Emergence of overt myeloma in a patient with chronic lymphocytic leukemia on ibrutinib therapy.

Ibrutinib is approved for chronic lymphocytic leukemia (CLL). However, its role in the treatment of multiple myeloma (MM) is not clear and is under investigation. We report a case of CLL that developed MM while on therapy with ibrutinib indicating that this drug may not be active against MM.

Disease Progression in a Patient With Indolent T-Cell Lymphoproliferative Disease of the Gastrointestinal Tract.

Indolent T-cell lymphoproliferative disorder (T-LPD) of the gastrointestinal (GI) tract is a new provisional entity in the 2016 revision of the World Health Organization classification. The disease has an indolent course and progression to aggressive T-cell lymphoma has rarely been reported. We describe a case of a 37-year-old male with indolent T-LPD of the GI tract who 3 years later developed aggressive T-cell lymphoma and died of progressive disease. An infiltrate of indolent T-LPD in the GI tract and aggressive lymphoma diagnosed from the liver biopsy had similar immunophenotype, but cellular infiltrate in the liver showed more atypia compared with the GI biopsies of indolent T-LPD. Moreover, T-cell gene rearrangement studies showed an identical clonal rearrangement in indolent T-LPD and aggressive lymphoma. Patients with indolent T-LPD of the GI tract need a long-term follow-up, as some of them may develop more aggressive lymphoma.

Utility of Additional Tissue Sections in Surgical Pathology.

BACKGROUND: To avoid diagnostic errors such as missed diagnosis and errors in staging tumors due to inadequate tissue sampling, pathologists submit additional sections (AS). OBJECTIVE: This study assessed frequency, diagnostic yield, distribution, and cost of AS. METHOD: Among 1542 AS cases, we calculated mean AS per case; fraction of AS that altered diagnosis or stage; AS variation by tissue, malignant versus benign lesions, presence or absence of neoadjuvant therapy, mass, margin, lymph nodes, or other source, resident versus pathologist assistant (PA) dissector; and AS cost per case. RESULTS: Overall 9.2 ± 8.8 AS were collected per case. In only 3.8% (58/1542) of cases AS altered diagnosis or stage. Urinary bladder cases provoked the most AS: 19.5 ± 15.1 per case. Significantly more AS came from malignant versus benign lesions (10.8 ± 9.7 vs 7.6 ± 7.5, P = <.0001) and from specimens treated with neoadjuvant therapy versus malignant lesions not so treated (12.3 ± 9.4 vs 10.3 ± 9.8, P = .02). Lymph nodes were sampled more heavily compared with mass, margin, and other sites combined (11.8 ± 11.4 vs 8.9 ± 8.4, P = .003), but in 78.4% (1209/1542) of cases, AS were from mass. Of diagnosis or stage altering AS cases, two thirds (38/58) were from masses, one fifth (11/58) from lymph nodes, a 10th (6/58) from margins, and a 20th (3/58) from other specimen sites. Resident versus pathologist assistant dissection caused no significant AS difference. AS contributed 40% cost per case. CONCLUSIONS: AS per case ranged widely; their diagnostic yield was low; they were highest in urinary bladder specimens, in malignant and particularly neoadjuvant-treated lesions. Although lymph nodes were most heavily sampled, most AS were from masses. Resident dissection did not increase AS and cost of AS was high.

Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes.

We identified 120 multiple myeloma (MM) cases with satisfactory cytogenetic evaluation and abnormal karyotypes. Hyperdiploid karyotype was found in 77 cases (64%), hypodiploid in 30 cases (25%), and the remaining 13 cases (11%) had a pseudodiploid karyotype. The most common numerical abnormalities were gains of chromosomes 15, 9, 3 followed by chromosomes 19, 11, 7, 21, and 5. Whole chromosome losses were also frequent involving primarily chromosomes X/Y, 8, 13, 14, and 22. Most cases showed also structural rearrangements leading to del(1p), dup(1q), del(5q), del(6q), del(8p), del(9p), del(13q), and del(17p). Chromosome 13/13q deletion was found in 52% of cases; complete loss of 13 was observed in 73% of cases, whereas 27% had interstitial deletions. In addition, 13/13q deletions occurred in 75% of nonhyperdiploid myeloma but only 39% of the hyperdiploid had 13/13q deletions. Translocations affecting 14q32/IGH region was seen 40 cases; t(11;14)(q13;q32) in 17 cases, t(14;16)(q32;q23) and t(8;14)(q24;q32) in three cases each, and t(6;14)(p21;q32) and t(1;14)(q21;q32) in two cases each. The remaining 14q32 translocations had various t(V;14) partners or of an undetermined origin. Remarkably, the 14q32/IGH translocations were less frequent in the hyperdiploid karyotypes than the nonhyperdiploid karyotypes (17 vs. 63%). Fourteen cases showed break at 8q24/CMYC site; seven of those had Burkitt's-type translocations. Our results revealed that conventional cytogenetics remains an important tool in elucidating the complex and divers genetic anomalies of MM. Cytogenetics identifies two distinct groups of MM, hyperdiploid and nonhyperdiploid, and establishes the presence of prognostic chromosomal markers such as 13/13q, 17p, 8q24, and 16q aberrations.

