Impact of a Modified HistoGel Method for Processing Endocervical Curettage Specimens on Diagnostic Yield.

OBJECTIVES: Endocervical curettage (ECC) specimens may be limited by scant tissue. We evaluated whether a cellular concentration processing method could improve their diagnostic quality. METHODS: Between October 2018 and June 2019, ECC specimens were assigned chronologically to one of two groups: nonconcentrated ECC (NECC) or concentrated ECC (CECC). NECC specimens underwent routine histologic processing. CECC specimens were processed using a published HistoGel-based cell block method. We reviewed diagnoses for ECCs, concurrent cervical biopsies and/or loop electrosurgical excision procedures (LEEPs), and preceding Papanicolaou (Pap) smears. We performed multivariate logistic regression analyses to evaluate the impact of processing method on ECC adequacy and discordance between Pap smear and worst tissue diagnoses. RESULTS: NECC and CECC adequacy was 88.2% and 84.7% (P = .06). ECC adequacy was greater if concurrent biopsy/LEEP was performed (odds ratio [OR] = 1.76, P < .01). Discordance between Pap smear and worst tissue diagnoses was 9.5% and 13.3% (P = .04) for cases with NECC and CECC processing, although processing method was not significant in multivariate analysis (OR = 0.74, P = .11). Adequate ECC sampling and concurrent biopsy/LEEP were independently associated with concordance between Pap smear and worst tissue diagnosis (OR = 0.46, P < .01 and OR = 0.65, P = .02). CONCLUSIONS: ECC processing method did not significantly affect either specimen adequacy (P = .06) or diagnostic discordance (P = .11) when controlled for other factors.

Thoracic nuclear protein in testis (NUT) carcinoma: expanded pathological spectrum with expression of thyroid transcription factor-1 and neuroendocrine markers.

AIMS: Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor-1 (TTF-1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum. METHODS AND RESULTS: We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA-based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31-80 years; four never-smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3-12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF-1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT-positive cases were found by immunohistochemical screening. CONCLUSIONS: Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF-1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive-appearing tumours, regardless of their immunophenotypic features.

Clinical, cytologic, and immunohistochemical features of sarcomas involving body cavity fluids.

BACKGROUND: Sarcomas are uncommon findings in body cavity fluids. Diagnosis may be challenging because sarcoma cells in fluids can round up and lose their characteristic appearance seen on smears and histologic sections. This study characterizes the cytologic features of sarcomas involving body cavity fluids. METHODS: Effusion fluids and cerebrospinal fluids diagnosed as positive for sarcoma were reviewed. RESULTS: Forty-three fluids from 28 patients (median age, 47 years) were positive for sarcoma. Four patients who presented with positive fluids were alive at 1 to 10.7 years' follow-up (median, 22.5 months). Twenty-four patients died 2 days to 2 years (median, 19 days) after their positive fluid diagnoses. Twenty-eight specimens from 20 patients had slides available for review. Although 18 of the 28 positive fluids had a morphology comparable to that of their primary, 4 small round blue cell tumors (SRBCTs) and 4 spindle cell tumors showed epithelioid morphology, 1 SRBCT had pleomorphic morphology, and 1 epithelioid primary had SRBCT morphology. Nine fluids had tumor cells in large, cohesive clusters mimicking carcinoma; workup was performed for 10, predominantly to rule out carcinoma and mesothelioma. CONCLUSIONS: Sarcoma morphology may be altered in exfoliated cytology specimens. Workup on cell blocks aids in the differential diagnosis, especially for carcinoma and mesothelioma. Unsurprisingly, fluid cytology positive for sarcoma portends poor survival.

Thyroid FNA biopsies comprised of abundant, mature squamous cells can be reported as benign: A cytologic study of 18 patients with clinical correlation.

