CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Editors: Michael Cibull, MD, professor emeritus, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, PhD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.
Value of Ki-67 proliferative index in WHO-classified pulmonary carcinoids
Chromosomal abnormalities and genetic changes in uterine smooth muscle tumors
Expression of divergent endodermal lineage markers in yolk sac tumors
Interobserver reproducibility of percent GP4 in prostatic adenocarcinoma on biopsies
MELF pattern invasion: a report of FIGO grade 1 endometrial endometrioid adenocarcinomas
Cost-effectiveness of identifying H. pylori in gastric biopsies without ancillary stains
Value of Ki-67 proliferative index in WHO-classified pulmonary carcinoids
Pulmonary carcinoids are separated into typical and atypical based on mitotic count and the presence of necrosis, according to the World Health Organization. At variance with gastroenteropancreatic neuroendocrine tumors, which are graded based on mitotic count and Ki-67 proliferative index, the use of Ki-67 for grading pulmonary carcinoids is still under debate. The authors conducted a study in which they evaluated the prognostic impact of Ki-67 assessment in a multicenter cohort of 201 carcinoids (147 typical carcinoids [TCs] and 54 atypical carcinoids [ACs]) using manual analysis (2,000 cells counted) and digital image analysis (in-house Leica Qwin program; 4,500 or more cells counted). The Ki-67 proliferative index was correlated with overall survival by means of univariate analysis and, in comparison to clinical data, by means of multivariable analysis. The Ki-67 index was significantly higher in ACs than in TCs for both counting methods (P ≤ 2.7e–5). Using cutoffs of 2.5 and four percent (manual counting) or one and five percent (digital analysis), the highest differences in overall survival were observed (P ≤ .0067). Nevertheless, histopathological classification into TCs and ACs showed an equally strong association with disease outcome, although Ki-67 had some additive value within TCs. The Ki-67 index was not an independent predictor of survival in multivariable analysis. The authors concluded that although Ki-67 is a strong prognostic factor for pulmonary carcinoids, its usefulness, in addition to histopathology, in predicting prognosis is limited. However, it may have additional value in combination with histopathology and other molecular markers, especially in cases that are difficult to classify.
Swarts DR, Rudelius M, Claessen SM, et al. Limited additive value of the Ki-67 proliferative index on patient survival in World Health Organization-classified pulmonary carcinoids. Histopathol. 2017;70:412–422.
Correspondence: Dr. E. J. Speel at ernstjan.speel@mumc.nl
Chromosomal abnormalities and genetic changes in uterine smooth muscle tumors
Smooth muscle tumors of the uterus are a diagnostically challenging group of tumors. Molecular surrogate markers that reliably distinguish between benign and malignant tumors are not available. Therefore, the diagnosis is based on morphologic criteria. The authors conducted a study in which they investigated copy number alterations, MED12 mutations, and FH deletions in a well-characterized group of challenging uterine smooth muscle tumors consisting of 20 leiomyomas, 13 leiomyomas with bizarre nuclei, and 14 leiomyosarcomas to find potential diagnostically useful surrogate markers. MED12 mutations were detected in 47 percent of leiomyomas, 15 percent of leiomyomas with bizarre nuclei, and 25 percent of leiomyosarcomas. The MED12 mutations in leiomyomas with bizarre nuclei were detected outside the hot spot region. FH deletions were seen in 27 percent of leiomyomas, 30.8 percent of leiomyomas with bizarre nuclei, and 25 percent of leiomyosarcomas. Using copy number alteration profiling, the authors could not observe a clear separation of leiomyomas, leiomyomas with bizarre nuclei, and leiomyosarcomas. Copy number alterations revealed clear genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas. Leiomyosarcomas showed a similar pattern of gains and losses as leiomyomas with bizarre nuclei, with additional copy number alterations and more homozygous losses and high-level amplifications compared to leiomyomas with bizarre nuclei. The authors concluded that this study demonstrates that known FH deletions, a recurrent molecular change in leiomyomas, occur in morphologically challenging variants of leiomyomas, leiomyomas with bizarre nuclei, and leiomyosarcomas. Although MED12 mutations are common in leiomyomas, they occur infrequently in leiomyomas with bizarre nuclei and leiomyosarcomas. The genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas raise the intriguing possibility that uterine leiomyomas with bizarre nuclei and leiomyosarcomas are closely related and challenge the traditional concept that leiomyoma with bizarre nuclei is a tumor with just marked “degenerative” cellular changes. These findings support the hypothesis that tumor progression within uterine smooth muscle tumors might occur.
