High-grade Nuclear Features Research Articles

International medullary thyroid carcinoma grading system: an Indian tertiary care centre experience.

Medullary carcinoma (MTC) is a rare neuroendocrine thyroid neoplasm. The international medullary thyroid carcinoma grading scheme (IMTCGS), which has prognostic significance, has been introduced recently. The present study graded MTC cases using the IMTCGS and evaluated it in our study cohort. All MTC thyroidectomy cases over 6years were evaluated. Low-grade (LG) and high-grade (HG) were compared. Survival analysis included overall survival (OS), loco-regional free survival and distant metastasis free survival (DMFS). Of 32 cases, 31.25% were HG and 68.75% LG. The mean age was 44.0years and M:F ratio 1:1.146. HG patients were older and had tumour cells with high-grade nuclear features and prominent nucleoli and showed distant metastasis. Necrosis was found more in patients with high grade nuclear features. There was discordance between the high Ki67 (60%) and increased mitotic activity (20%). Univariate survival analysis revealed poor DMFRS and OS in the cohorts with high grade, Ki67 > 5% and coagulative necrosis. The multivariate cox regression analysis showed IMTCGS significantly associated with overall survival (HR 28.30, p = 0.009) and DMFS (HR 15.70, p = 0.02). This is the first Indian study evaluating IMTCGS, a very simple and convenient grading system that can be readily used in any tertiary health care centre. IHC for Ki 67 should mandatorily be done irrespective of the low mitotic activity on the HPE and necrosis should be diligently searched in cases with high-grade nuclear morphology. HG MTC cohorts were associated with poor OS as well as DMFRS.

Breast Carcinoma With Tubulopapillary Features Has a Distinct Immunophenotypic and Molecular Signature: A Report of Two Tumors and Literature Review.

Breast carcinoma with tubulopapillary features is a newly described entity associated with poor prognosis with only 14 tumors reported in the literature. We report 2 additional tumors and identify novel immunohistochemical and molecular features of the tumor. The first tumor was from a 72-year-old woman with nonmetastatic breast carcinoma and the second was from a 32-year-old woman with metastatic breast carcinoma who received neoadjuvant therapy. Both tumors had high-grade nuclear features with a distinctive morphology characterized by infiltrating open glands with intratubular papillary and micropapillary projections in >90% of the invasive carcinoma. In addition to the usual predictors of aggressive behavior, both tumors showed a high expression of p16 and SOX10, which has not been previously described. Targeted tumor sequencing revealed pathogenic variants of TP53 in both tumors, in agreement with previous reports. Prior studies have shown a correlation between p16 and SOX10 expression with high-grade features and worse prognosis; typically seen in triple-negative carcinomas as demonstrated in both of our tumors. However, not all reported tumors of breast carcinoma with tubulopapillary features have demonstrated a triple-negative profile as there are a few reports of tumors with estrogen receptor and/or human epidermal growth factor 2 expression. Due to their distinct morphologic and molecular characteristics, breast carcinoma with tubulopapillary features may represent a new breast cancer histologic subtype.

Collecting Duct Carcinoma of the Kidney

Purpose: Collecting duct carcinoma of the kidney (CDC) is an aggressive subtype of renal cell carcinoma with a dismal prognosis. The available knowledge concerning optimal management is still unclear. We report the largest single-institutional experience in the management of CDC. Materials and Methods: All the cases of CDC which were diagnosed at our center following a radical or partial nephrectomy in the past 15 years were included. Treatment details, radiological features, and histological features were reviewed. Descriptive statistics were used to show the clinicopathological profile and management of these patients, and Kaplan–Meier overall survival (OS) estimate was calculated. Results: Eighteen patients who were diagnosed and underwent the primary intervention at our center were included. The median age of patients was 40 years, with a male-to-female ratio of 5:1. Typical histopathological features included high-grade nuclear features, stromal desmoplasia, and tubular architecture. Surgery was the primary modality of treatment. Five (28%) patients who had metastases received adjuvant therapy, three received interferon-alpha therapy, and two received adjuvant chemotherapy with gemcitabine and cisplatin. The median follow-up was 19 months (range: 3–46 months). Kaplan–Meier OS estimate was 68% at 1 year and 48% at 3 years. Conclusion: CDC of the kidney often presents at an advanced stage, and has a poor prognosis. Survival remains poor despite surgery and adjuvant therapy.