BACKGROUND: A thyroid nodule comprised almost exclusively of mature, benign-appearing squamous cells is an uncommon finding in fine-needle aspiration (FNA) biopsies of thyroid nodules. Reporting such specimens was not originally addressed by The Bethesda System for Reporting Thyroid Cytopathology. The authors correlated the biologic behavior of the specimens with their benign cytologic appearance through clinical, radiographic, and surgical follow-up. METHODS: The pathology archives of 3 tertiary hospitals were searched for thyroid FNA specimens consisting of mature squamous cells without atypia. The authors reviewed all available slides and included only cases that were moderately to highly cellular; nucleated or anucleate squamous cells without atypia comprised the vast majority of the cellularity. Available clinical information and/or thyroid ultrasound examination(s) were reviewed by an endocrinologist or radiologist, respectively. RESULTS: A total of 18 patients (7 men and 11 women; age range, 19-76 years) with 20 nodules met the prespecified inclusion criteria. The average nodule size was 2.1 cm. Common sonographic characteristics included a well-defined appearance, the lack of internal vascularity, a thin outer wall, general hypoechogenicity with low-intermediate internal echoes, and posterior acoustic enhancement. Clinical and radiographic follow-up (mean, 3.8 years; range, <1 to 9 years) was available for 9 patients, and all nodules were stable. All 4 cases with histologic follow-up were benign squamous-lined cysts. CONCLUSIONS: The findings of the current study suggest that thyroid FNA specimens comprised almost exclusively of mature squamous cells can be reported as benign. Cancer Cytopathol 2018;126:336-41. © 2018 American Cancer Society.

The histologic evolution of revealed, acute abruptions.

There is considerable interest in using pathology to confirm acute abruptions. It has been suggested that pathologic findings can help to determine the timing of abruptions. Because of the dearth of evidence in the literature supporting this claim and its medicolegal implications, we undertook this study to explore further the possibility of timing abruptions by histopathology. We sought to correlate bleeding interval (duration from maternal presentation with vaginal bleeding [revealed abruption] to placental delivery) with placental histopathologic findings. We performed a retrospective review of clinical data and placental pathology from all cases of clinically diagnosed, acute, revealed abruptions at a single, large institution in New England between 2000 and 2015. Cases were identified based on clinical diagnoses, bleeding intervals were calculated from clinical notes, and histologic evaluations were performed by 2 pathologists blinded to the bleeding intervals. A total of 177 cases were analyzed. Of these, 103 (58%) had histologic findings corroborating the clinical diagnosis of abruption. The most frequent finding was maternal surface indentation (51 cases) followed by intravillous hemorrhage (50 cases). The former was also the earliest finding, with a minimum bleeding interval of 4 minutes. In multivariate modeling, plasma cell deciduitis was significantly associated with a longer bleeding interval (median 63 hours). If there were 2 pathologic findings, there was a trend toward a longer bleeding interval. There was modest sensitivity for the pathologic diagnosis of acute revealed abruption. Although there was not a clear, stepwise progression of histologic lesions; the presence of 2 or more findings tended to be seen with longer bleeding intervals. Our results suggest that histologic findings cannot be used to time acute revealed abruptions reliably, and any interpretation of such should be made with caution.

Acinar cell cystadenoma: A challenging cytology diagnosis, facilitated by moray® micro-forceps biopsy.

Acinar cell cystadenoma is a rare, benign cystic lesion of the pancreas. There have been only a few retrospective reports on its cytological features. We present the first case of acinar cell cystadenoma in a 65-year-old woman, diagnosed pre-operatively by pancreatic cyst fluid cytology and Moray® micro-forceps biopsy. We emphasize possible diagnostic pitfalls of acinar cell cystadenoma cyst fluid cytology and suggest useful morphologic, immunohistochemical, and other clues to aid in diagnosis. Diagn. Cytopathol. 2017;45:557-560. © 2017 Wiley Periodicals, Inc.

Smears are important for adequate cytologic diagnosis of kidney lesions.

