | Okazumi et al33 | 46 | M | Abdominal distention | 14 cm, 880 g | Spindle cell | 6 mo |
| 2 | Collina et al12 | 68 | F | Abdominal discomfort | 11 cm | Spindle cell | 6 mo |
| 3 | Decorato et al13 | 42 | F | Abdominal pain | 19 cm, 1400 g | Rhabdomyosarcoma | 7 mo |
| 4 | Fischler et al16 | 29 | F | Weight loss, virilization | 12.5 cm, 610 g | Rhabdomyosarcoma | 8 mo |
| 5 | Barksdale et al6 | 79 | F | Hypertension | 5 cm, 199 g | Osteosarcoma, chondrosarcoma | NA |
| 6 | Lee et al27 | 61 | M | Flank pain | 12 cm | Spindle cell | 2d |
| 7 | Sturm et al37 | 31 | M | Abdominal pain | 12 cm, 620 g | Spindle cell | 3 mo |
| 8 | Coli et al11 | 75 | F | Abdominal pain | 15 cm | Spindle cell | 12 mo |
| 9 | Sasaki et al35 | 45 | M | Abdominal pain | 17 cm, 2974 g | Rhabdomyosarcoma | 3 mo |
| 10 | Current study | 45 | M | Abdominal bloating, back pain | 24 cm, 6500 g | Pleomorphic rhabdomyosarcoma | 11 mo |
| NA indicates not applicable. | |||||||
helpful in confirming the oncocytic nature of the tumor cells. 46
The malignant potential of adrenal cortical neoplasms can be difficult to characterize. The most widely used system for predicting the biological behavior of conventional adrenal cortical tumors is that of Weiss,43,45 in which the presence of ≥ 3 of 9 criteria [high nuclear grade (Fuhrman 3 to 4), mitotic rate > 5/50 hpf, atypical mitoses, clear cells comprising ≤25% of the tumor, diffuse architecture (greater than one third of the tumor), necrosis, and invasion of venous, sinusoidal, and capsular structures] helps to distinguish malignant from benign tumors.43 ACC with > 20 mitoses/50 hpf were associated with worse prognosis and proposed to be designated as high grade.45 A modified Weiss system eliminating the criteria deemed more sub- jective or difficult to interpret (2 x mitotic rate > 5/50 hpf, +2 x clear cells comprising ≤25% of the tumor + abnormal mitoses + necrosis + capsular invasion, with a score of ≥3 considered indicative of malignancy)5,25 has been shown to be of diagnostic value in evaluating malignancy and to significantly correlate with time of survival in patients with ACC.41
However, not all criteria of the Weiss system are considered useful in predicting the biological behavior of OAN,28 as in essentially all OANs clear cells will comprise < 25% of tumor and most will have diffuse architecture and focal high-grade nuclear atypia.7,25,28,36 These 3 histologic parameters are therefore not considered useful in predicting prognosis in OAN and have not been associated with recurrent or metastatic tumors.25 In view of this, major and minor criteria are proposed for distinguishing benign from malignant OAN.7,25 A tumor with any major criterion (mitotic rate > 5/50 hpf, atypical mitoses, or venous in- vasion) may be defined as OAC, whereas a borderline OAN of uncertain malignant potential harbors any minor crite- rion (size > 10cm and/or > 200 g, necrosis, capsular in- vasion, or sinusoidal invasion), with this borderline category reflecting the scarcity of clinical information regarding the behavior of OAN.25 All major and minor criteria are absent in adrenocortical oncocytoma.7,25
This tumor had 2 of the major criteria for malig- nancy in OAN. In addition, although some authors re-
port that cytologic atypia or mitotic rate cannot reliably predict the biological behavior of OAC,19 they observe that large tumor size, extracapsular extension, vascular invasion, necrosis, and metastasis are features of malig- nancy for these tumors.19 The low proliferation index assessed by Ki-67 seen here has also been observed pre- viously in OAC.36 Although previous studies have sug- gested that MIB1 correlates with malignant behavior in adrenal cortical neoplasms, aiding differentiation between benign and malignant lesions,42 MIB1 has not been seen to be useful in case reports of OAC,23,28 and its role is unclear because of the small numbers of available tumors for assessment.
