RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Prevalence of Malignancy and Behavior Under Active Surveillance.

Background: Genomic profiling is now available for risk stratification of cytologically indeterminate thyroid nodules (ITNs). Mutations in RAS genes (HRAS, NRAS, KRAS) are found in both benign and malignant thyroid nodules, although isolated RAS mutations are rarely associated with aggressive tumors. Because the long-term behavior of RAS-mutant ITNs is not well understood, most undergo immediate surgery. In this multicenter retrospective cohort study, we characterize tumor growth kinetics of RAS-mutant ITNs followed with active surveillance (AS) using serial ultrasound (US) scans and examine the histopathologic diagnoses of those surgically resected. Methods: US and histopathologic data were analyzed retrospectively from two cohorts: (1) RAS-mutant ITNs managed with AS at three institutions (2010-2023) and (2) RAS-mutant ITNs managed with immediate surgery at two institutions (2016-2020). AS cohort subjects had ≥3 months of follow-up and two or more US scans. Cumulative incidence of nodule growth was determined by the Kaplan-Meier method and growth by ≥72% change in tumor volume. Pathological diagnoses for the immediate surgery cohort were analyzed separately. Results: Sixty-two patients with 63 RAS-mutated ITNs under AS had a median diameter of 1.7 cm (interquartile range [IQR] 1.2-2.6) at time of diagnosis. During a median AS period of 23 months (IQR 9.5-53.5 months), growth was observed in 12 of 63 nodules (19.0%), with a cumulative incidence of 1.9% (1 year), 23.0% (3 years), and 28.0% (5 years). Most nodules (81.0%) demonstrated stability. Surgery was ultimately performed in 6 nodules, of which 1 (16.7%) was malignant. In the cohort of 209 RAS-mutant ITNs triaged to immediate surgery, 33% were malignant (23.9% American Thyroid Association [ATA] low-risk cancers, 7.2% ATA intermediate-risk, and 1.9% ATA high-risk. During a median follow-up of 6.9 (IQR 4.4-7.1) years, there were no disease-specific deaths in these patients. Conclusions: We describe the behavior of RAS-mutant ITNs under AS and find that most demonstrate stability over time. Of the resected RAS-mutant nodules, most were benign; of the cancers, most were ATA low-risk. Immediate surgical resection of all RAS-mutant ITNs appears to be a low-value practice. Further research is needed to help define cases most appropriate for AS or immediate surgery.

Active Surveillance of Papillary Thyroid Cancer: Frequency and Time Course of the Six Most Common Tumor Volume Kinetic Patterns.

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8-20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively (p < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance.

The Milan System at Memorial Sloan Kettering: Utility of the categorization system for in-house salivary gland fine-needle aspiration cytology at a comprehensive cancer center.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) provides a standardized reporting system for salivary gland fine-needle aspiration (SGFNA). We review the clinical utility of the MSRSGC at a tertiary care cancer center by assessing the rates of malignancy (ROM) among different categories. METHODS: A retrospective search was performed to retrieve all SGFNA cases performed at our institution between 1/1/07 and 12/31/18. The initial primary diagnoses were recorded and cases were then assigned to appropriate MSRSGC categories. ROM was then calculated for all categories. RESULTS: A total of 976 cases were identified, and 373 with follow-up. The ROM was 19.7% (192/976) for all-comers and 51.3% (192/374) among cases with follow-up. Using MSRSGC, SGFNA showed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 65.6%, 87.4%, 100%, and 72.6%, respectively. ROM for MSRSGC categories I, II, III, IVa, IVb, V, and VI were 20.7%, 30.0%, 45.8%, 3.3%, 50.7%, 100%, and 100%, respectively. Utilizing MSRSGC resulted in a nondiagnostic rate of 14.4%. The nondiagnostic rate was lower when the procedure was performed by pathologists vs nonpathologists (12.9% vs 15.8%) but was comparable when rapid on site evaluation (ROSE) was performed (12.9% vs 11.6%). CONCLUSION: In our patient population, MSRSGC resulted in a perfect PPV and moderate NPV. Utilizing MSRSGC results in a higher nondiagnostic rate due to the inclusion of cases with benign elements or cyst contents only in this category. Performing ROSE is more important in attaining an adequate sample than the specialty of the person performing SGFNA.

Cytologic evaluation of p16 staining in head and neck squamous cell carcinoma in CytoLyt versus formalin-fixed material.

