18F-FDG and 18F-Fluciclovine Uptake in Poorly Differentiated Lung Adenocarcinoma in the Setting of Biochemically Recurrent Prostatic Adenocarcinoma.

ABSTRACT: A 64-year-old man with a history of Gleason 7 (3 + 4) pT2cN0 prostatic adenocarcinoma status post prostatectomy underwent a fluciclovine PET/CT that showed a tracer-avid right upper lobe spiculated solitary pulmonary nodule. Follow-up FDG PET/CT showed a hypermetabolic right upper lobe spiculated solitary pulmonary nodule. Fine-needle aspiration was consistent with primary lung adenocarcinoma. Subsequently, right upper lobectomy was performed, and poorly differentiated lung adenocarcinoma was confirmed.

Glomangiopericytoma of the sphenoethmoid complex.

Sinonasal glomangiopericytoma is a rare sinonasal tumour accounting for less than. 5% of all sinonasal tumours. This tumour often presents as another, more common type of vascular lesion and is similarly prone to haemorrhage. The optimal treatment includes complete surgical resection. We, herein, present two such cases adding to the world literature of this rare tumour.

Upgrade rate of intraductal papilloma without atypia on breast core needle biopsy: A clinical, radiological and pathological correlation study.

BACKGROUND: The aim of the study was to determine the upgrade rate on excision of intraductal papilloma (IDP) without atypia diagnosed on breast core needle biopsy (CNB). METHODS: We searched our pathology department database for breast CNB with a diagnosis of IDP from 2013 to 2018. The exclusion criteria included radiologic-pathologic discordance, atypia on the same CNB, absence of histologic slides to review or absence of excision information. Upgrade was defined as ductal carcinoma in situ (DCIS) or invasive cancer identified on excision. RESULTS: 126 IDP without atypia cases from 94 patients were identified. The upgrade rate was 1.58% (2/126). Both upgrade cases showed DCIS with low and intermediate nuclear grade. Histologic size of IDP ≥1 cm was the only statistically significant predictor factor for an upgrade on excision. CONCLUSION: The results suggest that non-surgical management of patients with radiologic-pathologic concordant IDP without atypia diagnosed on CNB may be appropriate in routine practice.

A 58-Year-Old Woman With Back Pain and an Unusual Diagnosis.

CASE PRESENTATION: A 58-year-old postmenopausal woman presented to her primary care physician with lower back pain. She denied respiratory symptoms. Her medical history is significant for hypertension, hyperlipidemia, and prediabetes. Her surgical history consists of a tonsillectomy and a remote dilatation and curettage procedure. She denied a history of smoking, alcohol use, or recreational drug use. A review of systems was otherwise negative.

Expression of GATA-3 in Testicular and Gynecologic Mesothelial Neoplastic and Non-neoplastic Tissues.

GATA-3 expression in testicular/gynecologic mesothelial neoplasms and benign mesothelia have not been completely investigated. We graded GATA-3, calretinin, and WT1 staining in 20 adenomatoid tumors [9/20 (para)testicular and 11/20 tubal/uterine] and 38 normal mesothelia (20/38 tunica vaginalis and 18/38 fallopian tubes) as either 0 (≤5%), +1 (>5% and <25%), +2 (≥25% and ≤50%), and +3 (>50%). Adenomatoid tumor GATA-3 staining: 2 urologic cases were positive (2/9, +3 and +1), no gynecologic cases were positive (0/11), and all were positive for WT1/calretinin (20/20,+2 to +3). The normal tunica vaginalis mesothelia: 3 of 20 were GATA-3 positive (+2) while 20 of 20 were WT1/calretinin (+2 to +3) positive. The gynecologic cases with walthard nests: are positive for GATA-3 (18/18,+3), WT1 (11/18, +2 to +3), and calretinin (1/18,+2). The nonmetaplastic gynecologic mesothelia were GATA-3 negative (18/18) and WT1/calretinin postive (18/18,+2 to +3). All 18 epididymi were GATA-3 positive (+3) and negative for WT1/calretinin. All 11 efferent ductules examined were negative for GATA-3, WT1/calretinin (0/11). Although GATA-3 rarely stains adenomatoid tumors, gynecologic walthard nests are consistently positive with GATA-3 staining but lose mesothelial markers reflecting a metaplastic change. Excluding the walthard nests, GATA-3 is rarely positive in normal urologic and gynecologic mesothelia. GATA-3 is uniformally positive in epididymi and negative in efferent ductules, which may be due to their embryological evolvement. Awareness of the GATA-3 staining patterns in the genitourinary and gynecologic mesothelial tissues and their respective neoplasms is important to prevent misdiagnosis and possible unnecessary interventions.

Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon.

Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAFV600E-positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases.

Cancer-Associated Mutations in Endometriosis without Cancer.

BACKGROUND: Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS: We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS: Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS: We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

Molecular Testing in Multiple Synchronous Lung Adenocarcinomas: Case Report and Literature Review.

Discovery of driver mutations in pulmonary adenocarcinoma has revolutionized the field of thoracic oncology with major impact on therapy and diagnosis. Testing for EGFR, ALK, and KRAS mutations has become part of everyday practice. We report a case with multiple synchronous primary pulmonary adenocarcinomas in a 72-year-old female with previous history of smoking. The patient presented with cough and bilateral lung ground glass opacities. A positron emission tomography/computed tomography scan showed no activity in mediastinal lymph nodes. She underwent a left upper lobe biopsy and a right upper lobe wedge resection. Pathology revealed 4 morphologically distinct adenocarcinoma foci, suggestive of synchronous primary lung tumors. Molecular testing demonstrated no mutation in the left tumor. Three different driver mutations were present in the right lung tumors: KRAS codon 12 G12D and G12V and EGFR exon 21 L858R mutation, confirming the initial histologic impression. Subsequently, left upper lobe lobectomy showed 3 additional foci of adenocarcinoma with different morphologies, suggestive of synchronous primaries as well. No additional molecular testing was performed. Synchronous pulmonary adenocarcinomas are not uncommon; however, 4 or more synchronous tumors are rare. Distinguishing multiple primary tumors from intrapulmonary metastases is a common problem in thoracic oncology with major implications for staging, prognosis, and treatment. Lung adenocarcinoma subclassification based on predominant and coexisting histologic patterns can greatly facilitate differentiation between intrapulmonary metastases and multiple synchronous tumors. Use of molecular profiling is recommended since it further increases confidence in the diagnostic workup of multiple pulmonary adenocarcinomas and helps guiding therapy.

Immunohistochemical staining with EGFR mutation-specific antibodies: high specificity as a diagnostic marker for lung adenocarcinoma.

We previously demonstrated a high specificity of immunohistochemistry using epidermal growth factor receptor (EGFR) mutation-specific antibodies in lung adenocarcinoma and correlation with EGFR mutation analysis. In this study, we assessed EGFR mutation status by immunohistochemistry in a variety of extrapulmonary malignancies, especially those that frequently show EGFR overexpression. Tissue microarrays containing triplicate cores of breast carcinomas (n=300), colorectal carcinomas (n=65), pancreatic adenocarcinoma (n=145), and uterine carcinosarcoma or malignant mixed müllerian tumors (n=25) were included in the study. Tissue microarray of lung adenocarcinoma with known EGFR mutation status was used as reference. Immunohistochemistry was performed using antibodies specific for the E746-A750del and L858R mutations. In pulmonary adenocarcinoma, a staining intensity of 2+ or 3+ correlates with mutation status and is therefore considered as positive. Out of 300 breast carcinomas, 293 (98%) scored 0, 5 (2%) had 1+ staining, 2 (1%) were 2+ for the L858R antibody. All breast carcinomas scored 0 with the E746-A750 antibody. All the colorectal, pancreatic carcinomas and malignant mixed müllerian tumors were negative (0) for both antibodies. Molecular analysis of the breast carcinomas that scored 2+ for L858R showed no mutation. Our results show that EGFR mutation-specific antibodies could be an additional tool distinguishing primary versus metastatic carcinomas in the lung. False-positivity can be seen in breast carcinoma but is extremely rare (1%).

Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas.

The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

Molecular characterization by immunocytochemistry of lung adenocarcinoma on cytology specimens.

The discovery of targetable driver mutations in pulmonary adenocarcinoma has revolutionized the field of thoracic oncology by the introduction of oral small molecule tyrosine kinase inhibitors that target specific EGFR mutations and EML-4/ALK rearrangement. Therefore, testing for EGFR gene mutations and ALK rearrangements has become part of everyday clinical practice. The majority of lung cancer patients present at an advanced stage, where small biopsy and cytology specimens are often the only available material for diagnostic workup and molecular characterization. Mutation testing has become the standard of care. Nonetheless, the technical complexity and relative high cost of the test have challenged the widespread use of molecular techniques in everyday clinical settings. Recently, antibodies to specific molecular alterations have become available and have the potential to become instruments for the molecular characterization of tumors. In this review article we will discuss practical issues in molecular characterization of lung adenocarcinoma on cytology material and the use of immunocytochemical stains for the detection of mutant protein as an alternative or adjunct to molecular techniques.

Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.

BACKGROUND: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist. We conducted a systematic search for tyrosine kinase fusions by screening all tyrosine kinases for aberrantly high RNA expression levels of the 3' kinase domain (KD) exons relative to more 5' exons. METHODS: We studied 69 patients (including five never smokers and 64 current or former smokers) with lung adenocarcinoma negative for all major mutations in KRAS, EGFR, BRAF, MEK1, HER2, and for ALK fusions (termed "pan-negative"). A NanoString-based assay was designed to query the transcripts of 90 tyrosine kinases at two points: 5' to the KD and within the KD or 3' to it. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3' to 5' expression ratios. Presumed novel fusion events were studied by rapid amplification of cDNA ends (RACE) and confirmatory reverse transcriptase PCR (RT-PCR) and FISH. RESULTS: We identified one case each of aberrant 3' to 5' ratios in ROS1 and RET. RACE isolated a GOPC-ROS1 (FIG-ROS1) fusion in the former and a KIF5B-RET fusion in the latter, both confirmed by RT-PCR. The RET rearrangement was also confirmed by FISH. The KIF5B-RET patient was one of only five never smokers in this cohort. CONCLUSION: The KIF5B-RET fusion defines an additional subset of lung cancer with a potentially targetable driver oncogene enriched in never smokers with "pan-negative" lung adenocarcinomas. We also report in lung cancer the GOPC-ROS1 fusion originally discovered and characterized in a glioma cell line.

Use of mutation specific antibodies to detect EGFR status in small biopsy and cytology specimens of lung adenocarcinoma.

BACKGROUND: EGFR mutation status is the best predictor of response to tyrosine kinase inhibitors (TKIS) in primary lung adenocarcinoma. Approximately 70% of lung cancers are diagnosed in advanced stages where small biopsies and cytological specimens are the only source of material for both diagnosis and mutation testing. Specific antibodies that can detect mutant EGFR protein were evaluated for the detection of EGFR mutation by immunohistochemistry (IHC) in cytology and small biopsy specimens. METHODS: Assessment of EGFR mutation status was performed by using antibodies specific to the two major forms of mutant EGFR, exon 21 L858R and exon 19 deletion (15bp). The study was performed in 145 lung adenocarcinomas, including cytology material, core biopsy, and decalcified bone biopsy. Stains were scored as negative (0), 1+ (weak and focal), 2+ (moderate intensity and focal), and 3+ (strong and diffuse). The result of the IHC stains was correlated with mutations status determined by standard molecular methods. RESULTS: Validation using clinical material showed deletions in exon 19 were detected in 35% and L858R mutation in 17.6% of all cases by standard molecular methods. A cutoff value of 2+ was used as positive by IHC. No wild type cases were immunoreactive. The positive predictive value (PPV) and specificity for both antibodies was 100%. The antibodies performed well in cytology, core biopsies and decalcified bone biopsies. CONCLUSION: Immunostaining to detect specific mutant EGFR shows a good correlation with mutation analysis and can be used as a screening method to identify patients for TKI therapy. IHC methodology is potentially useful when molecular analysis is not available and for use in small biopsies when material is too scant for molecular tests. Importantly mutation specific antibodies are useful in determining EGFR status in tissues obtained from bone biopsy as decalcification processes used in molecular based studies often result in DNA degradation hindering mutation detection.

Advances in fine needle aspiration cytology for the diagnosis of pulmonary carcinoma.

New developments in the field of thoracic oncology have challenged the way pathologists approach the diagnosis of pulmonary carcinoma. Nonsmall cell carcinoma is no longer an adequate diagnostic category. Pathologists are required to further classify tumors into adenocarcinoma and squamous cell carcinoma since specific therapies are now recommended depending on the histological tumor type. This change occurred following the discovery of specific molecular alterations that predict response to certain drugs and now molecular testing of tumor cells is often requested to direct therapy. The vast majority of lung cancer is diagnosed in advanced clinical stages, where cytologic or small biopsy material is the only form of tissue diagnosis, thus placing cytology, especially fine needle aspiration biopsy in the front line for management of patients with lung cancer. In this paper we will review the current concepts in the suitability and accuracy of fine needle aspiration biopsy, including diagnosis, classification, prognostic markers, and use of ancillary techniques.