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients

AbstractMost succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19–80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Collecting duct renal cell carcinoma: a single centre series and review of the literature.

Collecting duct, or Bellini duct, renal cell carcinoma (CDRCC) is a rare tumour, comprising only 0.4-2% of all renal cell carcinoma. The goal of this study was to evaluate the cases in our institution and look at current available literature. We searched all data on renal cell tumours in our institution between 2011 and 2021 and identified four cases with confirmed CDRCC pathology. Important features were listed and analysed. We also reviewed current available literature and compared it to our case series. All cases were men with a median age of 63.5 years. All were symptomatic at presentation. Two patients presented with flank pain and two with gross haematuria. Three patients had stage IV disease at time of presentation and one stage III disease. All cases had clear Bellini duct renal cell carcinoma appearance on microscopy with infiltrative tubular architecture and high-grade nuclear features. Immunohistochemic (IHC) staining was performed for diagnostic confirmation. Three patients underwent radical nephrectomy and received adjuvant chemotherapy. One case had kidney biopsy for diagnostic confirmation and received first line chemotherapy. Immunotherapy or tyrosine kinase inhibitor (TKI) were started for second, third or fourth line of treatment. Median overall survival after diagnosis was 11 months. CDRCC is a rare subtype of renal cell carcinoma with poor prognosis, typically presenting in a more advanced or metastatic stage. Diagnosis can be challenging. Multimodality treatment should be considered using radical surgery and systemic treatment.

Anaplastic Thyroid Carcinoma

A thyroidectomy was performed for a rapidly enlarging neck mass in a woman in her 70s. The tumor was diagnosed by pathology as an anaplastic thyroid carcinoma. Which of the following statements regarding anaplastic thyroid carcinoma is most accurate?a.Anaplastic thyroid carcinoma is a highly aggressive malignancy that usually occurs in persons in their second to third decade of life.b.Almost all anaplastic thyroid carcinomas occur in the setting of previous radiation to the neck.c.Anaplastic thyroid carcinomas are highly aggressive malignancies, usually fatal, and affect older persons.d.Anaplastic thyroid carcinomas may be associated with BRAF or RAS mutations but are not associated with TP53 or TERT promoter mutations. Answer: c. Anaplastic thyroid carcinomas are highly aggressive malignancies, usually fatal, and affect older persons. Anaplastic thyroid carcinoma is a highly aggressive thyroid malignancy composed of undifferentiated follicular thyroid cells. These tumors are uncommon, accounting for 1% of thyroid carcinomas in the United States.1Pereira M. Williams V.L. Hallanger Johnson J. Valderrabano P. Thyroid cancer incidence trends in the United States: association with changes in professional guideline recommendations.Thyroid. 2020; 30: 1132-1140Crossref PubMed Scopus (36) Google Scholar Anaplastic thyroid carcinoma usually affects older persons (seventh decade), often presenting as a rapidly enlarging mass that may be associated with compressive symptoms and, in some cases, paraneoplastic manifestations. Anaplastic thyroid carcinoma is generally lethal, and 56% of patients have lymph-node metastases and 38% distant metastases at presentation.2Hvilsom G.B. Londero S.C. Hahn C.H. et al.Anaplastic thyroid carcinoma in Denmark 1996-2012: a national prospective study of 219 patients.Cancer Epidemiol. 2018; 53: 65-71Crossref PubMed Scopus (12) Google Scholar The tumors are highly infiltrative, often have extrathyroidal growth, angiolymphatic invasion, and high-grade nuclear features. A variety of histologic subtypes of anaplastic thyroid carcinoma occur such as epithelioid, spindle cell/sarcomatoid, paucicellular, squamous, giant cell, rhabdoid/rhabdomyoblastic among others (Figures), making the differential diagnosis challenging in some cases. Approximately 10% of these tumors are associated with history of radiation exposure or iodine deficiency, respectively. Anaplastic thyroid carcinomas may occur with a previous or concurrent well-differentiated or poorly differentiated thyroid carcinoma.3Lam K.Y. Lo C.Y. Chan K.W. Wan K.Y. Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21.Ann Surg. 2000; 231: 329-338Crossref PubMed Scopus (132) Google Scholar,4Xu B. Fuchs T. Dogan S. et al.Dissecting anaplastic thyroid carcinoma: a comprehensive clinical, histologic, immunophenotypic, and molecular study of 360 cases.Thyroid. 2020; 30: 1505-1517Crossref PubMed Scopus (57) Google Scholar Anaplastic thyroid carcinomas are described as having “early” and “late” genetic alterations. Early driver mutations often involve BRAF V600E (especially in tumors associated with papillary thyroid carcinoma) or RAS and late mutations involve TP53 and TERT promoter.5Volante M. Lam A.K. Papotti M. Tallini G. Molecular pathology of poorly differentiated and anaplastic thyroid cancer: what do pathologists need to know?.Endocr Pathol. 2021; 32: 63-76Crossref PubMed Scopus (13) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Oncocytic features in salivary duct carcinoma, a potential pitfall for misdiagnosis as Warthin tumor in fine needle aspiration specimens: A cytomorphologic analysis of 14 cases.

