Base of the tongue hyalinizing clear cell carcinoma: Case report and literature review.

Hyalinizing clear cell carcinoma is an uncommon neoplasm arising in minor salivary glands. We present a rare case of hyalinizing clear cell carcinoma in the base of the tongue. We report a case of a 38-year-old female presented with a progressive history of hemoptysis and dysphagia over the course of 4 years. Examination revealed a mass originating from the base of the tongue with a biopsy confirmed as hyalinizing clear cell carcinoma . An Ovid MEDLINE and PubMed literature review was conducted due to the rarity of this type of tumor. The patient underwent surgical excision with immediate reconstruction with radial forearm free flap followed with adjuvant radiotherapy and was disease free at her most recent follow-up (12 months). Our review included a total of 13 new cases, including our case. The majority of the cases presented with dysphagia. Surgical excision is the mainstay of treatment, and overall these patients have a good prognosis. Our case highlights a rare presentation of hyalinizing clear cell carcinoma of the base of the tongue, successfully treated with surgical excision, free tissue reconstruction and adjuvant radiotherapy.

Glomangiosarcoma-like Anaplastic Transformation in Papillary Thyroid Carcinoma: A Novel Form of Heterologous Differentiation and a Systematic Review of Heterologous Element Prevalence.

Anaplastic thyroid carcinoma (ATC) demonstrates a wide variety of morphologies and is characteristically associated with a differentiated thyroid carcinoma component. Heterologous differentiation is a rare, potentially challenging phenomenon in ATC, mostly observed as osteosarcomatous or chondrosarcomatous differentiation. We now describe a novel 'glomangiosarcoma-like' differentiation, review our archival experience from two institutions (UPMC, CC), and perform a systematic review for the prevalence of heterologous elements in ATC. The patient is a 57-year-old female who presented with 4.5 cm left thyroid, and 3.4 cm neck masses. Histologically, the thyroid demonstrated a differentiated high grade papillary thyroid carcinoma, tall cell and hobnail/micropapillary subtypes transitioning into an anaplastic component with spindled to ovoid cells with hemangiopericytoma-like vasculature showing CD34 positivity, variable muscle marker expression and pericellular lace-like type IV collagen deposition. The neck mass consisted solely of the latter morphology. Targeted next-generation sequencing was performed on high grade DTC and adjacent ATC from the thyroid as well as ATC from the neck metastasis. All three components shared BRAFV600E, TERT promoter, and PIK3CA mutations confirming a clonal origin. Archival (UPMC: n = 150, CC: n = 74) and literature review showed no prior examples. Systematic review and meta-analysis of prevalence showed a baseline pooled prevalence (generalized linear mixed model) of heterologous elements of any type to be 1.6% (95% confidence interval: 1.0-2.6%) for studies where this was specifically addressed. ATC with glomangiosarcoma-like heterologous differentiation is a rarity among an already rare morphologic category with unique diagnostic pitfalls.

Negative Impact of COVID-19 Associated Health System Shutdown on Patients Diagnosed With Colorectal Cancer: A Retrospective Study From a Large Tertiary Center in Ontario, Canada.

