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Objectives: Small sample size limits the number of immunostains that may be attempted in colorectal carcinoma (CRC) biopsy specimens. We investigated the utility of dual stain with special AT-rich sequence binding protein 2 (SATB2) or caudal-type homeobox 2 (CDX2) and cytokeratin 20 (CK20) or villin in identifying CRC., Methods: Tissue microarrays with 222 CRCs and 375 other carcinomas were built. Dual stain was performed pairing nuclear stains CDX2 or SATB2 with CK20 or villin., Results: All four single stains showed excellent sensitivity (93%-99%) but variable specificity (56%-88%) for CRC. All four dual stains also showed excellent sensitivity (90%-96%) while much improved specificity (88%-98%) compared with single stains. SATB2 dual stain (with CK20 or villin) showed a higher specificity than CDX2 dual stain (with CK20 or villin) with a comparable sensitivity., Conclusions: SATB2 dual stain shows the greatest potential clinical utility in identifying CRC and is superior to CDX2 dual stain. More important, SATB2 dual stain could be helpful for specimens with limited tissues or those having a nonclassic staining pattern.

Objectives: Determination of the primary site of origin for mucinous neoplasms identified in the peritoneal and/or pelvic cavities may be challenging, with major differential diagnoses including appendiceal mucinous neoplasm (AMN) and ovarian mucinous neoplasm (OMN). Special AT-rich sequence binding protein 2 (SATB2) has been shown to be highly selectively expressed in the lower gastrointestinal tract, including the appendix., Methods: We investigated the utility of a dual stain (DS) with SATB2 or caudal type homeobox 2 (CDX2) and cytokeratin 20 (CK20) or villin in distinguishing AMNs from OMNs. Tissue microarrays with 40 AMNs and 18 OMNs were stained with SATB2 or CDX2 paired with either CK20 or villin., Results: SATB2 single stain showed a good sensitivity of 83% and the highest specificity of 78% for AMNs over OMNs among all four stains. DS with SATB2 and villin showed an identical sensitivity of 78% but specificity increased to 94%, while DS with SATB2 and CK20 showed a sensitivity of 80% and a specificity of 100%. In contrast, DS with CDX2 and CK20/villin showed slightly higher sensitivity but much lower specificity., Conclusions: DS with SATB2/CK20 shows the greatest potential clinical utility in distinguishing AMNs from OMNs and is superior to DS with CDX2/CK20. Importantly, DS could be helpful for specimens with limited tissues., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objectives: Somatic BRAF mutation in colon cancer essentially excludes Lynch syndrome. We compared BRAF V600E immunohistochemistry (IHC) with BRAF mutation in core, biopsy, and whole-section slides to determine whether IHC is similar and to assess the cost-benefit of IHC., Methods: Resection cases (2009-2013) with absent MLH1 and PMS2 and prior BRAF mutation polymerase chain reaction results were chosen (n = 57). To mimic biopsy specimens, tissue microarrays (TMAs) were constructed. In addition, available biopsies performed prior to the resection were available in 15 cases. BRAF V600E IHC was performed and graded on TMAs, available biopsy specimens, and whole-section slides. Mutation status was compared with IHC, and cost-benefit analysis was performed., Results: BRAF V600E IHC was similar in TMAs, biopsy specimens, and whole-section slides, with only four (7%) showing discordance between IHC and mutation status. Using BRAF V600E IHC in our Lynch syndrome screening algorithm, we found a 10% cost savings compared with mutational analysis., Conclusions: BRAF V600E IHC was concordant between TMAs, biopsy specimens, and whole-section slides, suggesting biopsy specimens are as useful as whole sections. IHC remained cost beneficial compared with mutational analysis, even though more patients needed additional molecular testing to exclude Lynch syndrome., (Copyright© by the American Society for Clinical Pathology.)

For primary bladder tumors, distinguishing urothelial carcinoma (UC) invading the fibromuscular stroma of the prostate (pT4a) from in situ UC involving prostatic ducts can be difficult. Immunohistochemical markers (cytokeratin [CK]5/6, CK5, CK7, CK20, p53, p63, high-molecular-weight keratin [HMWK], androgen receptor, prostate-specific antigen [PSA], prostate specific acid phosphatase [PSAP], laminin, CD44s, CD141) were assessed for their usefulness in determining depth of UC invasion in the prostate. In cystoprostatectomy specimens containing in situ UC in prostatic ducts, both CK5/6 and CK5 clearly differentiated prostatic basal cells from in situ UC. The remaining markers were not effective in determining depth of tumor invasion. Double-stain combinations CK7/CK5 and p53/CK5 were performed and robustly color contrasted in situ tumor from surrounding basal cells. The use of CK5/6, CK5, CK7/CK5, or p53/CK5 is recommended to assist in determining the depth of UC invasion in the prostate when histologic findings are equivocal.