Salivary duct carcinoma (SDC) is an uncommon and highly aggressive primary salivary gland neoplasm. Cytomorphologic features of SDC include cellular smears, nuclear atypia, prominent nucleoli, cribriform and papillary architecture, and background necrosis. The presence of oncocytic features has been described but not adequately characterized in the current literature. This study cohort consisted of 14 cases of histologically proven SDC with previous salivary gland fine needle aspiration (FNA). The cytologic material of each case was semi-quantitatively analyzed and evaluated for various cytomorphologic, architectural, and background features. Twelve SDCs were located in the parotid gland and two in the submandibular gland. In two cases the initial cytologic diagnoses was Warthin tumor or favor Warthin tumor. Moderate to marked degree of oncocytic changes were noted in all cases except one case. Nuclear atypia was variable with most cases exhibiting moderate to high-grade nuclear features, while four cases demonstrated low-grade nuclear cytomorphology. Cytoplasmic vacuolation was seen in nine cases and variable amount of background necrosis was observed in eight cases. Cribriform and papillary architecture was recognized in only six cases. Background lymphocytes were absent in all but one case. Precise diagnosis of SDC based on cytomorphologic features alone can be challenging. Oncocytic change is one of the most consistent features observed in this case series and when associated with less pronounced cytologic atypia, can potentially lead to misdiagnosis as Warthin tumor. SDC should be considered in the differential diagnosis of oncocytic salivary gland neoplasms where precise diagnosis is not possible.

2652 Primary Malignant Peripheral Nerve Sheath Tumor of Small Bowel and Colon Presenting With Metastases to Bone, Lung, Liver, Spleen, and Brain

INTRODUCTION: Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare diagnosis, with an incidence of 1:100,000 per year and 4–10% of soft tissue sarcoma, contains properties both neural crest cells and mesenchymal cells. Gastrointestinal MPNSTs are rare disease conditions with only 10 cases reported worldwide in the literature. CASE DESCRIPTION/METHODS: A 71-year old Portuguese male, presented with 8-week history of abdominal pain, anorexia with 20Ib weight loss. Vital signs were normal. On physical examination, a firm, tender, fixed abdominal mass in the RLQ was palpated. CT scan of the abdomen showed a 10 cm necrotic mass on the right side of the abdomen with communication to the small bowel was detected with a suggestion of a walled off perforation. Colonoscopy revealed a flattening of the terminal ileum suggesting an extrinsic compression. Biopsy of tumor consisting of mixed spindle and pleomorphic cells with focal rhabdoid features, high grade nuclear features and brisk mitotic activity. A week later, he presented with symptoms of small bowel obstruction, the CT scan at this time showed a 8 cm left sided abdominal mass with communication to the small bowel with dilation of the jejunum suggesting a new partial obstruction in addition. The patient underwent a palliative debulking of the tumor. Multiple large obstructive masses were found in the Ligament of Treitz,significant portion of the small bowel, right colon, left upper quadrant and omentum. For palliation purposes, these masses were resected and anastomosis was performed. Gross examination of the surgical specimens revealed grayish-tan cystic masses filled with brownish tan hemorrhagic material. Histology of the masses were similr to previous mass. On immunohistochemistry, showed patchy weak S100 immunoreactivity and focal BCL-2 and Neuron Specific Enolase stain immunoreactivity. Ki-67 proliferation index was 70%. The pathologic diagnosis of MPNST was established. He developed multiple bone, pulmonary, liver, splenic and hemorrhagic brain metastases. He died under hospice care within six months of his initial presentation. DISCUSSION: MPNST, occurs mostly in association with Neurofibromatosis Type 1 (8–13%). The tumor typically originates from the nerve sheaths of the major nerves in the extremities (40%), trunk/ retroperitoneal (38%) and head and neck region (21%). However, recent case reports have also documented MPNST of the liver, thyroid gland, skin, eighth cranial nerve and rarely the greater omentum without a history of radiation or NF1.