Background: In March 2020, a directive to halt all elective and non-urgent procedures was issued in Ontario, Canada because of COVID-19. The directive caused a temporary slowdown of screening programs including surveillance colonoscopies for colorectal cancer (CRC). Our goal was to determine if there was a difference in patient and tumour characteristics between CRC patients treated surgically prior to the COVID-19 directive compared to CRC patients treated after the slowdown. Methods: CRC resections collected within the Champlain catchment area of eastern Ontario in the 6 months prior to COVID-19 (August 1, 2019-January 31, 2020) were compared to CRC resections collected in the 6 months post-COVID-19 slowdown (August 1, 2020-January 31, 2021). Clinical (e.g., gender, patient age, tumour site, and clinical presentation) and pathological (tumour size, tumour stage, nodal stage, and lymphovascular invasion) features were evaluated using chi-square tests, T-tests, and Mann-Whitney tests where appropriate. Results: Three hundred and thirty-eight CRC specimens were identified (173 pre-COVID-19, 165 post-COVID-19 slowdown). CRC patients treated surgically post-COVID-19 slowdown had larger tumours (44 mm vs. 35 mm; P = 0.0048) and were more likely to have presented emergently (24% vs. 10%; P < 0.001). Although there was a trend towards higher tumour stage, nodal stage, and clinical stage, these differences did not reach statistical significance. Other demographic and pathologic variables including patient gender, age, and tumour site were similar between the two cohorts. Interpretation: The COVID-19 slowdown resulted in a shift in the severity of disease experienced by CRC patients in Ontario. Pandemic planning in the future should consider the long-term consequences to cancer diagnosis and management.

Glial Fibrillary Acidic Protein Expression Helps Distinguish Pleomorphic Adenoma from Histologic Mimics.

Pleomorphic adenoma (PA) is the most common biphasic type of salivary gland tumour to arise in adults. It is a biphasic tumour composed of both luminal (ductal) cells and abluminal (basal and myoepithelial) cells. Other biphasic salivary gland type tumours, both benign and malignant, can mimic PA, especially on small biopsies. Previous studies have shown that glial fibrillary acidic protein (GFAP) is preferentially expressed in PA and can be useful in the distinction from other salivary gland tumours. However, most of these studies were performed on a small subset of tumour types at a time when the classification of salivary gland type tumours was less refined. The purpose of this study was to assess the expression of glial fibrillary acidic protein (GFAP) in a broad group of both benign and malignant salivary gland tumours. The expression of GFAP was assessed in 99 tumours including 54 PAs, 5 basal cell adenomas, 1 myoepitheliomas, 5 adenoid cystic carcinomas, 6 epithelial-myoepithelial carcinomas (EMCA), 6 mucoepidermoid carcinomas, 7 salivary duct carcinomas, 1 adenocarcinomas NOS, 2 myoepithelial carcinomas, 4 basal cell adenocarcinomas, 5 acinic cell carcinomas and 3 polymorphous adenocarcinomas. Of the malignant cases, 8 were classified as carcinomas ex PA. GFAP was also assessed in 19 concurrent biopsy specimens. GFAP was expressed in the resections of 51 PAs examined (94%). Expression was predominantly strong and diffusely seen in myoepithelial cells. Strong and diffuse GFAP expression was also seen in two EMCAs (33%) and one myoepithelial carcinoma (50%). On biopsy specimens, 100% of PAs and basal cell adenomas expressed GFAP. GFAP was also seen in 1 out of 3 carcinomas ex PAs on biopsies. Almost all PAs show strong and diffuse expression of GFAP. In contrast, most malignant neoplasms that can mimic PA on biopsies show only rare, focal expression. Other benign tumours composed of abluminal/myoepithelial cells also show focal expression of GFAP, highlighting the spectrum these tumours share with PA. Overall, the presence of strong and diffuse GFAP expression can favour a benign neoplasm, specifically a PA, on limited biopsy specimens.

Putting the patient at the centre of pathology: an innovative approach to patient education-MyPathologyReport.ca.

In many centres, patients now have access to their electronic medical record (EMR) and laboratory results, including pathology reports, are amongst the most frequently accessed pieces of information. The pathology report is an important but highly technical medical document that can be difficult for patient and clinicians alike to interpret. To improve communication and patient safety, pathologists are being called upon to play a more direct role in patient care. Novel approaches have been undertaken by pathologists to address this need, including the addition of patient-friendly summaries at the beginning of pathology reports and the development of patient education tools. MyPathologyReport.ca is a novel website exclusively providing pathology education to patients. It has been designed to help patients understand the language of pathology and to effectively navigate their pathology report. At present, the website includes over 150 diagnostic articles and over 125 pathology dictionary definitions. The diagnostic articles span all body sites and include a variety of malignant, benign and non-neoplastic conditions. Since its creation, this website has been visited over 14 000 times, with cancer-related diagnoses and definitions representing the most commonly accessed articles. This website has been embedded in patient accessible EMRs and shared through partnerships with patients, caregivers and their respective advocacy groups. Our next steps involve longitudinal assessment of MyPathologyReport.ca from non-medical community members, evaluation of patient satisfaction and understanding and further collaboration with hospitals and care-providers to increase patient access to this resource.