We performed a histologic and immunohistochemical assessment of 53 noninvasive appendiceal epithelial proliferations, appropriating terminology and using markers shown useful in differentiating serrated colorectal polyps. These were classified as hyperplastic polyp (HP), sessile serrated adenoma (SSA), mixed serrated and adenomatous lesion (MSAL), mucinous cystadenoma (MCA), or conventional adenoma (CAD). Immunohistochemical analysis for cytokeratin (CK) 20, Ki-67, MUC6, and beta-catenin was performed. Diagnoses were as follows: HP, 6; SSA, 12; HP vs SSA, 3; MSAL, 16; MCA, 14; and CAD, 2. All HPs showed expanded (beyond surface) CK20 and expanded or normal (base) Ki-67; 1 was MUC6+. Most SSAs and MSALs were CK20-expanded or expanded with random expression in deep crypts (Ex/I) and Ki-67-expanded, Ex/I (expanded with asymmetry), or normal. All SSAs and 8 of 16 MSALs were MUC6+. CADs were CK20-Ex/I, Ki-67-Ex, and MUC6-; 1 showed nuclear beta-catenin expression. Serrated appendiceal lesions can be categorized using colorectal terminology. MUC6 is associated with SSA morphologic features. Similar immunohistochemical patterns in SSA and MSAL suggest a link between these lesions.

Reduction mammaplasty (RM) is a common surgical procedure that yields a variable amount of tissue for pathologic examination. Occult breast carcinomas are detected rarely in these specimens. We evaluated the pathologic findings in RM specimens performed in our institution during an 11.5-year period (July 1989 to December 2000). A total of 560 patients who had undergone RM were identified, 503 bilateral and 57 unilateral. The average number of blocks submitted per breast was 3.9 (range, 1-23). Pathologic changes were present in 338 cases (60.4%). Unsuspected carcinomas (small invasive carcinomas, 3; ductal carcinoma in situ, 1) were found in 4 cases (0.7%). Atypical ductal and/or atypical lobular hyperplasia were identified in 8 cases (1.4%). Lesions associated with a mildly increased carcinoma risk (moderate/florid ductal hyperplasia, sclerosing adenosis, and papilloma) were identified in 52 cases (9.3%). Other findings included fibrocystic changes, fibrosis, mild ductal hyperplasia, fibroadenoma, and adenosis. Pathologic examination of RM specimens provides important clinical information and should be performed routinely.

We determined whether there were additional diagnostic findings in additional level sections performed on polyps with no pathologic diagnosis (NPD) or those in which only lymphoid aggregates (LAs) were seen initially and determined the level at which findings were identified. All colorectal biopsy specimens submitted with a clinical diagnosis of polyp during a 6-month period were included (N = 733). Initially, 3 level sections were cut for each polyp, and if a cause for the polyp was found, no additional levels were evaluated. If LAs or no cause for the polyp was found, 5 additional levels through each block were examined. Any diagnostic findings and the level at which they were identified were recorded. A discrete cause for the polyp was identified in routine levels in 574 cases (78.3%). Deeper levels were performed in 159: 23 for clarification of a suspected diagnosis, 38 for LAs, and 98 for NPD. Findings were identified in 31 (22.8%) of 136 stepped for LA or NPD with neoplastic findings in 13 (9.6%). Most diagnoses were identified in levels 4 or 5, but tubular adenomas were found in levels 7 and 8. These results support level sectioning specimens submitted as polyps with NPD or LAs on initial sections.

For many neoplasms, the status of regional lymph nodes is a critical prognostic factor with direct therapeutic implications. Despite the importance of lymph node status, there is no consensus on whether lymph nodes from node dissections should be submitted in their entirety. To study this issue, for a 4-month period, all lymph nodes from node dissections were submitted in their entirety. The larger nodes were submitted systematically to determine whether the additional tissue blocks contained metastases that were not identified in the initial tissue block. We also analyzed the cost of submitting, processing, and interpreting these extra blocks. During the study period, 149 patients underwent lymph node dissections, yielding a total of 2,915 lymph nodes. Submitting the larger nodes in their entirety resulted in processing 808 additional tissue blocks that demonstrated a total of 9 additional metastases in 7 patients. In 2 of these patients, the additional metastases changed the stage of the neoplasm and may have contributed to an alteration in therapy. By using median salary figures, the estimated cost for submitting, processing, and interpreting the additional blocks was $5,935.62. Whether the additional positive nodes justify this cost should be determined by individual pathology practices.