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant.

The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a "second hit." This case further underlines the close link between the "rhabdoid phenotype" and the SWI/SNF pathway.

CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression

Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases. Given our prior observation of trisomy 8 in these tumors, we assayed for amplification and expression of MYC (c-Myc) and representative downstream targets. Trisomy 8 was detected in 5/7 testable cases, with further amplification of MYC locus in 6/7 testable cases and immunohistochemical expression of MYC in 10/10. The canonical MYC transcriptional target, p21, but not MTDH, was differentially expressed compared with Ewing sarcomas. Given prior observation of induction of ETS-family transcription factors by the fusion oncoprotein, we assayed and identified highly prevalent positivity for ERG (9/10) and FLI1 (8/8). These findings are cautionary regarding use of these immunostains in prospective case workup, whereas the prevalent MYC amplification may represent a therapeutically targetable oncogenic pathway in CIC-DUX sarcomas.

Cytological features of pure micropapillary carcinoma of various organs: A report of eight cases.

Micropapillary carcinoma (MPC) is a rare aggressive tumor, which generally accompanies the primary carcinoma of the organ of its origin, while the pure form is extremely uncommon. Angiolymphatic involvement is widespread and a considerable proportion of the cases present with metastases. The current study presents eight pure MPC cases arising from the breast (n=3), urinary bladder (n=3), parotid gland (n=1) and lung (n=1, presenting with pericardial effusion), with the cytological findings. The eight patients included three female and five male cases aged between 48 and 74 years. The most common cytological findings were three-dimensional aggregates, cell clusters with angulated or scalloped borders, single cells with a columnar configuration and eccentric nuclei, and high-grade nuclear features. Histopathological sections showed accompanying in situ ductal carcinoma in the cases of MPC arising in the parotid gland and breast (n=3), and one case in the bladder exhibited only in situ MPC. The average follow-up period was 20 months (range, 6–54 months) and, during this period, three patients succumbed to the disease. At present, four patients are alive with disease and one patient is alive and disease-free. In conclusion, cytology is an important tool for the diagnosis and management of MPC.

Diagnostic criteria for ductal adenocarcinoma of the prostate: interobserver variability among 20 expert uropathologists

Ductal adenocarcinoma of the prostate (DAC) is clinically important, because its behaviour may differ from that of acinar adenocarcinoma. Our aims were to investigate the interobserver variability of this diagnosis among experts in uropathology and to define diagnostic criteria. Photomicrographs of 21 carcinomas with ductal features were distributed among 20 genitourinary pathologists from eight countries. DAC was diagnosed by 18 observers (mean 13.2 cases, range 6-19). In 11 (52%) cases, a 2/3 consensus was reached for a diagnosis of DAC, and in five (24%) there was consensus against. In DAC, the respondents reported papillary architecture (86%), stratification of nuclei (82%), high-grade nuclear features (54%), tall columnar epithelium (53%), elongated nuclei (52%), cribriform architecture (40%), and necrosis (7%). The most important diagnostic feature reported for DAC was papillary architecture (59%), whereas nuclear and cellular features were considered to be most important in only 2-11% of cases. The most common differential diagnoses were intraductal prostate cancer (52%), high-grade PIN (37%), and acinar adenocarcinoma (17%). The most common reason for not diagnosing DAC was lack of typical architecture (33%). Papillary architecture was the most useful diagnostic feature of DAC, and nuclear and cellular features were considered to be less important.