The major autopsy findings in adult patients after hematopoietic stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative treatment option for hematological malignancies, but this treatment can be associated with a mortality risk. MATERIAL/METHODS: A ten-year retrospective review of all autopsies was performed where those who underwent HSCT were studied. The major autopsy findings and the cause of death were characterized and compared between those seen in allogeneic and those in autologous HSCT recipients. The study period preceded the use of prophylactic antifungal agents. RESULTS: A total of 66 autopsies were identified; 52 (79%) received allogeneic and 14 (21%) autologous transplantation. Death occurred at a median of 85 days post transplantation (range 2-1825 days); 36 (55%) died within the first 100 days post stem cells infusion. The major complications for HSCT patients were pulmonary, including diffuse alveolar damage (DAD), acute pneumonia and invasive pulmonary aspergillosis. The most common cause of death in the allogeneic HSCT group was DAD (13/52; 25%), followed by invasive pulmonary aspergillosis (10/52; 19%), acute pneumonia (10/52; 19%) and massive gastrointestinal bleeding (6/52; 12%); in the autologous group causes were disease relapse/progression of the underlying malignancy (4/14; 29%), acute pneumonia (3/14; 21%) and DAD (2/14; 14%). CONCLUSIONS: We conclude that the spectrum of disease entities, commonly diagnosed at autopsy in HSCT recipients may provide insight to clinicians for anticipating complications and consequently help in the management of these high risk patients. The increased infectious complications observed in the allogeneic transplant cases may be explained by immunosuppression and that the study period preceded the use of prophylactic antifungal agents. However, relapse/progression of the disease is the predominant cause of mortality after autologous transplant.

A proposal for a new and more practical grading scheme for pancreatic ductal adenocarcinoma.

There is no uniformly applied grading system for pancreatic ductal adenocarcinoma (DA). The scheme advocated by the WHO is essentially that of Kloppel et al, and is based on the "highest grade" focus. Although it is precise with good prognostic value, it is unfortunately not widely applied, largely because of the lack of recognition and partly because of its complex nature (interpretation of multiple parameters). Furthermore, it is fundamentally different from the one used in Japan, which evaluates the overall pattern. To establish a more widely applicable, practical, and clinically relevant grading system, a scheme similar to Gleason's scoring system was developed and tested on 112 cases of resected pancreatic DA and was compared with the WHO system. In the grading system devised, patterns (P) of infiltration were classified as follows: P1, well-defined glands with easily discernible contours; P2, fused or poorly formed glands with ill-defined contours; P3, nonglandular patterns. A score was then obtained by the summation of the predominant and the secondary patterns. Scores < or =3 (at least some well-formed glands and no nonglandular pattern) was graded as G1, 4 as G2, and > or =5 (at least some nonglandular patterns and no well-formed glandular pattern) as G3. Seventy-three percent of the cases displayed mixed patterns, with disparate patterns (P1 with P3) in 13%, confirming the high degree of heterogeneity of DA. There was a significant correlation between grade and survival, better than the correlation between survival and either the major or minor patterns evaluated separately. The median survival for G1, G2, and G3 were 22, 14, and 8 months; 1-year survival 68%, 44%, and 33%; 2-year was 67%, 11%, and 0%; and 3-year was 23%, 4%, and 0%, respectively (P = 0.0019). In a multivariate analysis, correlating survival with grade, tumor size, and lymph node status, the grade was the strongest independent predictor of survival. Odds ratio of dying of disease were 3.56 (P < 0.0001) in G3 versus G1, 1.79 (P = 0.058) in G2 versus G1, and 1.98 (P = 0.03) in G3 versus G2. Compared with this, the same odds ratio were 1.17 (P = 0.01) in tumors >2 cm versus < or =2 cm and 1.78 (P = 0.01) in cases with positive versus negative lymph nodes. The WHO grading scheme was not found to have as good a correlation with survival in this study, with WHO grade 2 showing a better survival than 1. The reproducibility of both the proposed grading system and that of WHO were found to be moderately good (with kappa values of 0.43 and 0.44, respectively), when 32 slides of DA were graded by four independent observers. The grading scheme for pancreatobiliary adenocarcinoma proposed here is highly applicable because it is practical and readily adoptable. It reflects biologic characteristics of ductal carcinoma (prominent tubule formation and tumor heterogeneity). Most importantly, it is clinically relevant with good prognostic value. Lastly, it is also applicable for use in research, by utilizing "patterns," even in small specimens like microarrays or biopsies.

