Too Much of a Good Thing: Severe Hypercalcemia Presenting with Lethargy and Kidney Failure.

INTRODUCTION: We present a case of a 58-year-old man with a history of laryngo-pharyngectomy including bilateral thyroidectomy due to hypopharyngeal cancer presenting with lethargy, acute kidney failure, and hypercalcemia. Milk alkali syndrome was diagnosed given the history of high-dose calcium / vitamin D supplementation after ruling out other causes of hypercalcemia. After initial treatment with normal saline, furosemide and denosumab, the patient developed severe symptomatic hypocalcemia as a rare adverse effect of denosumab.

Molecular diagnosis of antibody-mediated rejection: Evaluating biopsy-based transcript diagnostics in the presence of donor-specific antibodies but without microvascular inflammation, a single-center descriptive analysis.

Biopsy-based transcript diagnostics may identify molecular antibody-mediated rejection (AMR) when microvascular inflammation (MVI) is absent. In this single-center cohort, biopsy-based transcript diagnostics were validated in 326 kidney allograft biopsies. A total of 71 histological AMR and 35 T cell-mediated rejection (TCMR) cases were identified as molecular AMR and TCMR in 55% and 63%, respectively. Among 121 cases without MVI (glomerulitis + peritubular capillaritis = 0), 45 (37%) donor-specific antibody (DSA)-positive and 76 (63%) DSA-negative cases were analyzed. Twenty-one out of the 121 (17%) cases showed borderline changes, or TCMR, while BK nephropathy was excluded. None of the 45 DSA-positive patients showed molecular AMR. Among 76 DSA-negative patients, 2 had mixed molecular AMR/TCMR. All-AMR phenotype scores (sum of R4-R6) exhibited median values of 0.13 and 0.12 for DSA-positive and DSA-negative patients, respectively (P = .84). A total of 13% (6/45) DSA-positive and 11% (8/76) DSA-negative patients showed an all-AMR phenotype score > 0.30 (P = .77). Patients with a higher all-AMR phenotype score showed 33% more histologic TCMR (P = .005). The median all-AMR phenotype scores of glomerular basement membrane double contours = 0 and glomerular basement membrane double contours > 0 biopsies were 0.12 and 0.10, respectively (P = .35). Biopsy-based transcript diagnostics did not identify molecular AMR in cases without MVI. Follow-up biopsies and outcome data should evaluate the clinical relevance of subthreshold molecular alterations.

Neurologic involvement in cystinosis: Focus on brain lesions and new evidence of four-repeat (4R-) Tau immunoreactivity.

Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.

The Molecular Diagnosis Might Be Clinically Useful in Discrepant Kidney Allograft Biopsy Findings: An Analysis of Clinical Outcomes.

BACKGROUND: The Molecular Microscope Diagnostic System (MMDx) may overcome histology shortcomings. Previous studies have simply examined discrepant findings but have not attempted to determine clinical endpoints. To measure performance, clinical outcomes are strongly required. METHODS: This single-center cohort study described discrepancies between MMDx and histology from 51 kidney transplant recipients (KTRs) and analyzed 72 indication biopsies, including 21 follow-up biopsies. Clinical performance was assessed by a combined endpoint of graft failure, rejection on follow-up biopsy, de novo donor-specific antibody, and improvement of kidney allograft function upon antirejection treatment. RESULTS: MMDx agreed in 33 (65%) and differed in 18 (35%) of 51 KTRs. Most discrepancies occurred in biopsies called no rejection by MMDx and rejection by histology (15/24, 63%). In contrast, in biopsies called rejection by MMDx, 3 were classified as no rejection by histology (3/27, 11%). Discrepant findings between MMDx and histology occurred following delayed graft function and MMDx from biopsies with a low percentage of cortex. Among 15 biopsies classified as no rejection by MMDx but rejection by histology, the clinical course suggested no rejection in 9 cases. Six KTRs reached the endpoint, showing predominant t ≥ 2 lesions. CONCLUSIONS: The most often occurring discrepancy is rejection by histology but no rejection by MMDx. As more KTRs do not meet the combined endpoint for rejection, MMDx might be clinically useful in these discrepant cases. Although strong histological findings have priority in indicating the treatment, clinical implementation of MMDx could strengthen treatment strategies.

Is Regular Radiographic Upper Urinary Tract Imaging for Surveillance of Non-Muscle Invasive Bladder Cancer Justified?