Perivascular Epithelioid Cell Neoplasm (PEComa) of the Gynecologic Tract

Perivascular epithelioid cell tumor (PEComa) belongs to a family of tumors characterized by coexpression of melanocytic and muscle markers. Recent studies have shown that sporadic and tuberous sclerosis complex-associated PEComa may respond to mTOR inhibitors underscoring the importance of recognizing this tumor. However, its occurrence in the gynecologic tract continues to be disputed owing to its common misclassification as other types of uterine sarcoma and its controversial relationship with epithelioid smooth muscle tumors. To more fully characterize PEComa of the female genital tract, 16 cases of gynecologic PEComa were identified (1990 to 2012) and formed the basis of this study. Each case was analyzed for conventional morphologic and immunohistochemical characteristics established for PEComa of extrauterine sites; clinical outcome data were obtained for all cases. The 16 patients were aged 28 to 60 (mean 49; median 50) years, and 1 had a history of tuberous sclerosis complex. Thirteen cases were primary of the uterus, 2 of the adnexa, and 1 of the vagina. Tumor size ranged from 0.3 to 25.0 (mean 8.7) cm. Three patients died of disease, 6 were alive with disease, and 7 were alive without evidence of disease at last follow-up (1 mo to 13 y follow-up; mean 26 mo). All patients with an adverse outcome met established criteria for malignancy as proposed for extrauterine sites (ie, 2 or more features present: size ≥5 cm, high-grade nuclear features, infiltration, necrosis, lymphovascular invasion, or a mitotic rate ≥1/50 high-power fields). Of the melanocytic markers, HMB45 was most commonly expressed (16/16 positive, 100%), followed by microphthalmia transcription factor (11/12 positive, 92%), MelanA (14/16 positive, 88%), and S100 protein (2/10 positive, 20%). Of the smooth muscle markers, desmin was most commonly expressed (15/15 cases, 100%), followed by SMA (14/15 cases, 93%) and h-caldesmon (11/12 cases, 92%). TFE3 immunopositivity was identified in 5 of 13 cases; however, 3 tested cases were negative for a TFE3 rearrangement by fluorescence in situ hybridization. Current criteria for malignancy appear to be valid in the female genital tract, although modified criteria, as described herein, may be more specific. Awareness of the characteristic features of PEComa is important to help distinguish it from epithelioid smooth muscle tumors and other mimics as PEComa may respond to unique chemotherapeutic regimens.

Abstract 2365: Defining the role of Akt activation in melanoma development and progression