The sarcomatous element of the tumor was frankly malignant. To our knowledge, a sarcomatous component has not been reported in any OAN. Although a myeloli- pomatous component has been reported in association with a malignant OAN,46 this was peripheral and largely separate from it. Adrenocortical adenoma with sarcoma has not been described, although spindle cell sarcoma (with no specific immunohistochemical differentiation) has been reported to apparently arise from the pheochromocytomatous compo- nent of an adrenal corticomedullary tumor.29 The presence of multiple copy numbers of signals to PAX3 and FOXO1 probes within the pleomorphic rhabdomyosarcoma (but not in the OAC) is consistent with unbalanced karyotype/aneu- ploidy of the rhabdomyosarcoma and in keeping with its pleomorphic phenotype. Although pleomorphic rhabdo- myosarcoma appears to be the best morphologic fit for this tumor, the unique circumstances of this case make it difficult to precisely subtype; in some areas the characteristics were reminiscent of embryonal rhabdomyosarcoma, particularly its anaplastic variant. Pleomorphic rhabdomyosarcomas generally occur in elderly patients, and most exhibit complex karyotypes, without characteristic cytogenetic aberrations,1 although 1 case of pleomorphic rhabdomyosarcoma dem- onstrating evidence of a PAX3-FOXO1 gene fusion charac- teristic of alveolar RMS has been previously described.1
The clinical and immunohistologic findings rule out other diagnoses. The differential diagnosis includes the angiomyolipoma-perivascular epithelioid cell neoplasm (PEComa) family of tumors. Sarcomatoid dedifferentiation
has been described in the epithelioid variant of angio- myolipoma, with renal tumor that metastasized to the liver.10 Although our case showed MelanA positivity, the absence of expression of other markers of melanocytic differentiation, and of smooth muscle markers, excluded PEComa. The patient’s resected intact and unremarkable kidney excluded renal cell carcinoma with sarcomatoid change, as well as the eosinophilic variant of chromo- phobe renal cell carcinoma, as did the immunoprofile, including absence of CD10 and EMA expression. Pheo- chromocytoma was ruled out morphologically (no Zell- ballen or S100 protein-positive sustentacular cells) and by absence of expression of neuroendocrine markers. The focal cytokeratin expression argues against clear cell sarcoma, for which a coexistent rhabdomyosarcomatous component would be inexplicable. Dedifferentiated lip- osarcoma with heterologous rhabdomyoblastic differ- entiation is excluded by oncocytic morphology, absence of supportive immunohistochemical markers (CDK4, MDM2, and p16), and of any well-differentiated lip- osarcomatous component.
The presence of an apparently intact adrenal gland abutting the tumor, with unremarkable adrenal tissue within the tumor capsule, is notable, and a thin rim of normal adrenal tissue is well described in large ACCs and OAC.19 A nonrhabdomyosarcomatous sarcomatoid ACC also showed a normal adrenal gland remaining at the periphery of a 12-cm tumor mass.37 Conceivably, some examples of ACC might arise in accessory/ectopic adrenal tissue, and the presence of islands of normal-looking adrenal tissue within the capsule well away from the adrenal gland in this case might suggest this. Another possibility is that the tumor arose directly within the gland and grew slowly, becoming eventually separated from the normal non-neoplastic adrenal parenchyma.
Although no relationship of ACC or rhabdomyo- sarcoma with the sickle cell trait carried by the patient is apparent, interestingly Surveillance, Epidemiology and End Results data from the United States suggest a trend of increased rates for ACC in African Americans. 44 Adrenocortical carcinoma, along with bone and soft tis- sue sarcomas, breast carcinoma, and brain tumors,4 is one of the most common malignant neoplasms associated with Li-Fraumeni syndrome, in which there are germline mutations of the tumor suppressor gene p53. ACC has been described developing synchronously with or sub- sequently to rhabdomyosarcoma in children with Li- Fraumeni syndrome,9,22 and ACC and embryonal rhab- domyosarcoma have been reported separately in siblings as infants in a family with Li-Fraumeni syndrome.4 Patients with Beckwith-Wiedemann syndrome also have a high incidence of ACC and rhabdomyosarcoma, among other tumors. This patient, however, had no family history of note.
In summary, we present what seems to be the first case of OAC. In this case, the sarcomatous component was pleomorphic rhabdomyosarcoma, which accounted for widespread metastases to retroabdominal lymph no- des, lung, and, apparently, brain. As shown in previous
cases of adrenal cortical carcinosarcoma, this is an ag- gressive, rapidly metastasizing neoplasm that resulted in the patient’s death.
ACKNOWLEDGMENTS
The authors are grateful to Mr John Swansbury and Dr Toon Min (Haematology Cytogenetics, Royal Marsden Hospital and The Institute of Cancer Research, Sutton, Surrey) for performing FISH for FOXO1 rearrangements and for their advice with the manuscript; to Drs David Gonzalez and Lisa Thompson (Molecular Diagnostics, Royal Marsden Hospital and The Institute of Cancer Re- search, Sutton, Surrey) for performing RT-PCR; and also to Mrs Reem Al-Saadi ( Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey) for technical assistance. The authors also acknowledge NHS funding to the NIHR Biomedical Research Centre.
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ERRATUM
Synchronous Breast Cancers With Different Morphologic and Molecular Phenotypes Occurring in Lynch Syndrome: What Does the Heterogeneity Imply ?: Erratum
This article appeared on page 1743 of the November 2011 issue of the journal and the correction below is needed.
On page 1744, the last line of the left panel: “IVS5+SA → T” is incorrect. It should be: IVS5+3A → T.
REFERENCE
D’Arcy C, Wen YH, Stadler Z, et al. Synchronous breast cancers with different morphologic and molecular phenotypes. Am J Surg Pathol. 2011;35:1743-1748.