INTRODUCTION: Traditionally at our institution, smears with or without liquid-based cytology (LBC) and core biopsies (CBs) have been obtained by radiologists performing image-guided fine-needle aspiration biopsies (FNABs) of deep organs. Since 2015, however, there has been a shift to providing cytology with samples for LBC only when obtaining CBs. The impression among our institution's cytologists is that LBC alone is less often adequate for diagnosis compared with smears and LBC together. We examined a series of kidney FNABs pre- and post-"LBC only" to evaluate this impression. MATERIALS AND METHODS: With institutional review board approval, we compared all kidney FNABs from 2012 to those from 2015. We recorded the type(s) of cytology preparation(s), the number of cytology slides, the cytology diagnosis, the concurrent CB diagnosis, and whether there was a subsequent excision and the excision diagnosis. We examined cytology and CB slides as needed. RESULTS: In 2012, 105 patients underwent 111 kidney biopsies, 109 with smears made. In 2015, 58 patients underwent 62 kidney biopsies, 7 with smears made. In 2012, there were 13 (12%) nondiagnostic (ND) cytology cases and 19 (17%) cases where the cytology and CB diagnoses were discrepant. By comparison, in 2015, there were 20 (32%) ND cytology cases and 21 (33%) discrepant cases. CONCLUSIONS: There were more cytology slides per case and fewer ND diagnoses in 2012 compared with 2015 (12% versus 32%, respectively, P = 0.001). Concordance was also better in 2012 (83% versus 67%, P = 0.015). We believe that our metrics would improve if we returned to the procedures followed in 2012.

Touch Preps of Products of Conception for Rule-Out Ectopic Pregnancy: A Viable Alternative to Frozen Section.

OBJECTIVES: Tissue confirmation of the intrauterine location of a pregnancy can be difficult grossly, necessitating a frozen section diagnosis. First-trimester tissue is often scant and can be exhausted by frozen section. We examined 39 endometrial curettings performed for rule-out ectopic pregnancy by touch prep to examine the utility of cytopathology in documenting trophoblast or chorionic villi (products of conception [POC]). METHODS: First-trimester curettage specimens sent to the Massachusetts General Hospital Pathology Departmentreceived a gross examination followed by a touch prep of the area most suspicious for villi. Touch preps were reviewed blinded to the final diagnosis and then compared. RESULTS: Thirty-three of the 39 touch preps and histology specimens were concordant, including all 11 negative histology specimens and 22 of the 28 positive histology specimens. CONCLUSIONS: POC can be diagnosed by touch prep and may offer confirmation of grossly identified villi. Positive predictive value is 100%. Negative touch preps should receive further evaluation.

Influence of orbital eye position on vertical saccades in progressive supranuclear palsy.

Disturbance of vertical saccades is a cardinal feature of progressive supranuclear palsy (PSP). We investigated whether the amplitude and peak velocity (PV) of saccades are affected by the orbital position from which movements start in PSP patients and age-matched control subjects. Subjects made vertical saccades in response to ±5° vertical target jumps with their heads in one of three positions: head "center," head pitched forward ∼15°, and head pitched back ∼15°. All patients showed some effect of starting eye position, whether beginning in the upward or downward field of gaze, on saccade amplitude, PV, and net range of movement. Generally, reduction of amplitude and PV were commensurate and bidirectional in the affected hemifield of gaze. Such findings are unlikely to be because of orbital factors and could be explained by varying degrees of involvement of rostral midbrain nuclei in the pathological process.

Effects of cerebellar disease on sequences of rapid eye movements.

Studying saccades can illuminate the more complex decision-making processes required for everyday movements. The double-step task, in which a target jumps to two successive locations before the subject has time to react, has proven a powerful research tool to investigate the brain's ability to program sequential responses. We asked how patients with a range of cerebellar disorders responded to the double-step task, specifically, whether the initial saccadic response made to a target is affected by the appearance of a second target jump. We also sought to determine whether cerebellar patients were able to make corrective saccades towards the remembered second target location if it were turned off soon after presentation. We tested saccades to randomly interleaved single- and double-step target jumps to eight locations on a circle. Patient's initial responses to double-step stimuli showed 50% more error than saccades to single target jumps, and often, they failed to make a saccade to the first target jump. The presence of a second target jump had similar, but smaller effects in control subjects (error increased by 18%). During memory-guided double-step trials, both patients and controls made corrective saccades in darkness to the remembered location of the second jump. We conclude that in cerebellar patients, the second target jump interferes with programming of the saccade to the first target jump of a double-step stimulus; this defect highlights patients' impaired ability to respond appropriately to sudden, conflicting changes in their environment. Conversely, since cerebellar patients can make corrective memory-guided saccades in darkness, they retain the ability to remember spatial locations, possibly due to non-retinal neural signals (corollary discharge) from cerebral hemispheric areas concerned with spatial localization.