Metastasizing Pleomorphic Adenoma: Recurrent PLAG1/HMGA2 Rearrangements and Identification of a Novel HMGA2-TMTC2 Fusion.

Pleomorphic adenoma (PA) is the most common salivary gland neoplasm. On a molecular level PA is characterized by a translocation involving PLAG1 or HMGA2. PA is considered to be a benign tumor although it can undergo malignant transformation. Alternatively, cases of histologically benign PA "metastasizing" to lymph nodes or distant body sites are well documented. Several theories have been proposed to explain this behavior. However, there is a lack of molecular data available to assess the relationship of metastasizing PA (MPA) and their benign counterparts. In this study we describe 4 cases of MPAs and perform the first molecular study linking them to conventional PA. The index case was identified in the course of routine clinical practice, while the other cases were retrieved from the archives of the authors. Slides were reviewed to confirm the diagnosis of both the primary/recurrent tumor and the metastasis. Fluorescence in situ hybridization (FISH) was performed in all cases and RNA sequencing was performed on the index case. In all cases there was a history of recurrent PA involving the parotid. Lymph node metastases were identified in 2 cases; non-lymph node metastases were identified in 3 cases. All the metastases were histologically benign. RNA sequencing performed on the index case demonstrated a novel HMGA2-TMTC2 translocation, which was confirmed by separate FISH break-apart assays for both genes. FISH performed on the remaining cases demonstrated rearrangement of PLAG1 in all 3 cases. This study demonstrates that MPA harbors the same disease-defining molecular hallmark as their benign counterparts.

P53 Gene Mutation Identified by Next Generation Sequencing in Poorly Differentiated Neuroendocrine Carcinoma of the Nasal Cavity.

Neuroendocrine carcinomas (NECs) are epithelial neoplasms showing morphologic, immunophenotypic or ultrastructural evidence of neuroendocrine differentiation. The 2017 WHO Classification of Head and Neck Tumours classifies NECs into well, moderately and poorly differentiated NECs according to light microscopic features, mitotic rate and presence of tumour necrosis. In this study, we performed next generation sequencing (NGS) using a targeted 161 cancer gene panel on a poorly differentiated NEC of the nasal cavity. The tumour was composed of large cells arranged in poorly formed glands and solid nests. The mitotic count rate was 30/10 HPFs and p53 protein was strongly expressed in all tumour cells. NGS identified a missense mutation, c.764T > G (p.Ile255Ser) in the TP53 gene with an allele frequency of 85%. This mutation results in an isoleucine to serine substitution and a non-functional protein. No other mutations were identified. These results suggest that TP53 mutations may drive oncogenesis in poorly differentiated NECs of the head and neck.

Correction to: HPV DNA in saliva from patients with SCC of the head and neck is specific for p16-positive oropharyngeal tumours.

Following publication of the original article [1], the authors reported an error in one of the author names. In this Correction the incorrect and correct author names are listed.

Epstein-Barr Virus-Positive Large Cell Neuroendocrine Carcinoma of the Nasopharynx: Report of a Case with Complete Clinical and Radiological Response After Combined Chemoradiotherapy.