Abstract We have developed a somatic cell gene delivery mouse model of human melanoma that allows for rapid validation of genetic alterations identified in this disease. A major advantage of this system is the ability to model the multi-step process of carcinogenesis in immune-competent mice using retroviral-mediated gene delivery. Mutant BRaf has been demonstrated to cooperate with Pten loss to induce metastatic melanoma in mice but the role of Akt in this context has not been evaluated. This is relevant because ∼60% of human melanomas contain amplification and activation of AKT. In this study, we evaluated the role of mutant Braf in melanoma initiation in the context of Ink4a/Arf loss and Akt activation. Ink4a/Arflox/lox mice expressing the viral receptor TVA specifically in melanocytes under control of the dopachrome tautomerase (DCT) promoter were crossed to Ptenlox/lox mice and mice carrying a conditional BrafV600E allele, which can be activated by Cre expression (BrafCA). Cohorts of newborn mice were injected subcutaneously with retroviruses containing Cre recombinase. Melanoma developed in 100% (8/8) of the DCT-TVA/BrafCA mice following Cre mediated Braf activation combined with Pten and Ink4a/Arf loss; median survival was 62 ± 6.7 days in this cohort. The incidence was reduced to 43% (6/14) if Pten was retained (Pten+/+ mice); median survival of tumor bearing mice in this group was 72 ± 6.7 days. Kaplan Meier survival analysis revealed a highly significant difference between these cohorts (P = 0.01). Interestingly, Akt expression could substitute for Pten loss in this context. Melanoma developed in 88% (15/17) of the DCT-TVA/BrafCA mice following viral delivery of activated Akt and Cre, which mediated Braf activation combined with Ink4a/Arf loss; median survival of tumor bearing mice in this group was 60 ± 6.6 days. Kaplan Meier survival analysis revealed that there was no significant difference between cohorts with Pten loss or Akt expression (P = 0.658). Expression of virally delivered Akt in the absence of Cre did not lead to tumor formation in control cohorts (0/7) and no uninfected mice developed melanoma (0/14). Histological examination of the tumors generated in the BrafCA mice with delivery of Cre and Akt viruses demonstrated that they were very similar to tumors lacking Pten. Importantly, the tumors were similar to human melanoma consisting primarily of short spindle cells exhibiting high grade nuclear features and prominent nucleoli. Mitotic figures were abundant, and some tumors possessed giant cells with epitheliod features. Occasional neoplasms exhibited regions of necrosis. Extensive lung metastases were evident following Pten loss or Akt expression, but not in tumors lacking activation of Akt, confirming a role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in melanoma progression and metastasis. Our ongoing experiments seek to further characterize the role(s) of the PI3K/AKT pathway in melanoma progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2365. doi:1538-7445.AM2012-2365

Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases.

Iatrogenic angiosarcomas (AS), following treatment of breast carcinomas and attributed to chronic lymphedema, were first described by Stewart and Treves. With emphasis on breast-conserving therapy combined with adjuvant radiation, a recently recognized form of cutaneous postradiation angiosarcoma of the breast (CPRASB) has emerged. To more completely characterize CPRASB, 27 cases were analyzed. Histologic features studied included pattern of growth (vasoformative, sieve-like, or solid), nuclear grade, necrosis, and mitotic rate. Clinical and follow-up information was obtained. The patients received relatively standard radiation treatment. The median interval to diagnosis of CPRASB was 59 months; 5 occurred in less than 3 years. Lymphedema was largely absent, and when present was only mild in nature. CPRASB was frequently multifocal at presentation (13 of 27). All tumors had a vasoformative pattern of growth; the majority (16 of 27) had areas with a sieve-like pattern. The solid pattern was less frequent (7 of 27). The majority had high-grade nuclear features (16 grade 3, 8 grade 2, 3 grade1). The mean mitotic rate was 9/10 HPF. Necrosis was rare (2 of 27). All were treated with wide excision or mastectomy. Follow-up was available on 22 of 27 cases (median 44 months). Fourteen experienced local recurrence and 6 had multiple recurrences. Metastasis was documented in 9 of 22 patients and involved lungs (6), contralateral breast (3), skeleton (2), lymph nodes (1), and soft tissue (1). Eight patients died of disease, 2 died with disease, 4 were alive with disease, and 8 are alive without disease. The median interval to death was 33.5 months. All 4 patients with disease have documented metastasis. CPRASB differs from Stewart-Treves AS by its shorter latency period and lack of association with lymphedema.

Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance.