Histopathologic analysis of atypical lesions in image-guided core breast biopsies.

Appropriate follow-up of patients with needle core breast biopsies (NCBB) showing atypical hyperplasia remains unclear because previous studies show that subsequent open biopsies in variable proportions of these patients reveal ductal carcinoma in situ (DCIS) or even invasive carcinoma, indicating significant sampling artifact. NCBB with diagnoses of atypia were morphologically classified into groups as follows: I, ALH (n = 24); II, ADH with minimal cytologic atypism (n = 90); III, atypia, other (9 columnar, 2 apocrine, 11 atypical papillary); IV, severe ADH/borderline DCIS (n = 31). Mammographic and histologic features, including the number of foci of atypia in the NCBB and the calcification span, were then correlated with presence of DCIS or invasive tumor in subsequent open excisions. Open excisional biopsies showed more severe lesions in 12% of Group I-III cases (8% in Group I, 9% in Group II, and 27% in Group III), of which 15 were DCIS and one was an invasive tubular carcinoma (0.3 cm). Of the DCIS, 60% (n = 9) were < or =5 mm, and 13 of 15 (87%) were low grade. The NCBB cavity was immediately adjacent to the more severe lesions in 88% (n = 14) of cases, in keeping with sampling error. The subset showing severe ADH with borderline nuclear features in contrast was associated with a high likelihood (63%) of DCIS in follow-up excisions. NCBB with atypical papillary features also showed a high frequency of DCIS (4/11, 36%) in subsequent open excisions. Other factors associated with more severe lesions on open biopsy included the number of atypical foci in the NCBB (>4, P <.05) and the mammographic calcification span (>2.0 cm, P <.0001). Atypical lesions diagnosed in NCBB samples are radiographically and morphologically heterogeneous, accounting for the variable frequency of DCIS or invasive neoplasm identified in subsequent open excisions, which are usually focal, low grade, and a consequence of sampling artifact (i.e., adjacent to the NCBB cavity). DCIS is more likely if microcalcifications are mammographically extensive or if atypia is multifocal or is associated with borderline cytologic features.

Histologic and radiographic analysis of ductal carcinoma in situ diagnosed using stereotactic incisional core breast biopsy.

BACKGROUND: Stereotactic incisional core breast biopsy (SCBB) is a highly specific technique for diagnosing ductal carcinoma in situ (DCIS) in patients with suspicious mammographic microcalcifications. However, its sensitivity for excluding the presence of coexisting occult invasive disease in this setting is not fully established. DESIGN: We correlated SCBB findings to subsequent lumpectomy/mastectomy (lx/mx) results in 122 cases of DCIS. In 29 of these cases, the SCBB showed microscopic invasion (n = 15) or foci that were suspicious for invasion (n = 14). Likelihood for invasive disease in subsequent lx/mx samples from each case then was compared with various parameters, including DCIS grade, extent and mammographic findings. RESULTS: Overall, 13% of cases in which the SCBB showed DCIS only (i.e., without any evidence of invasion), had invasive disease in the subsequent excision. This finding was significantly correlated with DCIS grade (low: 0/26 [0%], intermediate: 2/31 [6%], high: 10/36 [28%], P <.001). Invasive lesions were usually small (nine T1a, one T1b, and two T1c) and typically present within more extensive fields of DCIS (no invasion: 1.5 cm DCIS size; invasion: 2.8 cm mean DCIS size, P =.01). This was reflected by greater extent of involvement in the SCBB (5/8 cases with invasion had >15 ducts involved, versus 4/23 with <15 ducts involved, P =.03). SCBB that were suspicious or positive for microinvasion demonstrated invasion in most subsequent excision (susp: 7/14 [50%], microinv: 11/15 [73%]), generally of significant extent (11/18 T(1b-c)). CONCLUSIONS: 1. Patients with SCBB showing high grade DCIS and DCIS suspicious or positive for microinvasion have a significant and high likelihood, respectively, of harboring occult invasive neoplasm. They should accordingly be carefully evaluated radiographically, and possibly with sentinel node biopsy to facilitate axillary staging. 2. Likelihood of occult invasion is correlated with overall DCIS size/extent.