Neuroendocrine carcinomas of the head and neck are rare and are classified as well differentiated, moderately differentiated, and poorly differentiated carcinomas with the latter category being subdivided into small cell and large cell neuroendocrine carcinoma (LCNEC). While most carcinomas in the nasopharynx are associated with Epstein-Barr virus (EBV), there has been only one previous report demonstrating a link between EBV and LCNEC of the nasopharynx. In this report we describe a second case of EBV-positive LCNEC arising in the nasopharynx with bilateral cervical metastases. The patient was treated with a combination of radiation and chemotherapy which resulted in a complete clinical and radiological response. The patient is still disease free 3 years after presentation. The results of this case suggest that EBV-positive LCNEC is sensitive to chemoradiotherapy and as a result may have better prognosis than EBV-negative LCNEC arising in the nasopharynx or other sites.

Laryngeal Squamous Cell Carcinomas are Commonly Associated With Differentiated Squamous Intraepithelial Neoplasia With or Without an Admixture With Usual Type of Squamous Intraepithelial Neoplasia: Clinical and Pathologic Significance.

BACKGROUND: Differentiated squamous intraepithelial neoplasia (dSIN) is a pathway in the development of invasive squamous cell carcinoma (SCC) distinct from the usual-type squamous intraepithelial neoplasia (uSIN) and has not been described in the larynx. MATERIALS AND METHODS: Sixty-nine consecutive cases of SCC were identified which included 25 dSIN, 13 uSIN, and 31 mixed dSIN+usual-like SIN (u-like SIN) cases. RESULTS: dSIN was characterized by atypical squamous cells limited to the basal/parabasal layers and u-like SIN was characterized by cytologic atypia limited to less than full thickness. Despite the lack of neoplastic involvement of the full thickness of the epithelium, these types of SIN were commonly connected with invasive carcinoma. Prior biopsies demonstrating only dSIN, without the underlying invasive SCC, were underdiagnosed in 2 cases. Because of the frequent keratinization, u-like SIN likely represents the "keratinized dysplasia" and shows changes suggestive of dSIN with upward spread of neoplastic cells into the upper layer of the epithelium. CONCLUSIONS: Laryngeal dSIN represents an important but under recognized pathway of invasive SCC development. As moderate dysplasia of uSIN type are not associated with invasive SCC, labeling u-like SIN as dysplasia of grade 2 or 3 likely leads to the controversies in the current grading systems in the upper aerodigestive system and causes confusion for clinicians.

Chordoma of the Head and Neck: A Review.

Chordoma is a rare malignant bone tumor that can arise anywhere along the central neural axis and many involve head and neck sites, most commonly the skull base. The relative rarity of these tumors, combined with the complex anatomy of the head and neck, pose diagnostic challenges to pathologists. This article describes the pertinent clinical, pathologic, and molecular features of chordomas and describes how these features can be used to aid in formulating a differential diagnosis. Emphasis is placed on key diagnostic pitfalls and the importance of incorporating immunohistochemical information into the diagnosis.

HPV DNA in saliva from patients with SCC of the head and neck is specific for p16-positive oropharyngeal tumours.

BACKGROUND: Human papillomavirus (HPV) is an important cause of head and neck squamous cell carcinoma (HNSCC), especially in young people. These tumours overexpress p16 and respond well to treatment. The rapid detection of HPV in patients with HNSCC may expedite treatment when p16 status is not immediately available. METHODS: Saliva-based DNA collection kits and nested polymerase chain reaction (PCR) were used to determine the HPV status of 62 individuals with biopsy-proven HNSCC. Immunohistochemistry was used to determine tumour p16 status. RESULTS: A total of 62 patients were included in the study. Twenty-nine samples (47%) were positive for HPV DNA, the majority of which were high risk (HR) subtypes (79%). Patients who tested positive for HR HPV were more likely to have a tumour arising in the oropharynx compared to a non-oropharyngeal site (74 vs 26%; p = 0.003). A positive HR HPV saliva assay was 100% specific (95% CI 59-100%) and had a 100% positive predictive value (95% CI 75-100%) for a p16 positive tumour arising in the oropharynx. In contrast, a negative HR HPV assay had a 96% negative predictive value (95% CI 80-100%) for tumours arising in a non-oropharyngeal site. Independent of site, the saliva assay had a sensitivity of 77% (95% CI 54-91%) and a specificity of 94% (95% CI 77-99%), respectively, for a p16 positive tumour. CONCLUSION: We show that a saliva based assay is an effective method for detecting HPV in patients with HNSCC and that a positive HR HPV test is highly specific for p16 positive tumours arising in the oropharynx. This simple and rapid test could be used in cases where a biopsy of the primary tumour is not readily available.