BACKGROUND: The management of high-risk human papillomavirus (HR-HPV)-related oropharyngeal head and neck squamous cell carcinomas (HNSCCs) are distinct from HNSCC linked to smoking and alcohol use. HR-HPV-positive HNSCC frequently presents as a cervical lymph node metastasis. Because fine-needle aspiration (FNA) is often the initial diagnostic procedure, evaluating HR-HPV status in cytology specimens is important. The overexpression of p16 is a surrogate for HR-HPV; however, the evaluation of p16 in FNAs remains controversial. METHODS: From September 2015 to December 2016, cytopathologists performed 25 FNAs of neck lymph nodes that were suspicious for HR-HPV-positive HNSCC. Initial passes produced smears for on-site evaluation and CytoLyt material. Additional passes were formalin-fixed. A CytoLyt cell block (CCB) and a formalin-fixed cell block (FFCB) were prepared, and p16 immunocytochemistry was performed. RESULTS: In 24 of 25 cases, the FFCB had diffuse (≥70% of cells), strong nuclear/cytoplasmic p16 staining. In all 24 of these cases, HR-HPV was detected by in situ hybridization. The corresponding CCB had weak-to-moderate p16 staining in <70% of cells (range, 5%-60% of cells) in 17 cases, 4 had weak-to-moderate diffuse staining, and 4 were acellular. The percentage of p16-positive cells was significantly higher with FFCB than with CCB (formalin: 94% ± 2%; CytoLyt, 38% ± 7%; 2-tailed, paired Student t test; P < .001; Fisher exact test, P < .001). CONCLUSIONS: The fixative used had a drastic impact on p16 staining, which explained the staining variability reported in the literature. FFCBs show a diffuse staining pattern, which correlates with HR-HPV status, whereas CCBs show a weaker and inconsistent staining pattern, which is more difficult to interpret.

Genomic comparison of paired primary breast carcinomas and lymph node macrometastases using the Oncotype DX Breast Recurrence Score® test.

PURPOSE: Adjuvant therapy decisions may in part be based on results of Oncotype DX Breast Recurrence Score® (RS) testing of primary tumors. When necessary, lymph node metastases may be considered as a surrogate. Here we evaluate the concordance in gene expression between primary breast cancers and synchronous lymph node metastases, based on results from quantitative RT-PCR-based RS testing between matched primary tumors and synchronous nodal metastases. METHODS: This retrospective, exploratory study included patients (≥ 18 years old) treated at our center (2005-2009) who had ER+ , HER2-negative invasive breast cancer and synchronous nodal metastases with available tumor blocks from both sites. Paired tissue blocks underwent RS testing, and RS and single-gene results for ER, PR, and HER2 were explored between paired samples. RESULTS: A wide distribution of RS results in tumors and in synchronous nodal metastases were modestly correlated between 84 paired samples analyzed (Pearson correlation 0.69 [95% CI 0.55-0.78]). Overall concordance in RS group classification between samples was 63%. ER, PR, and HER2 by RT-PCR between the primary tumor and lymph node were also modestly correlated (Pearson correlation [95% CI] 0.64 [0.50-0.75], 0.64 [0.49-0.75], and 0.51 [0.33-0.65], respectively). Categorical concordance (positive or negative) was 100% for ER, 77% for PR, and 100% for HER2. CONCLUSIONS: There is modest correlation in continuous gene expression, as measured by the RS and single-gene results for ER, PR, and HER2 between paired primary tumors and synchronous nodal metastases. RS testing for ER+ breast cancer should continue to be based on analysis of primary tumors.

Unilateral upper extremity lymphedema in metastatic prostate cancer.

Upper extremity lymphedema and cutaneous spread are atypical behavior of prostate disease and should be kept in the differential for selected patients. This presentation in these patients may be underdiagnosed and potentially an ominous sign. Our case adds to our continued learning of possible prostate malignancy behavior.

Clinical Experience With Mammary Ductoscopy.

