Inny Busmanis

Predicting clinical behaviour of breast phyllodes tumours: a nomogram based on histological criteria and surgical margins

Aim To define a predictive model for clinical behaviour of breast phyllodes tumours (PT) using histological parameters and surgical margin status. Methods Cases of breast PT diagnosed in the Department of Pathology Singapore General Hospital between January 1992 and December 2010 were stratified into benign, borderline and malignant grades based on a combination of histological parameters (stromal atypia, hypercellularity, mitoses, overgrowth and nature of tumour borders). Surgical margin status was assessed. Clinical follow-up and biostatistical modelling were accomplished. Results Of 605 PT, 440 (72.7%) were benign, 111 (18.4%) borderline and 54 (8.9%) malignant. Recurrences, which were predominantly local, were documented in 80 (13.2%) women. Deaths from PT occurred in 12 (2%) women. Multivariate analysis revealed stromal atypia, overgrowth and surgical margins to be independently predictive of clinical behaviour, with mitoses achieving near significance. Stromal hypercellularity and tumour borders were not independently useful. A nomogram developed based on atypia, mitoses, overgrowth and surgical margins (AMOS criteria) could predict recurrence-free survival at 1, 3, 5 and 10 years. This nomogram was superior to a total histological score derived from adding values assigned to each of five histological parameters. Conclusion A predictive nomogram based on three histological criteria and surgical margin status can be used to calculate recurrence-free survival of an individual woman diagnosed with PT. This can be applied for patient counselling and clinical management.

MED12 is frequently mutated in breast phyllodes tumours: a study of 112 cases

Aim To determine the frequency of MED12 mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes. Methods Phyllodes tumours from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of the MED12 gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out. Results There were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosing MED12 mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harboured MED12 mutations experienced improved disease-free survivals, with higher recurrence likelihood in those without MED12 mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015). Conclusions Similar to fibroadenomas, phyllodes tumours show a high frequency of MED12 mutations, affirming the close biological relationship between these fibroepithelial neoplasms.

HER2 Amplification and Clinicopathological Characteristics in a Large Asian Cohort of Rare Mucinous Ovarian Cancer

Mucinous epithelial ovarian cancer has a poor prognosis in the advanced stages and responds poorly to conventional chemotherapy. We aim to elucidate the clinicopathological factors and incidence of HER2 expression of this cancer in a large Asian retrospective cohort from Singapore. Of a total of 133 cases, the median age at diagnosis was 48.3 years (range, 15.8–89.0 years), comparatively younger than western cohorts. Most were Chinese (71%), followed by Malays (16%), others (9.0%), and Indians (5%). 24% were noted to have a significant family history of malignancy of which breast and gastrointestinal cancers the most prominent. Majority of the patients (80%) had stage I disease at diagnosis. Information on HER2 status was available in 113 cases (85%). Of these, 31 cases (27.4%) were HER2+, higher than 18.8% reported in western population. HER2 positivity appeared to be lower among Chinese and higher among Malays patients (p = 0.052). With the current standard of care, there was no discernible impact of HER2 status on overall survival. (HR = 1.79; 95% CI, 0.66–4.85; p = 0.249). On the other hand, positive family history of cancer, presence of lymphovascular invasion, and ovarian surface involvements were significantly associated with inferior overall survival on univariate and continued to be statistically significant after adjustment for stage. While these clinical factors identify high risk patients, it is promising that the finding of a high incidence of HER2 in our Asian population may allow development of a HER2 targeted therapy to improve the management of mucinous ovarian cancers.

Spontaneous uterine perforation from uterine infarction: a rare case of acute abdomen

Summary: A case of spontaneous uterine perforation from uterine infarction is presented. The authors believe that this is the first reported case.

Recurrent immature teratoma: Lack of correlation between serum level and immunohistochemical detection of serum alpha-fetoprotein

Summary We present the clinicopathologic and immunohistochemical features of a pure immature ovarian teratoma that had arisen in a 15-year-old girl. At original diagnosis immature extra ovarian implants were noted (grade 3) accompanied by moderately elevated serum alpha-fetoprotein (AFP) levels. AFP was immunohistochemically demonstrable in immature endodermal elements. The immature neural tissue present was negative for AFP, and no other tumor elemens were recognisable. Serum AFP fell post-operatively to within normal limits. Despite five courses of chemotherapy and asymptomatic status, the patient re-presented 15 months after original diagnosis with a massive abdominal and pelvic tumor recurrence with predominantly mature glial tissue, but some persistent immature foci. There was no associated increase in serum AFP at this time. AFP was, however, persistently detectable immunohistochemically in immature endodermal components only. Immature neural elements were no longer identified. Disappearance of immature neural tissue in the tumor recurrence may have been related to chemotherapy. This case demonstrates the lack of correlative ability of serum AFP levels with both clinical behaviour and immunohistochemical demonstration of AFP expression in the tumor recurrence.Abbreviations: AFP, alpha-fetoprotein.

Uterine leiomyosarcoma in asian patients: validation of the revised Federation of gynecology and obstetrics staging system and identification of prognostic classifiers.