INI1 (SMARCB1)-Deficient Sinonasal Carcinoma: A Clinicopathologic Report of 2 Cases.

Poorly differentiated sinonasal malignancies are amongst the hardest differential diagnoses in pathology, owing to the large number of rare entities that arise there. Complicating the matter is that most pathologists, including those with experience in head and neck pathology, have little experience in any one of these rare entities. Most patients with sinonasal carcinoma present with locally advanced disease and in the past a combination of chemotherapy, radiotherapy, and surgery would usually be recommended without the specific disease subtype playing a large part of the decision making. However, in the era of "precision medicine" and targeted therapies, the specific tumour subtype and an accurate diagnosis will become increasingly important even for the so-called "undifferentiated carcinoma". Specific entities that tend to enter into the differential diagnosis include olfactory neuroblastoma, sinonasal undifferentiated carcinoma (SNUC), and non-keratinizing squamous cell carcinoma (viral and non-viral). However, recent new entities, such as NUT-midline carcinoma also have to be considered. Recently it was found that a subset of tumours originally diagnosed as one of the aforementioned entities all demonstrated loss of the ubiquitously expressed protein Integrase Interactor 1 (INI1; SMARCB1). These tumours were often basaloid with at least partial rhabdoid differentiation and most were considered a part of the SNUC spectrum. In this report, we describe two additional cases of INI1-deficient sinonasal carcinoma prospectively identified, both of which appeared to have a marked response to neo-adjuvant chemoradiation, a finding not previously described.

GATA-3 expression is not associated with complete pathological response in triple negative breast cancer patients treated with neoadjuvant chemotherapy.

OBJECTIVE: The prognosis for patients with triple negative breast cancer (TNBC) is poor, however, a subset will demonstrate complete pathological response (pCR) to chemotherapy. GATA-3 and AR may be a negative predictors for pCR although it is unclear if these results apply to TNBC. METHODS: Patients diagnosed with TNBC and treated with neoadjuvant chemotherapy were identified. Immunohistochemistry was performed for GATA-3 and AR. Both were scored using a composite of staining intensity and percentage cells stained. The primary outcome was pCR. RESULTS: Twenty-four patients were included and 7 achieved pCR. There was no difference in the pre-chemotherapy tumor size (44±28mm vs. 54±30mm; p=0.764) or lymph node status (86% vs. 71%; p=0.629) between patients with and without pCR. GATA-3 expression was present in 20 cases (83%) while AR was present in 6 cases (25%). No AR expression was seen in 15 cases (63%) with GATA-3 positivity. There was no difference in either GATA-3 (4.3±2.7 vs. 3.6±2.5; p=0.549) or AR (1.4±2.5 vs. 1.1±2.4; p=0.778) expression between patients with and without pCR. CONCLUSIONS: GATA-3 expression is frequent in TNBC even in the absence of AR. However, neither GATA-3 nor AR are associated with pCR after neoadjuvant chemotherapy.

Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm; however, it is the most common cause of tumor-induced osteomalacia (TIO), a paraneoplastic syndrome characterized by renal phosphate wasting and hypophosphatemia. A subset of PMTs harbours an FGFR1 translocation although this alteration has not been demonstrated in PMT involving a head and neck site. We present a series of five PMTs involving the head and neck and demonstrate the diagnostic utility of fluorescence in situ hybridization (FISH) for detecting FGFR1 translocations. Patients' age and sex, tumor location, original diagnosis, the duration of symptoms, the presence of TIO, biochemical results, and medical management were reviewed. The median age at presentation was 45 (range, 24-58 years) and TIO was present in three cases. Four tumors involved soft tissue and one involved bone. Four out of the five tumors in our series were initially misdiagnosed. Three tumors were ultimately categorized as malignant PMT (two patients developed metastatic disease). FGFR1 translocation was present in two out of four cases and remained unknown in one case. In summary, we report on five cases of PMTs arising in the head and neck and confirm utility of FGFR1 FISH in the diagnosis of a subset of PMT.

Differentiated squamous intraepithelial neoplasia associated with squamous cell carcinoma of the anal canal.

AIMS: Differentiated squamous intraepithelial neoplasia (DSIN) has been described in several sites, including the upper aerodigestive tract and vulva, so this study investigated whether it also occurred in the anal canal. METHODS AND RESULTS: All cases of squamous cell carcinoma (SCC) involving the anal canal diagnosed between 2009 and 2015 at our institution were reviewed. Eighty-six cases were included, and 13 (15%) showed features consistent with DSIN: 10 were 'pure' DSIN, and three were 'mixed' DSIN and squamous intraepithelial lesion. DSIN was characterized by atypical keratinocytes limited to the basal/parabasal layers, acanthosis, and a 'cobblestone' appearance. Among specimens with pure DSIN, the surface was flat in eight cases. In five cases, the DSIN was extensive, and associated with deeply invasive SCC requiring radical surgical resection. Immunohistochemically, the epithelia showing changes consistent with DSIN were p16-negative, whereas the invasive component was p16-positive in 12 cases. Both Ki67 and p53 showed strong nuclear positivity in the basal/parabasal layers of DSIN. CONCLUSIONS: Invasive SCC associated with DSIN often presents at an advanced stage of disease, requiring radical surgical treatment. The neoplastic changes in DSIN are limited to the basal/parabasal layers, which may account for the negative diagnoses by anal cytopathology and late clinical diagnosis. The recognition of anal DSIN is important in order to avoid underdiagnosis in superficial biopsies.

Primary cutaneous adenoid cystic carcinoma with brain metastases: case report and literature review.

Primary cutaneous adenoid cystic carcinoma (ACC) is a rare skin tumor that is unlikely to metastasize. We present a case of primary cutaneous ACC in a 67-year-old male with axillary lymph node, pulmonary and brain metastases. To the best of our knowledge, this is the first reported case of cutaneous ACC with distant metastases to the brain.

Immunohistochemistry in the Diagnosis of Mucinous Neoplasms Involving the Ovary: The Added Value of SATB2 and Biomarker Discovery Through Protein Expression Database Mining.

