Preoperative diagnosis of benign thyroid nodules with indeterminate cytology
Approximately 15 percent to 30 percent of thyroid nodules evaluated by fine-needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. The authors performed a 19-month, prospective, multicenter validation study (funded by Veracyte) involving 49 clinical sites, 3,789 patients, and 4,812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. They obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules, and its performance was assessed. The authors found that of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92 percent sensitivity; 95 percent confidence interval [CI], 84–97) with a specificity of 52 percent (95 percent CI, 44–59). The negative predictive values for atypia (or follicular lesion) of undetermined clinical significance, follicular neoplasm or lesion suspicious for follicular neoplasm, and suspicious cytologic findings were 95 percent, 94 percent, and 85 percent, respectively. An analysis of seven aspirates with false-negative results revealed that six had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. The authors concluded that these data support consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results.
Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8):705–715.

Stem cell-related markers in primary breast cancers and associated metastatic lesions
It has been reported that normal breast epithelial cells that are CD24-/44+ express higher levels of stem/progenitor cell-associated genes. It has also been reported that cancer cells that have undergone epithelial to mesenchymal transition display CD24-/44+ cell-surface expression, a marker for breast cancer stem cells; that loss of E-cadherin is a preliminary step in epithelial to mesenchymal transition; and that vimentin is a
marker of mesenchymal phenotype. The authors hypothesized that stem cell subpopulations would be more frequent in metastatic than in primary tumors. Therefore, they assessed, by immunohistochemical analysis, tissue microarrays containing tissue from primary and associated
metastatic breast cancers for expression of CD24, CD44, E-cadherin, and vimentin to evaluate candidate cancer-initiating cell populations in breast cancer subtypes and metastatic lesions. The occurrence of CD24-/44+ and CD24+/44- cells did not differ in primary versus matched lymph node or distant and locoregional metastatic lesions. E-cadherin expression was decreased in primary versus lymph node metastases (P=.018) but not in distant and locoregional metastases relative to primary tumor. Vimentin was more frequently expressed in lymph node
and distant and locoregional metastases (P=.013; P=.004) than in matched primary cancers. The authors concluded that the frequency of
CD24-/44+ cells does not differ in metastases relative to the primary breast cancer but differs by tumor stage and subtype.
Guler G, Balci S, Costinean S, et al. Stem cellrelated markers in primary breast cancers and associated metastatic lesions. Mod Pathol. 2012;25:949–955.

DOG1: a marker of salivary acinar and intercalated duct differentiation
Anoctamin-1 (ANO1) (DOG1, TMEM16a) is a calcium-activated chloride channel initially described in gastrointestinal stromal tumors but now known to be expressed in a variety of normal and tumor tissues,  including salivary tissue in murine models. The authors performed a comprehensive survey of DOG1 expression in 156 cases containing nonneoplastic human salivary tissues and tumors. ANO1 mRNA levels were significantly higher (eight-fold increase; P<.0001) in normal parotid tissue (n=6) than in squamous mucosa (n=15). By immunohistochemistry, DOG1 showed a diffuse moderate (2+) apical membranous staining pattern in normal serous acini, 1+ apical membranous pattern in mucous acini, and variable 1–2+ apical staining of distal intercalated ducts. Myoepithelial cells and striated and
excretory ducts were invariably negative. All acinic cell carcinomas (n=28) were DOG1 positive, demonstrating a complex mixture of intense (3+) apical membranous, cytoplasmic, and complete membranous staining. Most ductal tumor types were negative or showed only a subset of positive cases. Within the biphasic tumor category, adenoid cystic carcinomas (18 of 24 cases) and epithelial-myoepithelial carcinomas (eight of 15 cases) were frequently positive, often show-membranous/cytoplasmic myoepithelial staining profile. Therefore, DOG1 staining is a marker of salivary acinar and, to a lesser extent, intercalated duct differentiation. Strong staining can be used to support the diagnosis of acinic cell carcinoma. DOG1 may also be a marker of a transformed  myoepithelial phenotype in a subset of biphasic salivary gland malignancies.
Chênevert J, Duvvuri U, Chiosea S, et al. DOG1: a novel marker of salivary acinar and intercalated duct differentiation. Mod Pathol. 2012;25:919–929.

Anaplastic large cell lymphoma associated with breast implants
The authors reported on 13 cases of anaplastic large cell lymphoma associated with breast implants. Patients ranged in age from 39 to 68 years, and the interval from implant to anaplastic large cell lymphoma (ALCL) was four to 29 years. All tumors were composed of large, pleomorphic cells that were CD30+ and ALK1–, and all seven cases that were assessed had monoclonal T-cell receptor γ-chain rearrangements. Two patient subgroups were identified. Ten patients presented with effusion surrounded by fibrous capsule without a
grossly identifiable tumor mass. Nine patients had stage I and one had stage II disease. Eight patients underwent implant removal and capsulectomy. Four patients received chemotherapy, and four received radiation therapy. All patients were alive without disease at last followup. A second subgroup of three patients had effusion and a distinct mass adjacent to the implant. One patient had stage I, and two had stage II disease. One patient had a three-year history of lymphomatoid papulosis, and one patient had a one-year history of CD30+ T-cell
lymphoma adjacent to the breast before the diagnosis of ALCL associated with breast implants. Two patients received chemotherapy, and one received radiation therapy. Two patients died two and 12 years after diagnosis, respectively. The authors concluded that the clinical behavior of ALCL associated with breast implants is heterogeneous. Patients who present with effusion without a distinct mass have an indolent disease course, similar to CD30+ lymphoproliferative disorder of skin. In contrast, patients who present with a distinct mass may have advanced
stage or possibly systemic disease and have a poorer prognosis.
Aladily TN, Medeiros LJ, Amin MB, et al. Anaplastic large cell lymphoma associated with breast implants: a report of 13 cases. Am J Surg Pathol. 2012;36(7):1000–1008.