BACKGROUND In 2008, the Federation of Gynecology and Obstetrics (FIGO) revised their 1988 staging system for uterine leiomyosarcomas. In this article, we compare performance of the 2008 and 1988 FIGO systems. METHODS Individual case data were manually culled. Staging was retrospectively assessed according to revised and 1998 FIGO criteria. Overall survival distribution was assessed by the Kaplan-Meier method. Harrells concordance index was used to assess the discriminative ability of a fitted Cox model to predict overall survival. RESULTS A total of 110 cases of uterine leiomyosarcomas were reviewed and data from 88 patients were analyzed. In all, 71% of cases were classified as stage I, 7% as stage II, 3% as stage III, and 19% as stage IV under the revised FIGO staging system. Nine patients (10.2%) were downstaged and none were upstaged. The revised FIGO system did not show a significant improvement over the 1988 FIGO system in the ability to discriminate the risk of death of patients between stages, with concordance indexes of 0.70 and 0.71, respectively. Most patients were classified as stage I with age, tumor grade, tumor size, and lymphovascular invasion as prognostic factors. CONCLUSION The 2008 revised FIGO staging system for uterine leiomyosarcomas does not perform better than the 1988 system for uterine endometrial carcinomas. A better staging system is needed for these cases.

An 81-Year-Old Man With Cutaneous Periumbilical Purpura

An 81-year-old man complained of abdominal pain and distension and had worsening pulmonary infi ltrates and a new rash. He had a background of cryptogenic organizing pneumonia for which he had been on prednisolone 20 mg po every morning for 4 months prior to admission to hospital. He had been admitted to the ICU 1 month prior for pseudomonas pneumonia, and the stay had been complicated by persistent Pseudomonas cultures, Escherichia coli bacteremia, cytomegalovirus antigenemia, and failure to wean from mechanical ventilation requiring tracheostomy. CT scan of the chest on day 17 of admission showed bilateral honeycomb appearance with widespread ground-glass changes, and BAL the same day was negative for bacterial, fungal, and Mycobacterium smears as well as viral studies. His prednisolone dose was increased to 30 mg every morning.

Dual p16/Ki-67 immunocytochemical stain in cervical smears: A triage comparison with HPV testing, and also with biopsy double immunolabelling (dil) for benign/low grade lesions

Testing for high risk human papilloma virus (HPV) subtypes has been incorporated to triage cervical smears with low grade (LG) squamous abnormalities, atypical squamous cells of uncertain significance (ASCUS) and low grade dysplasia (LGD), as many patients with these findings have infection without any accompanying high grade dysplasia (HGD). Addition of a dual p16/Ki67 immunocytochemical stain (CINtecPLUS) potentially assists prediction of any HG lesion, thereby avoiding unnecessary colposcopy. Comparison of sensitivity and specificity for detection of biopsyproven HGD was made between the 3 modalities of Pap cytology, CINtecPLUS, and HPV testing in a total of 102 smears. CINtecPLUS was found to be the most sensitive method (93.8%) and more specific (76.3%) than HPV testing (21.1%). The most specific method was Pap cytology (89.5%). Comparison of sensitivity and specificity for detection of HGD was made between the 3 modalities of CINtecPLUS, p16 alone, and DIL, in a total of 38 Pap-diagnosed cases of benign/LG lesions. The most sensitive was CINtecPLUS (91.7%), but with a specificity intermediate between DIL (88.5%) and p16 alone (65.4%). Comparison of 7 CINtecPLUS +ve cases with DIL disclosed 2 totally discrepant cases, with confirmed –ve biopsies. Of 6 CINtecPLUS –ve cases, one totally and 5 partly discrepant cases were all LGD. In conclusion, no single investigational modality demonstrated a clearly superior performance.

Images in transplant dermatology

Transplant recipients can develop various skin conditions throughout their lives. Of concern are skin cancers, which are best treated with early detection. We report two cases seen in the transplant dermatology clinic in Singapore General Hospital.

Blistering Eruption of the Buttocks

A woman in her 80s presented with a 1-week history of progressive, painful blisters and ulcers of the groin. This was associated with enlargement of the tongue over the past 3 months, leading to difficulty with mastication. She also reported numbness with no associated weakness of her distal lower limbs for 3 months. This restricted her mobility to the extent that she required diapers. However, she declined any further investigations for her peripheral neuropathy. She had IgG λ-type multiple myeloma complicated by anemia and lytic lesions in the calvarium, which was managed conservatively with transfusions. She was taking folic acid and intramuscular cyanocobalamin supplements owing to deficiencies attributed to a dietary cause. On examination, there were circinate purpuric patches with erosions on the natal cleft, buttocks, inguinal creases, and vulva (Figure, A). Hemorrhagic flaccid bullae were observed on the posterior perineum. This was accompanied by macroglossia, glossitis, and a hemorrhagic erosion on the hard palate (Figure, B). There were purpuric macules periorbitally and on the lips, inframammary folds, forearms, and thighs. Laboratory findings revealed a platelet count of 171 × 103/μL (reference range, 140-440 × 103/μL), prothrombin time of 11.7 seconds (reference range, 9.9-11.4 seconds), activated partial thromboplastin time of 36.0 seconds (reference range, 25.732.9 seconds), and serum zinc levels of 34.4 μg/dL (reference range, 72.4-124.4 μg/dL). (To convert zinc to micromoles per liter, multiply by 0.153.) Results from initial punch biopsies from a purpuric macule on the right inframammary fold and a blister at the perineum were inconclusive. A repeated biopsy from a hemorrhagic blister at the left groin was performed (Figure, C and D). Clinical photograph A Oral examination B