Navigating HER2-Low Testing in Invasive Breast Cancer: Update Recommendations for Pathologists.

The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma.

Desmoplastic stroma (DS) and the epithelial-to-mesenchymal transition (EMT) play a key role in pancreatic ductal adenocarcinoma (PDAC) progression. To date, however, the combined expression of DS and EMT markers, and their association with variations in survival within each clinical stage and degree of tumor differentiation is unknown. The purpose of this study was to investigate the association between expression of DS and EMT markers and survival variability in patients diagnosed with PDAC. We examined the expression levels of DS markers alpha smooth muscle actin (α-SMA), fibronectin, and vimentin, and the EMT markers epithelial cell adhesion molecule (EPCAM), pan-cytokeratin, and vimentin, by immunohistochemistry using a tissue microarray of a retrospective cohort of 25 patients with PDAC. The results were examined for association with survival by clinical stage and by degree of tumor differentiation. High DS markers expression -α-SMA, fibronectin, and vimentin- was associated with decreased survival at intermediate and advanced clinical stages (p=0.006-0.03), as well as with both poorly and moderately differentiated tumor grades (p=0.01-0.02). Interestingly, the same pattern was observed for EMT markers, i.e., EPCAM, pan-cytokeratin, and vimentin (p=0.00008-0.03). High expression of DS and EMT markers within each clinical stage and degree of tumor differentiation was associated with lower PDAC survival. Evaluation of these markers may have a prognostic impact on survival time variation in patients with PDAC.

A Novel, Likely Pathogenic MAX Germline Variant in a Patient With Unilateral Pheochromocytoma.

CONTEXT: Inherited MYC-associated factor X (MAX) gene pathogenic variants (PVs) increase risk for pheochromocytomas (PCCs) and/or paragangliomas (PGLs) in adults and children. There is little clinical experience with such mutations. OBJECTIVE: This report highlights an important approach. METHODS: Clinical assessment, including blood chemistry, imaging studies, and genetic testing were performed. RESULTS: A 38-year-old Hispanic woman was diagnosed with PCC in 2015, treated with adrenalectomy, and referred to endocrinology clinic. Notably, she presented to her primary care physician 3 years earlier complaining of left flank pain, intermittent diaphoresis, and holocranial severe headache. We confirmed severe hypertension (180/100 mm Hg) over multiple antihypertensive regimens. Biochemical and radiological studies workup revealed high plasma metanephrine of 255 pg/mL (normal range, < 65 pg/mL) and plasma normetanephrine of 240 pg/mL (normal range, < 196 pg/mL). A noncontrast computed tomography scan of the abdomen revealed a 4.2 × 4.3 × 4.9-cm, round-shaped and heterogenous contrast enhancement of the left adrenal gland, and a 2-mm nonobstructive left kidney stone. A presumptive diagnosis of secondary hypertension was made. After pharmacological therapy, laparoscopic left adrenalectomy was performed and confirmed the diagnosis of pheochromocytoma. Based on her age, family history, and a high suspicion for genetic etiology, genetic testing was performed that revealed the presence of a novel likely pathogenic variant involving a splice consensus sequence in the MAX gene, designated c0.64-2A > G. CONCLUSION: The phenotype of MAX PV-related disease and paraganglioma are highlighted. The novel c0.64-2A > G mutation is reported here and should be considered in the diagnostic workup of similar cases.

ACROMEGALY AND A GIANT RETROPERITONEAL LIPOSARCOMA PRODUCING IGF-1.

OBJECTIVE: Liposarcoma is the most common histotype of retroperitoneal sarcomas, representing up to 45% of all cases. We report a rare combination of acromegaly and liposarcoma in the same individual. METHODS: Laboratory and imaging studies including an oral glucose tolerance test, measurements of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), and a computed tomography scan were performed. RESULTS: The patient was a 60-year-old male with a history of acromegaly diagnosed on the basis of elevated IGF-1 at 1,373 ng/mL (age-appropriate reference range is 87 to 225 ng/mL) and macroadenoma treated with transsphenoidal surgery. He presented 8 years later with a history of abdominal distension and weight loss. Physical examination was notable for a right-sided abdominal mass that was tense and non-fluctuant. Two years earlier, he had a post oral glucose tolerance test GH level <0.25 ng/mL and IGF-1 level of 256 ng/mL (age-appropriate reference range is 55 to 206 ng/mL). Pituitary magnetic resonance imaging reported a 3.7 × 2.0-mm left-sided parasagittal lesion. Computed tomography scan showed a 25.0 × 22.0 × 32.3-cm heterogeneous giant mass in the right abdomen corresponding to a liposarcoma causing displacement of kidney, liver, and bowel loops. The patient was treated with a complete en bloc resection of the liposarcoma with the right kidney (45 × 33 × 17 cm) and tumor (9,400 g). Immunohistochemical examination revealed positive IGF-1 and GH staining. The patient suffered postoperative gastrointestinal bleeding that resulted in hemorrhagic shock and died on the 29th postoperative day after a cardiorespiratory arrest. CONCLUSION: Acromegalic patients are at increased risk of developing various types of neoplasms. This is the first documented coexistence of liposarcoma and history of acromegaly.