An invasive micropapillary component has been described in tumors of several organs and is nearly always associated with aggressive biologic behavior. We present 14 cases of salivary duct carcinoma (SDC) with an invasive micropapillary component (invasive micropapillary SDC) and compare the clinicopathologic findings of these cases with those of cases of conventional SDC. The mean age of the 14 patients (10 men, 4 women) was 65.8 years (range, 26-80 years). The mean size of the tumors was 2.4 cm (range, 1.3-5 cm). The parotid gland was involved in 12 patients and the submandibular gland in 2. Histologically, all tumors had an invasive micropapillary architecture admixed with features typical for SDC. Invasive micropapillary carcinoma was characterized by morula-like small cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells exhibited moderate- to high-grade nuclear features, conspicuous nucleoli, and eosinophilic cytoplasm. This component was distributed diffusely in 9 tumors and focally in 5. Angiolymphatic and perineural invasion was seen in all tumors. A residual pleomorphic adenoma was detected in four tumors. Of the 12 tumors examined, all were diffusely positive for cytokeratin 7 and epithelial membrane antigen (with a distinctive "inside-out" pattern) but negative for cytokeratin 20. Tumors were frequently immunoreactive for BRST-2 (gross cystic disease fluid protein-15) and androgen receptor protein. Aberrant expression of HER-2/neu or p53 was detected in seven tumors each. The mean Ki-67 labeling index was 33.1% (range, 6.3%-61.6%). All 14 patients with invasive micropapillary SDC had cervical or periglandular lymph node metastasis, and this value was significantly higher than for conventional SDCs. Local recurrence developed in 4 patients and distant metastatic disease in 9. Clinical follow-up (mean, 25.5 months) was available for 13 patients: 9 died of disease within 24 months after the diagnosis (mean, 17.6 months), 1 was alive with metastatic disease at 19 months, and 3 were free of disease. Overall survival of these patients with invasive micropapillary SDC was significantly shorter than that of patients with conventional SDC (n = 49) in our series (P = 0.031). Our results suggest that invasive micropapillary SDC is a distinct, aggressive variant of SDC, with a propensity for extensive lymph node metastasis and rapid disease progression.

Pleomorphic lobular carcinoma: morphology, immunohistochemistry, and molecular analysis.

Infiltrating pleomorphic lobular carcinoma (PLC) is an aggressive variant of infiltrating lobular carcinoma. Recently, in situ changes identical to PLC (PLCIS) have been described. The role of prognostic markers and their correlation with therapeutics, clinical outcome, and genetic changes is not well established in PLC. The authors examined 38 cases of this entity to understand better this tumor's biology. Immunohistochemical (IHC) analysis was performed in 21 specimens for estrogen and progesterone steroid receptors, p53, Her 2 (p185), and GCDFP-15. Genomic deoxyribonucleic acid was obtained from microdissected tumor as well as normal control cells, and loss of heterozygosity was investigated at the ESR (16q24), p53 (TP53 17p), Her 2 (17q 11-12), and BRCA 1 (17q12-25) loci. In this series, the average patient age was 57.5 years (age range, 24-92 years). Twenty-seven women were postmenopausal. Tumor size ranged from 1.2 to 25 cm. Six patients were a pathologic stage I; 19, stage II; 12, stage III; and one, stage IV. Histologically, multifocal nodular aggregates of discohesive pleomorphic tumor cells were seen interspersed in dense and fibrotic breast parenchyma. Twenty-nine percent of the specimens demonstrated associated signet ring cells. The remainder had dishesive, globoid, plasmacytoid cells with high-grade nuclear features. PLCIS was identified in 17 of 38 patients (45%), and lobular carcinoma in situ (LCIS) was noted in 8 patients (21%). IHC analysis showed estrogen immunoreactivity in 81%, progesterone in 67%, GCDFP-15 in 71%, and Her 2 in 81% (2+ to 3+ membranous staining) of specimens. Antibodies to p53 stained the tumor cell nuclei in 48% of the tumors. Loss of heterozygosity was identified in 52% of the specimens at the p53 locus, 18% at the ESR locus, 19% to 24% at the Her 2 loci, and 27% to 32% at the BRCA 1 locus. Follow-up was available in 19 patients and ranged from 12 months to 15 years (mean, 73 months). Seven patients had no evidence of disease at last examination (range, 1-15 years), three patients were alive with disease (range, 2-14 years), and nine patients were dead of disease (range, 2 months-9 years). Six patients had subsequent diagnoses of tumor in the contralateral breast. Analysis shows that PLC tends to appear in older postmenopausal women who present with locally advanced disease. PLCIS was found to be associated with PLC 45% of the time. The aggressive clinical course of patients with PLC is supported by tumor immunoreactivity with unfavorable markers Her 2 and p53. Overexpression of Her 2 in PLC may be therapeutically relevant, enabling the use of novel chemotherapeutic drugs like Herceptin. Interestingly, tumors that were Her 2 immunoreactive also maintained estrogen hormone immunoreactivity.