BACKGROUND: Most breast cancers begin in the ductal epithelium with normal cells and progress to atypia and finally to carcinoma. Mammary ductoscopy enables one to directly visualize and sample the ductal epithelium and, therefore, identify early changes cytologically. This article describes our initial experience with mammary ductoscopy at Beth Israel Medical Center. METHODS: A prospective review of all patients who underwent ductoscopy at Beth Israel Medical Center from November 2001 to February 2004 was performed. The indications for ductoscopy were a persistent nipple discharge, high-risk status, or intraoperative margin assessment in patients undergoing lumpectomy. RESULTS: Seventy-four patients underwent ductoscopic evaluation of 88 ducts. Of the 32 patients who underwent office ductoscopy, 15 were high risk, and 17 had spontaneous nipple discharge. Spontaneous nipple discharge was the indication for ductoscopy in 40 of 42 intraoperative procedures. The remaining two patients underwent ductoscopy for margin assessment during breast conservation, and final pathologic analysis revealed negative margins. Thirty-eight of the 40 patients who had spontaneous nipple discharge had abnormal findings during ductoscopy and therefore underwent ductoscopically guided duct excision. Carcinoma was the final diagnosis in 5 (8.8%) of the 57 patients who were scoped for nipple discharge. CONCLUSIONS: Mammary ductoscopy is a potentially useful tool in the evaluation of patients with spontaneous nipple discharge. This is a well-tolerated office procedure with minimal risks and complications. Mammary ductoscopy may have a role in the assessment of high-risk women. Further research is necessary to confirm these potential applications.

A Case of Secondary Angiosarcoma of the Breast after Breast-conserving Surgery and Radiation: Review of Radiologic and Pathologic Findings.

Angiosarcoma of the breast is a rare and potentially life-threatening disease. It can present as a palpable mass or subtle erythematous lesion, depending on the predisposing clinical factors. Erythematous skin lesions may be confused for a benign process, which may lead to a delay in diagnosis. We present a case of an 80-year-old woman who developed secondary angiosarcoma after undergoing breast-conserving therapy for Stage IA breast cancer. In this article, we review our experience with a case of secondary angiosarcoma of the breast and discuss the presentation, evaluation, and treatment of this disease. This case demonstrates the importance of vigilance regarding erythematous or papular breast lesions in the setting of prior local radiation.

Mammary ductoscopy for evaluation of nipple discharge.

BACKGROUND: Most breast cancers originate in the ductal epithelium with normal cells progressing to atypia and finally to carcinoma. Ductoscopy enables one to visualize and sample the ductal epithelium and therefore identify early changes cytologically. This report describes our experience with mammary ductoscopy as a tool for evaluation of nipple discharge at Beth Israel Medical Center. METHODS: A prospective review of all patients who have undergone ductoscopy for evaluation of persistent nipple discharge was performed. The Acueity ductoscopy system with .9-mm scope and a video monitor with x60 magnification were used. Brush biopsy samples and lavage fluid were obtained from some patients and were sent for cytologic analysis. A subset of patients underwent ductoscopically guided duct excision. RESULTS: Ninety-three patients underwent ductoscopic evaluation of 110 ducts. Of these, 67 patients had abnormal findings and therefore underwent ductoscopically guided duct excision. The remaining 26 patients (28%) had normal ductoscopic examinations. The depth at which intraductal abnormalities were visualized was from 3 to 8 cm with an average of 4.4 cm for cancer cases and from 1 to 10 cm with an average of 4.5 cm for papillomas. Forty-two patients were diagnosed with papilloma/papillomatosis, six patients were diagnosed with atypical papilloma/atypical ductal hyperplasia/atypical lobular hyperplasia, and six patients were diagnosed with cancer. Of the six patients diagnosed with cancer, 67% had normal breast imaging, and other than nipple discharge, 67% had normal breast examinations. CONCLUSION: Mammary ductoscopy is a useful tool in the evaluation of patients with nipple discharge. Although the most common cause of nipple discharge is an intraductal papilloma, nipple discharge can be the presenting symptom for cancer. Our experience revealed a papilloma rate of 45% (42 of 93), cancer rate of 6.5% (6 of 93), and an atypia rate of 6.5% (6 of 93) among the patients with nipple discharge. Mammary ductoscopy allows for accurate visualization, analysis, and excision of intraductal abnormalities. Many deeper intraductal abnormalities could be missed by blind surgical excision.

Intraoperative touch preparation cytology for margin assessment in breast-conservation surgery: does it work for lobular carcinoma?