Spindle epithelial tumor with thymus-like differentiation of the thyroid (SETTLE): Report of two cases (one associated with a parathyroid adenoma).

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare tumor usually localized in the thyroid gland and perithyroid tissues. It is considered to arise from ectopic thymic tissue or branchial pouch remnants. It occurs more frequently in children and adolescents. We report 2 cases of spindle epithelial tumor with thymus-like differentiation localized in the thyroid gland, and 1 of them was associated with a parathyroid adenoma. We emphasize the need for a close and long-term follow-up in these patients.

Ovarian dysgerminoma associated with fibrosarcoma: a case report.

A 35-year-old woman presented with abdominal pain and weight loss. Pelvic computed tomography showed a 15 cm mass in the left ovary. Grossly, the removed ovary was completely replaced by a solid tumor mass. On histological analysis (100 sections), the lesion showed the typical morphological features of dysgerminoma (20%) admixed with a major (80%) fibrosarcoma component. Tumors did not have well-demarcated boundaries with a close intermingling of both cell types. Despite surgery and combination chemotherapy, the disease progressed rapidly and the patient died of disease 18 months after diagnosis. Review of the literature showed that soft tissue sarcomas of several types may occasionally be associated with gonadal and extragonadal mixed germ-cell tumors or with spermatocytic seminoma of the testis. However, no previously published report of an ovarian fibrosarcoma associated with a pure dysgerminoma was found in the literature.

Nonhepatosplenic γδ T-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation.

γδ T cells represent a minor T-cell subset that is mainly distributed in mucosal surfaces. Two distinct lymphomas derived from these cells have been recognized: hepatosplenic γδ T-cell lymphoma (HSTL) and primary cutaneous γδ T-cell lymphoma (PCGD-TCL). However, whether other anatomic sites may also be involved and whether they represent a spectrum of the same disease are not well studied. The lack of T-cell receptor (TCR)ß expression has been used to infer a γδ origin when other methods are not available. We studied 35 T-cell tumors suspected to be γδ TCL using monoclonal antibodies reactive with TCR δ or γ in paraffin sections. We were able to confirm γδ chain expression in 22 of 35 cases. We identified 8 PCGD-TCLs, 6 HSTLs, and 8 γδ TCLs without hepatosplenic or cutaneous involvement involving mainly extranodal sites. Two such cases were classified as enteropathy-associated T-cell lymphoma, type II. The other γδ TCL presented in the intestine, lung, tongue, orbit, and lymph node. In addition, we observed 13 cases with mainly extranodal involvement that lacked any TCR expression ("TCR silent"). In all cases, a natural killer cell origin was excluded. In conclusion, the lack of TCRß expression does not always predict γδ-T-cell derivation, as TCR silent cases may be found. The recognition of γδ TCL presenting in extranodal sites other than skin and liver/spleen expands the clinical spectrum of these tumors. However, non-HSTL γδ TCL do not seem to represent a single entity. The relationship of these tumors with either HSTL or PCGD-TCL requires further study.

Neuroendocrine metastatic tumors of the liver resembling hepatocellular carcinoma.

Certain neuroendocrine tumors (NET) metastasized to the liver can resemble hepatocellular carcinoma (HCC) in cytological needle biopsy. Experience concerning the histologic characteristics of metastatic NET resembling HCC in core needle hepatic biopsies has been scarce. The aim of this study is to describe the histological criteria in seven metastatic NET that resembled HCC in core needle hepatic biopsy. From a total of 285 needle biopsies with primary or metastasized hepatic neoplasms, seven cases were selected originally diagnosed as HCC or HCC vs. NET metastasized to the liver. Fourteen needle biopsies of hepatocellular carcinomas were also studied for comparative purposes. In all of these neoplasms the diagnosis of endocrine tumor was confirmed by immunohistochemical studies and the following information was recorded: age, sex, radiological alterations, primary site of the NET, and follow-up. The following histological data were also recorded: fibrotic stroma associated or not with the neoplastic cells, growth pattern, form of the cells, cellular size, mitotic figures, nucleomegaly, apparent nucleoli, chromatin in salt and pepper, plasmacytoid cells, intranuclear inclusions, and biliary pigment. In conclusion, these characteristics were common in metastasized neuroendocrine tumors: extensive stromal fibrosis, slight to moderate atypia, hyperchromatic nuclei, plasmacytoid cells, and thin delicate strands of fibrovascular tissue supporting larger acinar groups of net cells. HCC had a more infrequent fibrotic stroma, moderate to marked atypia, and in some biopsies biliary pigment, intranuclear inclusions, and clear cells.