The role of the medial longitudinal fasciculus in horizontal gaze: tests of current hypotheses for saccade-vergence interactions.

Rapid shifts of the point of visual fixation between equidistant targets require equal-sized saccades of each eye. The brainstem medial longitudinal fasciculus (MLF) plays a cardinal role in ensuring that horizontal saccades between equidistant targets are tightly yoked. Lesions of the MLF--internuclear ophthalmoparesis (INO)--cause horizontal saccades to become disjunctive: adducting saccades are slow, small, or absent. However, in INO, convergence movements may remain intact. We studied horizontal gaze shifts between equidistant targets and between far and near targets aligned on the visual axis of one eye (Müller test paradigm) in five cases of INO and five control subjects. We estimated the saccadic component of each movement by measuring peak velocity and peak acceleration. We tested whether the ratio of the saccadic component of the adducting/abducting eyes stayed constant or changed for the two types of saccades. For saccades made by control subjects between equidistant targets, the group mean ratio (±SD) of adducting/abducting peak velocity was 0.96 ± 0.07 and adducting/abducting peak acceleration was 0.94 ± 0.09. Corresponding ratios for INO cases were 0.45 ± 0.10 for peak velocity and 0.27 ± 0.11 for peak acceleration, reflecting reduced saccadic pulses for adduction. For control subjects, during the Müller paradigm, the adducting/abducting ratio was 1.25 ± 0.14 for peak velocity and 1.03 ± 0.12 for peak acceleration. Corresponding ratios for INO cases were 0.82 ± 0.18 for peak velocity and 0.48 ± 0.13 for peak acceleration. When adducting/abducting ratios during Müller versus equidistant targets paradigms were compared, INO cases showed larger relative increases for both peak velocity and peak acceleration compared with control subjects. Comparison of similar-sized movements during the two test paradigms indicated that whereas INO patients could decrease peak velocity of their abducting eye during the Müller paradigm, they were unable to modulate adducting velocity in response to viewing conditions. However, the initial component of each eye's movement was similar in both cases, possibly reflecting activation of saccadic burst neurons. These findings support the hypothesis that horizontal saccades are governed by disjunctive signals, preceded by an initial, high-acceleration conjugate transient and followed by a slower vergence component.

Disorders of vergence eye movements.

PURPOSE OF REVIEW: The aim is to re-interpret disorders of vergence in the light of recent studies that view disjunctive eye movements as but one component of three-dimensional gaze control. RECENT FINDINGS: Most natural eye movements combine vergence with saccades, pursuit and vestibular eye movements. Electrophysiological studies in epileptic patients, as well as evidence from monkeys, indicate that frontal and parietal cortex govern vergence as a component of three-dimensional gaze. Clinicians apply Hering's law of equal innervation to interpret disjunctive movements as the superposition of conjugate and vergence commands. However, electrophysiological studies indicate that disjunctive saccades are achieved by programming each eye's movement independently. Patients with internuclear ophthalmoplegia (INO) may have preserved vergence, which can be recruited to compensate for loss of conjugacy. Vergence may also enable gaze shifts in saccadic palsy. Some forms of nystagmus suppress or change with convergence; co-contraction of the horizontal rectus muscles does not appear to be the explanation. Rather, effects of near viewing on central vestibular mechanisms or differential activation of specific types of extra-ocular muscle fiber may be responsible. SUMMARY: Interpretation of disorders of vergence is aided by applying a scheme in which their contributions to three-dimensional gaze control is considered.

The disturbance of gaze in progressive supranuclear palsy: implications for pathogenesis.

Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.