Patients with non-muscle invasive (NMI) urothelial bladder cancer (BC) are at increased risk for the development of a secondary upper-urinary-tract urothelial carcinoma (UTUC). We aimed to assess the usefulness of routine upper-tract imaging surveillance during NMIBC follow-up in a patient cohort of a tertiary academic center. All routine upper-tract-imaging scans using computerized tomography urography (CTU) between 2003 and 2016 were assessed for UTUC detection. A total of 315 patients were analyzed. Initial tumor stage was Ta in 207 patients (65.7%), T1 in 98 patients (31.1%) and pure CIS in 10 patients (3.2%). A total of 149 (47.3%) presented with low-grade (LG), and 166 (52.7%) with high-grade (HG) disease. Median follow-up was 48 months (IQR: 55). Four patients (1.2%) were diagnosed with UTUC during follow-up. All four patients presented with initial Ta HG BC. Two of the patients (50%) were diagnosed by routine upper tract imaging. The other two patients were diagnosed after development of symptoms. The 5- and 10-year UTUC-free survival was 98.5% (standard error (SE) 0.9) and 97.6% (SE 1.3), respectively. UTUCs were detected exclusively in patients with initial HG disease, indicating that upper-tract surveillance might only be necessary in these patients.

Incidence of new onset glomerulonephritis after SARS-CoV-2 mRNA vaccination is not increased.

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66-1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental.

Clinical spectrum of gross haematuria following SARS-CoV-2 vaccination with mRNA vaccines.

Background: Novel messenger RNA (mRNA)-based vaccines play an important role in current vaccination campaigns against SARS-CoV-2. They are highly efficacious and generally well tolerated. Vaccination in patients with immune-mediated kidney diseases is recommended. A number of cases with de novo or relapsing glomerulonephritis shortly after vaccine application have been reported, some of which presented with gross haematuria. Methods: We collected 10 cases of macrohaematuria following mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination at our tertiary care institution and referring centres. Additionally, we pooled all 25 published cases from the literature with ours to analyse their clinical characteristics. Results: Most macrohaematuria episodes (72.2%) began within 2 days after vaccination, the majority after the second dose. In some individuals, repeated episodes occurred after subsequent doses of the same vaccine. A total of 65.7% of patients never had macrohaematuria before. A total of 45.7% were known to suffer from immunoglobulin A nephropathy (IgAN); the rest had no prior renal diagnosis. IgAN was the most frequent new diagnosis, but anti-neutrophil cytoplasmic antibody-associated vasculitis and anti-glomerular basement membrane disease were also identified. Acute kidney injury (AKI) occurred in 28.6% of patients, with an increase in serum creatinine not meeting Kidney Disease: Improving Global Outcomes AKI criteria in 28.6%. Treatment ranged from conservative management, renin-angiotensin-aldosterone system inhibitors, steroids and cyclophosphamide to plasmapheresis. While renal outcomes were mainly favourable in isolated IgAN, they were poor in patients with additional or isolated small vessel vasculitis. Conclusion: Awareness of gross haematuria after SARS-CoV-2 vaccination is important. Close follow-up and additional work up, particularly in individuals without known underlying kidney disease or worsening renal function, is essential. For patients with vaccine-associated macrohaematuria, an alternative vaccine class might be considered for subsequent vaccinations.

Eosinophilic solid and cystic renal cell carcinoma and renal cell carcinomas with TFEB alterations: a comparative study.

AIMS: Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a recently described renal tumour entity with frequent cytokeratin (CK)20 positivity, commonly harbouring TSC mutations. In contrast, frequency of CK20 expression and presence of TSC mutations are unclear in TFEB-amplified RCC and TFEB-translocated RCC, which frequently express Melan A. Herein, we provide a comparative analysis of six ESC RCC with four TFEB-amplified/translocated RCC. METHODS AND RESULTS: We assessed the frequency of CK20 and Melan A expression by immunohistochemistry and of TSC mutations by next-generation sequencing. TFEB alterations were confirmed by fluorescence in-situ hybridisation (FISH). All tumours showed voluminous eosinophilic cells with granular cytoplasm, prominent nucleoli, and most showed admixture of solid and cystic areas. CK20 expression was found in all six ESC RCC and in all RCCs with TFEB alterations. Melan A positivity was identified in five of six ESC RCC and four of four RCC with TFEB alterations. We found TSC mutations in two ESC RCCs, including in one case also harbouring a CIC fusion, and identified a TSC mutation in one TFEB-amplified RCC. CONCLUSIONS: ESC RCC represents an emerging renal tumour entity with some histological, immunohistochemical and molecular overlap to TFEB-amplified/translocated RCC. FISH for TFEB aids in this differential diagnosis in challenging cases.

Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings.

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).

The Morphological Spectrum of Papillary Renal Cell Carcinoma and Prevalence of Provisional/Emerging Renal Tumor Entities with Papillary Growth.