Recently there have been several editorials suggesting that breast biopsies with small or nonpalpable lesions should not be subjected to frozen section examination. In this study, the approach of routinely performing frozen sections on all breast biopsies was compared to the recommended approach of performing frozen sections only on cases with gross lesions < 1.0 cm. From July 1, 1992 through June 30, 1993, there were 444 breast biopsies submitted. Nearly all of these (98%) had frozen sections performed. Among these cases, there were 14 false-negative frozen section diagnoses equating to a frozen section sensitivity of 84%, and a frozen section false-negative rate of 3.3%. From July 1, 1994 through June 30, 1995, there were 601 breast biopsies submitted. Of these cases, 310 contained a gross lesion > 1.0 cm and were subjected to frozen section examination. The remaining 291 cases contained either no distinct lesion or a gross lesion < 1.0 cm. These cases were not frozen. Among the 310 cases that were frozen, there were 3 false-negative frozen section diagnoses equating to a frozen section sensitivity of 96%, and a frozen section false-negative rate of 1.0%. These findings indicate that careful gross examination combined with selective freezing of only cases containing a gross lesion > 1.0 cm improves frozen section accuracy. This study provides statistical support for previous recommendations that frozen section examination should be limited to cases with distinct gross lesions > 1.0 cm.

Since the early 1970s, measurement of free erythrocyte protoporphyrin (FEP) (by microextraction or by hematofluorometer) has been widely used to screen for lead poisoning and to evaluate microcytic red blood cell (RBC) disorders in children. However, published information on normal values for FEP, performance of the hematofluorometer, and usefulness of FEP in classifying microcytic RBC disorders in adults is scant. In an adult population with normal hematocrit and MCV and normal values for serum ferritin, blood lead level, and serum bilirubin, we obtained normal hematofluorometer FEP levels of less than 30 micrograms/dL for men, and less than 40 micrograms/dL levels for women. We have evaluated a hematofluorometer against a standard microextraction procedure and feel that the hematofluorometer is superior for clinical laboratories if elevated FEPs are confirmed by retesting with washed RBC. In the second part of this paper we demonstrate the usefulness of the FEP in classifying microcytic RBC disorders in adults.

Microcytic red blood cells (RBC) are commonly encountered in clinical medicine and are caused by disorders of heme synthesis [usually iron deficiency anemia (IDA) or anemia of chronic disease (ACD)] or disorders of globin synthesis (usually thalassemia syndromes or HbE). Using the clinical history and standard laboratory tests (hematocrit, per cent saturation of transferrin (% sat), serum ferritin, Hb electrophoresis, HBA2, and HbF) we classified 198 adults with microcytic RBC as follows: 48 IDA, 11 probable IDA, 11 iron-deficient erythropoiesis without anemia, 13 ACD, 42 alpha-thalassemia trait, 35 probable alpha-thalassemia trait, 20 beta-thalassemia trait, and 15 unclassified. In addition, we demonstrated that the FEP test reliably (83-90% of the time, depending on FEP methodology) classifies microcytic RBC states into disorders of heme synthesis vs. disorders of globin synthesis. Because of reliability and ease of measurement, we recommend the hematofluorometer FEP as the first step in the clinical laboratory evaluation of microcytic RBC disorders in both adults and children.

Evaluation of 86 employees with a history of leukopenia at the Naval Weapons Center (NWC), China Lake, California, was done by exposure questionnaires, medical histories, physical examinations, peripheral blood smear, and bone marrow evaluations, including morphologic examination, stem cell culture, and cytogenetics. Forty-eight subjects were found to be leukopenic at the time of the study, and two subjects were found to have hairy cell leukemia. All subjects had positive exposure histories and were healthy at the time of the study. Review of peripheral smears identified the patients with marrow abnormalities. Bone marrow cultures revealed several patients with possible marrow suppression. Chromosome studies were not diagnostic. Five-year follow-up health questionnaires revealed no significant health problems; the two workers with hairy cell leukemia are alive and fully functional. Leukopenia in itself does not appear to be a risk factor for poor health, and it is unknown whether or not it may be a useful screening tool to identify workers at risk in toxic environments. Careful evaluation of blood cell counts and peripheral smears should be sufficient to identify people with potential marrow abnormalities.