Immunohistochemistry is frequently used to identify ovarian mucinous neoplasms as primary or metastatic; however, there is significant overlap in expression patterns. We compared traditional markers (CK7, CK20, CDX2, PAX8, estrogen receptor, ß-catenin, MUC1, MUC2, and MUC5AC) to 2 novel proteins identified through mining of the Human Protein Atlas expression database: SATB2 and POF1B. The study cohort included 49 primary gastrointestinal (GI) mucinous adenocarcinomas (19 colorectal, 15 gastric, 15 pancreatobiliary), 60 primary ovarian mucinous neoplasms (19 cystadenomas, 21 borderline tumors, 20 adenocarcinomas), and 19 metastatic carcinomas to the ovary (14 lower and 5 upper GI primaries). Immunohistochemistry was performed on tissue microarrays, scored and interpreted as negative (absent or focal/weak) or positive. Metastatic tumors were frequently unilateral (42.8% of tumors from lower and 40% of tumors from upper tract) and ≥10 cm (85.7% of tumors from lower and 80% of tumors from upper tract). CK7 was positive in 88.5% upper GI and 88.3% primary ovarian compared with 24.3% lower GI neoplasms. CK20 and CDX2 were positive in 84.8% and 100% of lower GI tumors, respectively; however, expression was also common in upper GI (CK20 42.8%, CDX2 50%) and primary ovarian neoplasms (CK20 65.7%, CDX2 38.3%). Conversely, SATB2 was more specific for lower GI origin, being positive in 78.8% lower GI but only 11.5% upper GI and 1.7% primary ovarian neoplasms. PAX8 expression was common in primary ovarian neoplasms (75% of all neoplasms, 65% of carcinomas); only 1 (1.5%) GI tumor was positive. MUC2 and ß-catenin were frequently positive in lower GI tumors (96.9% and 51.5%, respectively). Estrogen receptor expression was only seen in primary ovarian neoplasms (13.3%). Nuclear premature ovarian failure 1B (POF1B) expression was seen in malignant tumors regardless of their origin. A panel including CK7, SATB2, and PAX8 separated primary from secondary GI neoplasms with up to 77.1% sensitivity and 99% specificity, outperforming tumor laterality and size. Second-line markers such as CDX2, MUC2, estrogen receptor, MUC1, and ß-catenin increased the sensitivity of immunohistochemistry in excluding lower GI origin. Biomarker search using proteomic databases has a value in diagnostic pathology, as shown with SATB2; however, as seen with POF1B, expression profiles in these databases are not always reproduced in larger cohorts.

The Gross Appearance of a NUT Midline Carcinoma.

The NUT midline carcinoma (NMC) is a recently described and highly aggressive tumor that usually involves the head and neck and anterior mediastinum. Most patients with NMC present with metastases and are often treated with neoadjuvant chemotherapy and/or radiation therapy. As a consequence, surgical specimens are often piecemeal excisions demonstrating treatment effect. In this report, we provide what is to the best of our knowledge the first complete gross description of NMC resected in toto and without prior treatment. The patient in this case underwent a pneumonectomy for a lung mass with curative intent. On gross examination, the tumor was found to be arising from the mediastinum with a smooth border, and demonstrated only minimal invasion of the surrounding structures. However, lymphovascular invasion was present throughout and there was extensive involvement of surrounding lymph nodes. The gross appearance of the tumor in this case reaffirms that NMC is an aggressive malignancy that usually metastasizes before it invades locally.

Regressive change in high-grade ductal carcinoma in situ of the breast: histopathologic spectrum and biologic importance.

OBJECTIVES: High-grade ductal carcinoma in situ (HG-DCIS) of the breast often shows tumor attenuation and reactive fibrosis. These changes, previously described as "regressive," have been paradoxically associated with an increased risk of invasive carcinoma. We aimed to further characterize the spectrum of the so-called regressive changes (RCs) in HG-DCIS. METHODS: We reviewed 52 consecutive cases of HG-DCIS on biopsy specimens followed by excision. RCs were divided into early (stage 1) and advanced (stages 2 and 3) stages according to the degree of ductal fibrosis and tumor effacement. The presence of inflammation, hormone receptor status, and diagnosis on excision were recorded. RESULTS: RCs were seen in 51 (98%) cases: 96%, 76.4%, and 39.2% cases showed stages 1, 2, and 3, respectively. Periductal T cells with a normal CD4/CD8 ratio were constantly seen. Advanced RCs and inflammation were more frequent in estrogen and progesterone receptor-negative tumors. RCs were not associated with invasion but correlated with a larger residual HG-DCIS volume on excision. CONCLUSIONS: Regression in HG-DCIS is frequent. It may reflect a targeted immune response to certain phenotypes, mainly hormone receptor-negative lesions. Nonetheless, RCs do not lead to complete tumor obliteration but correlate with aggressive tumor characteristics instead.