BACKGROUND: Breast carcinoma is the most frequently diagnosed malignancy in women of the North America. The combination of breast-conservation surgery and radiotherapy has become a standard of treatment for most breast cancers. It is critical to obtain clear margins to minimize local recurrence. The literature suggests that intraoperative touch preparation cytology (IOTPC) can be useful in evaluation of margins. Invasive lobular carcinoma (ILC) accounts for 10% to 15% of all breast cancers. Obtaining clear margins in ILC can be more challenging. Literature shows the positive margin rate for ILC to be as high as 60%. This report describes our experience with IOTPC for margin assessment in ILC by a single surgeon at Beth Israel Medical Center. The purpose of this study is to determine whether IOTPC is reliable for ILC. METHODS: A prospective review of 73 patients who underwent breast-conservation surgery with the use of IOTPC for margin assessment at Beth Israel Medical Center was performed. Pathology revealed ILC in 12 of these patients (16.4%), who are the subjects of this study. The lumpectomy specimens were oriented by the surgeon intraoperatively and were submitted fresh to pathology for cytologic assessment. IOTPC consisted of touching the corresponding margin onto the glass slide. The principle of this technique is that if cancer cells are present, they will stick to the slide, whereas fat cells will not. Six slides were prepared for each lumpectomy specimen. Air-dried samples were stained immediately by the Diff-Quik method and examined under the microscope by a cytopathologist. RESULTS: Twelve patients with ILC underwent breast-conservation surgery with IOTPC for assessment of 72 margins. Ten patients had lobular carcinoma only, and the remaining two patients had a combination of lobular and ductal carcinoma. There was a correlation between IOTPC and final pathology in 60 of 72 margins, which accounted for 83.3% of the cases. IOTPC for assessment of margins in patients undergoing breast-conservation surgery for ILC has a sensitivity of 8.3%, specificity of 98.3%, positive predictive value of 50%, and negative predictive value of 84.3%. CONCLUSIONS: On the basis of our experience, IOTPC is of limited value for intraoperative assessment of margins for ILC.

Intra-operative touch preparation cytology; does it have a role in re-excision lumpectomy?

OBJECTIVE: Breast carcinoma is the most frequently diagnosed malignancy in women of North America. The combination of breast conservation surgery and radiotherapy has become a standard of treatment for the majority of breast cancers. It is critical to obtain clear margins to minimize local recurrence. However, avoiding multiple re-excisions for margin clearance helps optimize cosmetic results in patients undergoing breast conservation surgery. Intra-operative touch preparation cytology (IOTPC) may decrease the need for multiple re-excisions and thereby improve cosmesis. The literature suggests that IOTPC can be useful in evaluation of margins. Klimberg et al. evaluated the touch preparation technique prospectively in 428 patients undergoing breast biopsy for undiagnosed breast masses. Margin evaluation was correct in 100% of the lesions and was used to re-excise the margins when touch prep results were positive. They reported a diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 100% for the touch prep technique. To the best of our knowledge, there has been no published data on the role of IOTPC for evaluation of margins in re-excision cases. This report describes our experience with IOTPC for margin assessment for re-excision partial mastectomy at Beth Israel Medical Center (BIMC). The purpose of this study is to determine whether IOTPC is reliable for evaluating margins in patients undergoing re-excision for involved or close margins. METHODS: A prospective study of 30 patients, who have undergone re-excision partial mastectomy for involved or close margins after breast conservation surgery with the use of IOTPC for margin assessment at BIMC was performed. The re-excision lumpectomy specimens were oriented by the surgeon intra-operatively and were submitted fresh to pathology for cytologic assessment. The touch prep method consisted of touching the corresponding margin onto the glass slide. The principle of this technique is that if cancer cells are present they will stick to the slide, while fat cells will not. A slide was prepared for each re-excision specimen. Air-dried samples were stained immediately using the Diff-Quik method and examined under the microscope by a cytopathologist. RESULTS: Thirty patients underwent re-excision lumpectomy for involved or close margins with touch preparation cytology for assessment of 68 margins. Twenty-six patients had invasive ductal carcinoma and/or ductal carcinoma in situ, three patients had invasive lobular carcinoma and the remaining one patient had a combination of invasive lobular and ductal carcinoma. There was a correlation between touch prep cytology and final pathology in 56/68 margins, which accounts for 82.4% of the cases. CONCLUSION: Intra-operative touch preparation cytology for assessment of margins in patients undergoing re-excision lumpectomy for involved or close margins has a sensitivity of 75%, specificity of 82.8%, positive predictive value of 21.4%, and negative predictive value of 98.2%. This high negative predictive value and a single false negative margin are quite significant. Therefore, based on our experience, IOTPC can be a useful tool for intra-operative assessment of margins for patients undergoing re-excision partial mastectomy.

Association of breast cancer with papillary lesions identified at percutaneous image-guided breast biopsy.