Liegl-Atzwanger B, Heitzer E, Flicker K, et al. Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors. Mod Pathol. 2016;29:1262–1277.
Correspondence: Dr. B. Liegl-Atzwanger at bernadette.liegl-atzwanger@medunigraz.at; Dr. E. Heitzer at ellen.heitzer@medunigraz.at; and Dr. F. Moinfar at farid.moinfar@bhs.at
Expression of divergent endodermal lineage markers in yolk sac tumors
Yolk sac tumors occur at gonadal and extragonadal sites. A recent case of ovarian endometrioid-pattern yolk sac tumor with strong diffuse expression of thyroid transcription factor 1 (TTF-1) illustrated the potential for misdiagnosis due to divergent expression of endodermal lineage markers. The authors conducted a study to investigate the expression of four divergent endodermal lineage markers—TTF-1, CDX2, Hep Par 1, and Napsin A—in gonadal and extragonadal yolk sac tumors of differing age, sex, and location, excluding foci of overt hepatoid differentiation. They identified 26 cases—five ovarian, 15 testicular, and six extragonadal—containing yolk sac tumor as identified by typical histology and confirmed by positive immunohistochemical staining for alpha-fetoprotein and glypican-3. They confirmed mixed or ambiguous foci by immunohistochemistry (SALL4 positive and Oct4 negative) and estimated the relative proportion of three histologic patterns—reticular/cystic, solid/myxoid, and glandular. The authors also compared percent positivity for the four divergent endodermal lineage markers within yolk sac tumor areas according to site, age group, and histologic pattern. High-level (greater than 25 percent) staining for one or more divergent endodermal lineage markers was seen in 11 cases—Hep Par 1 in seven cases, all post-pubertal; TTF-1 in four cases, two ovarian and two extragonadal; and CDX2 in three cases, with no age or site predilection. No case highly expressed all three divergent endodermal lineage markers, but four co-expressed high levels of two markers: two ovarian yolk sac tumors with TTF-1 and Hep Par 1, one testicular yolk sac tumor with CDX2 and Hep Par 1, and one extragonadal yolk sac tumor with TTF-1 and CDX2. While no absolute correlation of high-level divergent endodermal lineage marker expression with histologic subtype was observed, TTF-1 and CDX2 expression was predominantly seen in reticular/cystic and glandular areas, and Hep Par 1 was most frequent in myxoid/solid and glandular areas.
Shojaei H, Hong H, Redline RW. High-level expression of divergent endodermal lineage markers in gonadal and extra-gonadal yolk sac tumors. Mod Pathol. 2016;29:1278–1288.
Correspondence: Dr. R. W. Redline at raymondw.redline@Uhhospitals.org
MELF pattern invasion: a report of FIGO grade 1 endometrial endometrioid adenocarcinomas
Microcystic, elongated, and fragmented pattern invasion has been associated with nonvaginal recurrences and lymph node metastases in multi-institutional case control studies, but it has not been well examined in large single-institution cohorts. The authors conducted a study in which they identified hysterectomy specimens with FIGO 1 endometrioid endometrial carcinoma and lymphadenectomies from 2007 to 2012 and reviewed electronic medical records and histologic slides. Of 464 cases identified, 163 (35.1 percent) were noninvasive, 60 (12.9 percent) had microcystic, elongated, and fragmented (MELF) pattern invasion, 222 (47.8 percent) had a component of the infiltrative invasion pattern without MELF, 13 (2.8 percent) had pure pushing borders of invasion, five (1.1 percent) had pure adenomyosis-like invasion, and one (0.2 percent) had pure adenoma malignum-like invasion. Sixteen cases had lymph node metastases. Significantly more MELF cases than non-MELF cases overall had positive lymph nodes (18.3 percent versus 1.2 percent; P < .001). The results were almost identical when invasive infiltrative cases with and without MELF were compared (18.3 percent versus 1.8 percent; P < .001). The maximum number of MELF glands per slide did not differ between cases with and without lymph node metastases (P = .137). A majority of positive lymph nodes, even in MELF cases, demonstrated nonhistiocyte-like metastases. Only five cases (all with MELF invasion) demonstrated micrometastatic lesions or isolated tumor cells only. MELF cases demonstrated a nonsignificant decrease in time to extravaginal recurrence (P = .082, log-rank test), for which analysis was limited by low recurrence rates. The authors concluded that MELF is associated with lymph node metastases, even when compared with other infiltrative cases, and shows multiple patterns of growth in positive lymph nodes. In addition, MELF cases trend toward decreased time to extravaginal recurrence.