Renal cell carcinoma (RCC) represents a heterogeneous disease, encompassing an increasing number of tumor subtypes. Post-2016, the World Health Organization (WHO) classification recognized that the spectrum of papillary renal cell carcinoma is evolving and has long surpassed the dichotomic simplistic "type 1 versus type 2" classification. The differential diagnosis of pRCC includes several new provisional/emerging entities with papillary growth. Type 2 tumors have been cleared out of several confounding entities, now regarded as independent tumors with specific clinical and molecular backgrounds. In this work we describe the prevalence and characteristics of emerging papillary tumor entities in two renal tumor cohorts (one consisting of consecutive papillary tumors from a single institute, the other consisting of consultation cases from several centers). After a review of 154 consecutive pRCC cases, 58% remained type 1 pRCC, and 34% type 2 pRCC. Papillary renal neoplasm with reversed polarity (1.3%), biphasic hyalinizing psammomatous RCC (1.3%), and biphasic squamoid/alveolar RCC (4.5%) were rare. Among 281 consultation cases, 121 (43%) tumors had a dominant papillary growth (most frequently MiT family translocation RCCs, mucinous tubular and spindle cell carcinoma and clear cell papillary RCC). Our data confirm that the spectrum of RCCs with papillary growth represents a major diagnostical challenge, frequently requiring a second expert opinion. Papillary renal neoplasm with reversed polarity, biphasic hyalinizing psammomatous RCC, and biphasic squamoid/alveolar RCC are rarely sent out for a second opinion, but correct classification and knowledge of these variants will improve our understanding of the clinical behavior of renal tumors with papillary growth.

Granulomatous lung disease and immune reconstitution inflammatory syndrome in Whipple's disease.

We present the case of a 70-year-old woman with a history of seronegative arthritis, recurrent pleural effusion and weight loss. A prior lung biopsy had revealed non-caseating epithelioid cell granulomas without evidence for microbial organisms on special stains. Intestinal biopsy findings where suspicious for Whipple's disease, which was confirmed by PCR testing, both on the intestinal and retrospectively on the lung tissue. Treatment with ceftriaxone resulted in clinical deterioration with fever, arthritis and recurrent pleuritis consistent with immune reconstitution inflammatory syndrome. Dose increase of glucocorticoids and therapy rotation to doxycycline and hydroxychloroquine resulted in rapid clinical improvement.

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach.

The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome-associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome-associated RCC exhibited an unusual morphology with accumulation of "colloid-like" cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next-generation sequencing analyses of HLRCC syndrome-associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC-RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome-associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC - and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome-associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the "second hit" hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.

Inter-observer reproducibility of classical lobular neoplasia (B3 lesions) in preoperative breast biopsies: a study of the Swiss Working Group of breast and gynecopathologists.

PURPOSE: Classical type of lobular neoplasia (LN) spans a spectrum of disease, including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), classical lobular neoplasia (LN), and the three-tiered classification of lobular intraepithelial neoplasia (LIN-1, -2, -3). This study addressed inter-observer variability of classical lobular neoplasias (LN) (B3 lesions) in preoperative breast biopsies among breast and gynecopathologists METHODS: A retrospective, observational, cross-sectional study was conducted. 40 preoperative digital images of breast core/vacuum biopsies were analyzed by eight experienced breast- and gynecopathologists. Evaluation criteria were ALH, LCIS, LN classic, LIN-1, LIN-2, LIN-3, focal B3 (one focus), extensive B3 (> one focus). Kappa-index and Chi-square tests were used for statistics. Digital scanned slides were provided to each participant. Agreement between the categories was defined as at least six of eight (cut-off 75%) concordant diagnoses. RESULTS: The highest agreement between eight pathologists was reached using the category lobular neoplasia (LN, classical), 26/40 (65%) cases were diagnosed as such. Agreements in other categories was low or poor: 12/40 (30%) (ALH), 9/40 (22%) (LCIS), 8/40 (20%) (LIN-1), 8/40 (20%) (focal B3), 3/40 (7.5%) (LIN-2), and 2/40 (5%) (extensive B3). Chi-square-test (classical LN versus the other nomenclatures) was significant (p = 0.001137). CONCLUSION: Our data suggest that among Swiss breast pathologists, the most reproducible diagnosis for B3 lobular lesions is the category of classical LN. These data further support lack of consistent data in retrospective studies using different terminologies. Validation of reproducible nomenclature is warranted in further studies. This information is useful especially in view of retro- and prospective data analysis with different diagnostic categories.

Spiradenocarcinoma: A Comprehensive Data Review.