BACKGROUND: The management of papillary lesions identified on image-guided breast biopsy remains controversial. In the literature, data regarding papillary lesions are limited because of small sample sizes. The purpose of this study was to identify the prevalence of atypical ductal hyperplasia and malignancy associated with papillary lesions identified on image-guided breast biopsy. METHODS: This study is a retrospective review of 9,310 consecutive image-guided biopsies performed at our institution between January 1996 and November 2003. Patients were included if they underwent an excisional biopsy after a papillary lesion was diagnosed on image-guided biopsy. RESULTS: Papillary lesions were identified in 153 (2%) of the 9,310 image-guided biopsies performed, and 87 of these patients underwent subsequent excisional biopsy at our institution. Breast cancer (in situ or invasive) was identified in 15 patients (17%), and 16 patients (18%) had atypical ductal hyperplasia identified at excisional biopsy. CONCLUSIONS: These data suggest that excisional biopsy should be considered when a papillary lesion is identified at percutaneous image-guided breast biopsy. The final surgical pathology may impact the treatment plan, risk reduction, and/or surveillance for more than a third of patients diagnosed with a papillary lesion on image-guided biopsy.

Postlactational microcalcifications.

A case of postlactational microcalcifications is reported. A 42-year-old woman presented for screening mammography 2 months after completion of breast-feeding. Comparison to her pregravid screening mammogram revealed the appearance of multiple groups of indeterminate microcalcifications bilaterally (BIRADS IV). She underwent bilateral stereotactic core biopsies of representative areas, yielding benign pathology. There have been anecdotal accounts and five reported cases of lactational microcalcifications in the radiology literature. We discuss the possible etiologies as well as implications of this mammographic finding.

Malignant fibrous histiocytoma, giant cell type, of the breast mimicking metaplastic carcinoma. A case report.

BACKGROUND: We report a case of malignant fibrous histiocytoma, giant cell type (MFHGC), of the breast. A review of the literature failed to reveal cytology-based reports on this entity. The cytologic similarity of breast MFHGC on fine needle aspiration biopsy (FNAB) to other malignant breast neoplasms, including carcinoma with osteoclastlike giant cells, metaplastic carcinoma and breast sarcomas, as well as benign reactive processes, makes the recognition of this tumor challenging. CASE: A 72-year-old woman presented with a 5-month history of an enlarging breast mass. FNAB of the mass showed a hypercellular smear composed of cohesive, branching clusters of spindle cells with ovoid, focally hyperchromatic nuclei and inconspicuous nucleoli. Interspersed osteoclastlike giant cells, some associated with clusters of spindle cells, were uniformly seen throughout the smear. The background was hemorrhagic, with cellular debris and occasional spindle cells and lymphocytes. No ductal epithelial or myoepithelial cells were seen. An incisional biopsy was performed, followed by radical mastectomy. The histologic examination was diagnostic of MFHGC. The diagnosis was supported by immunohistochemical and electron microscopic studies. CONCLUSION: MFHGC, also called primary giant cell tumor of soft tissues, is composed of a mixture of histiocytes, fibroblasts and bland-appearing osteoclastlike giant cells with a multinodular growth pattern. Although MFHGC rarely occurs in the breast and the definitive diagnosis is difficult based on cytology alone, the diagnosis can be considered when a cytologic examination reveals a hypercellular, spindle cell smear with osteoclastlike giant cells in the absence of ductal epithelial or myoepithelial cells.

Cytology of primary central nervous system neoplasms in cerebrospinal fluid specimens.

Although two-thirds of tumors occurring in the central nervous system (CNS) are primary neoplasms, only 10% of positive cerebrospinal fluid (CSF) specimens are from primary CNS tumors. In this study, we reviewed the cytologic findings of 21 positive CSF specimens from primary CNS tumors. A computer search identified 21 cases of positive CSF specimens from patients with primary CNS tumors from the archives. Follow-up included review of medical charts and histologic correlation. The specimens were from 20 patients (9 females and 11 males). Their ages ranged from 6-83 yr, old with a mean of 30 yr. The cases included 9 medulloblastomas, 7 gliomas (3 glioblastoma multiformes, 2 anaplastic astrocytomas, and 2 ependymomas), 2 germinomas, 2 non-Hodgkin's large B-cell lymphomas, and 1 ganglioneurocytoma. Two cases were classified as suspicious and the remaining as positive for malignancy. Immunocytochemistry was employed in 3 cases to support the cytologic diagnosis. These cases included one large-cell lymphoma (leukocyte-common antigen-positive), one germinoma (placental alkaline phosphatase-positive), and the ganglioneurocytoma (neuron-specific enolase- and synaptophysin-positive). There were no false-positive cases. Our results suggest that positive CSF cytology in patients with a primary CNS tumor is a reliable indicator of malignancy and reflects leptomeningeal involvement. The use of immunocytochemistry is helpful in confirming the cytologic impression in some cases.