Tissue-sparing application of IASLC/ATS/ERS classification of adenocarcinoma of lung
The histologic subtype of non-small cell lung cancer determines treatment strategies and the need for genetic analyses. Since most of these cancers are diagnosed on small biopsy or cytologic specimens, an accurate but tissue-sparing approach is necessary. To date, consensus for a general diagnostic algorithm is lacking. Therefore, the authors tested the diagnostic and clinical relevance of the recently published multidisciplinary guidelines from the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory
Society. They examined 371 surgically resected non-small cell lung cancers (NSCLCs) brought into tissue microarray format. The antibody panel of thyroid transcription factor-1 (TTF- 1), p63, cytokeratin (CK) 5/6, and CK7 is diagnostic for more than 94 percent of such cases. Faint/focal staining for CK7 is negligible for classificatory purposes. Grading adenocarcinomas according to histologic architecture is prognostically significant (median overall survival for well/moderate differentiation, 72.5 months; for poor differentiation, 38.5 months; P=.019).
Double stains combining the aforementioned nuclear and membranous markers are highly diagnostic for NSCLC, conserving tumor tissue for
subsequent analyses.
Sterlacci W, Savic S, Schmid T, et al. Tissuesparing application of the newly proposed IASLC/ATS/ERS classification of adenocarcinoma of the lung shows practical diagnostic and prognostic impact. Am J Clin Pathol. 2012;137(6):946–956.

Prognosis and risk factors for early stage adenoid cystic carcinoma of the major salivary glands
Adenoid cystic carcinoma is characterized by slow growth, frequent local recurrences, and distant metastasis. These findings frequently are reported in patients with advanced-stage tumors, while the outcomes of early stage tumors are poorly defined. The authors sought to evaluate the risk factors for developing distant metastasis in early stage adenoid cystic carcinoma (ACC). They retrospectively reviewed the charts of 60 patients who were diagnosed with clinical early stage (T1-2/N0) ACC to determine the risk factors for developing distant metastases as well as patients’ prognoses. Distant metastasis was detected in 12 (20 percent) of the patients, with a median latency of 31.5 months after diagnosis. Univariate analysis revealed that distant metastasis was associated with age of 45 years or greater, pathologically positive lymph nodes, extracapsular spread from lymph nodes, high-grade histology, and solid tumor subtype. Multivariate analysis revealed solid tumor subtype and extracapsular spread to be significantly associated with distant metastasis. Disease- specific survival rates at five and 10 years for patients with distant metastasis were 80 percent and 40 percent, respectively, and were both 100 percent for patients without distant metastases. The
authors concluded that although the majority of patients with clinical early stage ACC of the major salivary glands have a favorable prognosis, a significant percentage of patients will develop distant metastasis. Solid tumor subtype and nodal extracapsular spread were independent
predictors of distant metastasis in early stage ACC of major salivary glands. Other clinical and pathological variables may also contribute. These subgroups had poor overall and diseasespecific survival rates. Such patients should be observed closely for the development
of distant metastasis. Systemic therapy should be considered at the time of diagnosis.
Bhayani MK, Yener M, El-Naggar A, et al. Prognosis and risk factors for early-stage adenoid cystic carcinoma of the major salivary glands.
Cancer. 2012;118(11):2872–2873.

Histopathological features of Hashimoto’s thyroiditis relative to IgG4-related disease
A form of Hashimoto’s thyroiditis with lymphoplasmacytic sclerosing changes and increased numbers of IgG4-positive plasma cells has been
reported in the literature. These histopathological features suggest that this subtype of Hashimoto’s thyroiditis may be closely related to IgG4-related disease. Therefore, this unique form of IgG4-related Hashimoto’s thyroiditis, which is referred to as IgG4 thyroiditis, has its own clinical, serological, and sonographic features that are distinct from those associated with non-IgG4 thyroiditis. IgG4 thyroiditis shares similarities with the well-known fibrous variant of Hashimoto’s thyroiditis. However, the detailed histopathological features of IgG4 thyroiditis have not been well established. Based on immunostaining results, 105 patients with Hashimoto’s thyroiditis were divided into an IgG4 thyroiditis group (n=28) and a non-IgG4 thyroiditis group (n=77). As in the authors’ previous reports, IgG4 thyroiditis was associated with a patient population of a younger age, lower female-to-male ratio, rapid progression, higher levels of thyroid autoantibodies, subclinical hypothyroidism, and diffuse sonographic echogenicity. This group revealed severe lymphoplasmacytic infiltration, dense stromal fibrosis, marked follicular cell degeneration, numerous micro-follicles, and notable giant cell/histiocyte infiltration. The authors found that four cases (14 percent) in the IgG4 thyroiditis group presented only mild fibrosis in the stroma, whereas 29 cases (38 percent) in the non-IgG4 thyroiditis group met the diagnostic criteria for the fibrous variant of Hashimoto’s thyroiditis. Furthermore, the authors observed three patterns of stromal fibrosis in Hashimoto’s thyroiditis: interfollicular fibrosis, interlobular fibrosis, and scar fibrosis. The IgG4 thyroiditis group was significantly associated with the presence of predominant interfollicular fibrosis. The authors concluded that IgG4 Hashimoto’s thyroiditis presents histopathological features distinct from its non-IgG4 counterpart.
Li Y, Zhou G, Ozaki T, et al. Distinct histopathological features of Hashimoto’s thyroiditis with respect to IgG4-related disease. Mod Pathol. 2012;25(8):1086–1097.