INTRODUCTION: Spiradenocarcinomas (SCs) are rare and potentially aggressive skin adnexal tumors. Optimal treatment has not yet been established. Experiences with this carcinoma are mostly presented in case reports and few case series. OBJECTIVE: To generate to a synopsis of published data on SC with regard to diagnostic procedures, treatment, and outcome. RESULTS: Median patient age was 60 years and sex distribution was balanced. Tumor manifestations were evenly distributed within the sweat gland carrying skin. The most commonly reported symptom was accelerated growth of a longstanding indolent lesion, typically present for more than 2 years. Metastatic spread to the lung, bone, lymph nodes, liver, kidney, and breast has been documented. For staging computed tomography (CT) and positron emission tomography-CT are recommended, especially for detection of hematogenic metastases and lymph node involvement. Clear resection margins and tumor free regional lymph nodes reduce recurrence and carcinoma related death. Although low-grade SCs were reported over 3 times more often, high-grade carcinomas show a greater likelihood for recurrence and lethal outcome. CONCLUSION: Suspicion of an SC should lead to performance of a magnetic resonance imaging for defining tumor extent, and a fludeoxyglucose positron emission tomography-CT for detection of metastases. Radical tumor excision and resection of tumor involved regional lymph nodes are essential for a curative approach. Histopathological evaluation should involve determination of tumor differentiation grade, because high-grade carcinomas seem to have a much more aggressive behavior. Excision of distant metastases has no therapeutic value. Follow-up needs to be carried out in short intervals with frequent imaging.

Alveolar echinococcosis of the right adrenal gland: a case report and review of the literature.

BACKGROUND: Extrahepatic manifestations of Echinococcus multilocularis are very rare, especially in the adrenal glands. To the best of our knowledge, only seven cases of adrenal alveolar echinococcosis have been reported, all from the Far East. All of these occurred exclusively in the right adrenal gland. CASE PRESENTATION: We report a rare case of an extrahepatic alveolar echinococcosis in an asymptomatic 78-year-old white man with an incidentaloma of his right adrenal gland. After surgical resection and medical treatment with albendazole no recurrence of the disease appeared at 1-year follow-up. CONCLUSIONS: As the occurrence of Echinococcus multilocularis in Europe increases, alveolar echinococcosis should be included in the differential diagnosis of cystic adrenal incidentalomas.

An unusual case of mediastinal mass and bilateral nodules.

A 23-year-old woman presented with a mediastinal paraganglioma and multiple pulmonary chondromas following antral gastric resection for gastrointestinal stromal tumor. These tumors form the Carney triad, a rare disorder of unknown genetic background. First described in 1977, approximately 120 cases have been documented in the literature. The tumors do not harbor the specific c-kit or PDGFRA gene mutations often found in sporadic gastrointestinal stromal tumor. In most cases, gastric gastrointestinal stromal tumor is the first tumor to be detected, with secondary tumors appearing years later. Even if it is rare, Carney triad should be suspected in young patients with history of gastrointestinal stromal tumor.

Preinvasive colorectal lesion transcriptomes correlate with endoscopic morphology (polypoid vs. nonpolypoid).

Improved colonoscopy is revealing precancerous lesions that were frequently missed in the past, and ∼30% of those detected today have nonpolypoid morphologies ranging from slightly raised to depressed. To characterize these lesions molecularly, we assessed transcription of 23,768 genes in 42 precancerous lesions (25 slightly elevated nonpolypoid and 17 pedunculated polypoid), each with corresponding samples of normal mucosa. Nonpolypoid versus polypoid morphology explained most gene expression variance among samples; histology, size, and degree of dysplasia were also linked to specific patterns. Expression changes in polypoid lesions frequently affected cell-cycling pathways, whereas cell-survival dysregulation predominated in nonpolypoid lesions. The latter also displayed fewer and less dramatic expression changes than polypoid lesions. Paradigmatic of this trend was progressive loss through the normal > nonpolypoid > polypoid > cancer sequence of TMIGD1 mRNA and protein. This finding, along with TMIGD1 protein expression patterns in tissues and cell lines, suggests that TMIGD1 might be associated with intestinal-cell differentiation. We conclude that molecular dysregulation in slightly elevated, nonpolypoid, precancerous colorectal lesions may be somewhat less severe than that observed in classic adenomatous polyps.

Early Breast Cancer Precursor Lesions: Lessons Learned from Molecular and Clinical Studies.

Atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN) form a group of early precursor lesions that are part of the low-grade pathway in breast cancer development. This concept implies that the neoplastic disease process begins at a stage much earlier than in situ carcinoma. We have performed a review of the published literature for the upgrade risk to ductal carcinoma in situ or invasive carcinoma in open biopsy after a diagnosis of ADH, FEA, or LN in core needle biopsy. This has revealed the highest upgrade risk for ADH (28.2% after open biopsy), followed by LN (14.9%), and FEA (10.2%). With LN, the pleomorphic subtype is believed to confer a higher risk than classical LN. With all types of precursor lesions, careful attention must be paid to the clinicopathological correlation for the guidance of the clinical management. Follow-up biopsies are generally indicated in ADH, and if there is any radiological-pathological discrepancy, also in LN or FEA.