Joehlin-Price AS, McHugh KE, Stephens JA, et al. The microcystic, elongated, and fragmented (MELF) pattern of invasion: a single institution report of 464 consecutive FIGO grade 1 endometrial endometrioid adenocarcinomas. Am J Surg Pathol. 2017;41:49–55.
Correspondence: Dr. Adrian A. Suarez at adrian.suarez@osumc.edu
Interobserver reproducibility of percent GP4 in prostatic adenocarcinoma on biopsies
In the World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs published in 2016, it was officially recommended that the percent of Gleason pattern 4 be reported on pathology reports to better reflect the extent in Gleason score 7 tumors. The authors conducted a study in which they assessed the reproducibility of reporting Gleason pattern 4 (GP4) on prostate biopsies. They prospectively analyzed 422 cores containing GP4 from their consult cases over 2.5 months. The percent pattern 4 was assigned to all the cases in 10 percent increments from zero to 100 percent (with the addition of five percent) by one of four fellows in urological pathology and the expert urological pathologist. Of 422 cores, 32 percent were an exact match and 75 percent were within ± 10 percent (weighted κ [κW] value, 0.67). Cases were further stratified on the basis of scattered versus clustered GP4 in the background of Gleason pattern 3; continuous versus discontinuous tumor involvement; cribriform/glomeruloid pattern only versus poorly formed/fused pattern versus mixed cribriform and poorly formed/fused pattern; and total tumor involvement of the core (up to 10 percent of the core versus more than 10 percent). No significant differences were observed in the first three variables. However, in cases with 10 percent or less involvement of the core, 61 percent were within ± 10 percent (κW=0.50) compared with cases with more than 10 percent involvement of the core, in which 78 percent were within ± 10 percent (κW=0.70). In summary, the authors showed that assessment of percent GP4 was relatively reproducible, with substantial agreement within ± 10 percent in cases. However, with less than 10 percent involvement of the core, it was more difficult to assess percent GP4 in smaller foci, with only moderate agreement. Given that in a small focus only a few glands of a pattern can markedly affect the percent GP4, consideration should be given to not recording percent GP4 in small foci of Gleason score 7 tumors on needle biopsy.
Sadimin ET, Khani F, Diolombi M, et al. Interobserver reproducibility of percent Gleason pattern 4 in prostatic adenocarcinoma on prostate biopsies. Am J Surg Pathol. 2016;40:1686–1692.
Correspondence: Dr. Jonathan I. Epstein at jepstein@jhmi.edu
Cost-effectiveness of identifying H. pylori in gastric biopsies without ancillary stains
Despite the recommendation of expert gastrointestinal pathologists, private and academic medical centers, including the authors’ center, have continued to use ancillary stains to identify Helicobacter pylori. For a three-month period, the authors prospectively evaluated gastric biopsies for H. pylori using routine H&E and a reflex Diff-Quik stain. During this time, 379 gastric biopsies were collected on 326 patients. H. pylori organisms were prospectively identified in 23 (seven percent) patients, all of whom had superficial dense lymphoplasmacytic inflammation expanding the lamina propria. An additional two patients with neutrophilic inflammation were found to have H. pylori by immunohistochemical staining. One patient diagnosed as having normal gastric mucosa was retrospectively found to have inflammation with rare H. pylori organisms originally overlooked on both H&E and Diff-Quik but later identified on immunostain (0.5 percent). No patients with chemical gastritis (16 percent) or chronic inflammation (27 percent) were found to have H. pylori. During the study month, nine immunostains for H. pylori were performed in addition to the 379 Diff-Quik stains. After discontinuing reflex Diff-Quik, approximately 20 immunostains are performed for H. pylori each month, which decreases technical time spent processing gastric biopsies and reduces cost to the health care system. In the authors’ population with a low prevalence of H. pylori, reflex staining for organisms is not cost-effective. The organisms can be seen on routine H&E. When suspicious superficial or active inflammation is present without visible organisms, immunohistochemical stains will confirm the presence or absence of organisms within a day. Discontinuation of up-front ancillary studies is cost-effective without compromising patient care.
Pittman ME, Kharajian A, Wood LD, et al. Prospective identification of Helicobacter pylori in routine gastric biopsies without reflex ancillary stains is cost-efficient for our health care system. Hum Pathol. 2016;58:90–96.
Correspondence: Dr. Meredith E. Pittman, Weill Cornell Medicine, Dept. of Pathology, 525 E. 68th St., Starr Pavilion 1031, New York, NY 10065