Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies - results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers.

BACKGROUND: Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level. METHODS: We identified 6675 patients with a diagnosis of primary lung, breast, colorectal, or liver cancer who visited the Kimmel Cancer Center at the Thomas Jefferson University from 1998 to 2011. All patients had at least two Hb measurements within the first six months after diagnosis. We analyzed the main, dose-dependent, and time-dependent effects of Hb changes on patient survival. RESULTS: Compared to patients with a low Hb change (|∆Hb|≤2.6), those having a |∆Hb|>2.6 exhibited a significantly shorter survival (hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5 × 10(-22), Plog rank=1.6 × 10(-39)). This association remained significant across the four cancer types. Bootstrap resampling validated these findings 100% of the time with P<0.01 in all patients and in patients of individual cancers. The association exhibited an apparent U-shape dose-dependent pattern. Time-dependent modeling demonstrated that the effect of Hb change on the survival of the overall patient population persisted for approximately 4.5 years after diagnosis. CONCLUSION: Post-diagnosis Hb change associates with the survival of multiple cancers and may have clinical values in tailoring anti-anemia treatments. Because Hb level is frequently measured during cancer treatment, Hb changes may be a potentially important variable in building cancer prognosis models.

Do sporadic Peutz-Jeghers polyps exist? Experience of a large teaching hospital.

Most types of sporadic gastrointestinal (GI) polyps vastly outnumber their syndromic counterparts. In contrast, the incidence of sporadic Peutz-Jeghers polyps (PJP) is unknown. We examined all potential PJP seen at our hospital over a 22-year (y) period to assess the incidence of sporadic PJP. The pathology database of a large hospital was searched for "Peutz-Jeghers polyp(s)," yielding 121 polyps from 38 patients. The polyps were reviewed by 3 pathologists to confirm the diagnosis. Clinical information to confirm or refute a diagnosis of Peutz-Jeghers syndrome (PJS) was collected. Of the 102 polyps included after histologic review, 94 polyps arose in patients meeting the World Health Organization criteria for PJS. These PJS polyps were eliminated from further analysis. Clinical information was obtained for the remaining 8 patients with potential "sporadic" PJP (1 to 50 y; mean=14 y; median=4 y). Of the 8 potential sporadic PJP, only 3 polyps from 3 patients had unequivocal PJP histologic features, all from the small intestine. All 3 patients had clinical histories suggesting syndromic PJP although they did not meet World Health Organization criteria, that is, 2 developed pancreatic cancer, 1 had bilateral "ovarian cystic masses" and a glomus tympanicum tumor, and 1 had strong family history of GI malignancies. The 5 remaining patients each had a colonic polyp with features suggestive, but not definitely diagnostic of, PJP. In these cases, prolapse lesions could not be excluded. One patient had a history of high-grade dysplasia in a tubulovillous adenoma in the colon at 53 years, but no family cancer history. Another had a family GI cancer history. Another had a history of pituitary adenoma at age 39, and the last had ductal breast carcinoma diagnosed 4 years before the discovery of the polyp. Our findings suggest that if sporadic PJP exist, they are extremely rare. Moreover, our data suggest that individuals with a single PJP may have a cumulative lifetime risk of cancer similar to those with the syndrome.

Poorly differentiated colorectal carcinoma with invasion restricted to lamina propria (intramucosal carcinoma): a follow-up study of 15 cases.

Invasive colorectal carcinomas (CRCs) with invasion confined to the lamina propria (LP) [intramucosal carcinoma (IMC)] lack access to lymphatics and therefore have no potential for metastases and local intervention (usually polypectomy) should be adequate treatment. For this reason, they are classified as "Tis" in the TNM system. It is believed that carcinomas invading the submucosa with unfavorable histology (tumors at/near the margin, and/or vascular invasion, and/or poor differentiation) require additional intervention after polypectomy, whereas those with favorable histology can be safely treated endoscopically. However, there are few data on poorly differentiated (PD) carcinomas showing invasion confined to the LP. Polypectomy is theoretically curative but in practice this has not been well demonstrated. Thus, the clinicopathologic features of 15 cases of PD CRCs with invasion limited to the LP on initial biopsies were studied to determine the best course of management for this rare subset of carcinomas. A computer search and histologic review of cases seen at Johns Hopkins Hospital was performed. Fifteen cases of PD CRC with invasion limited to the LP were identified. The clinicopathologic features of these tumors were reviewed. All 15 cases showed PD IMC with single cells infiltrating only the LP. Patients were 38 to 79 years (median, 62) of age with a male predominance (M:F=4:1). Three cases had signet ring cell differentiation, 1 had focal small cell features, and another had focal squamous differentiation. Fourteen of the cases were associated with background adenomas or adenomalike lesions including: 7 involving tubulovillous or villous adenomas, 6 involving tubular adenomas, 1 involving dysplasia associated with chronic inflammatory bowel disease. Nine of the lesions had surrounding high-grade dysplasia. One case showed no background dysplasia or adenoma. One patient was lost to follow-up and the remaining 14 were followed for 1 to 96 months (mean, 21.3 mo; median, 13 mo). Seven patients had no residual disease on follow-up colonoscopy, and no resection was performed. The remaining 7 patients were treated with partial colectomy (6) or low anterior resection (1), and of these, 5 had no infiltrating carcinoma and negative lymph nodes. One patient had a separate large colorectal (T3) carcinoma with 8/10 positive regional lymph nodes; the IMC seen on biopsy was presumably a metastasis as it was unassociated with an in situ component. Finally, the resected rectum from which an IMC had been previously detected had no residual invasive carcinoma, but the anal skin was involved by Paget disease. Thus, of the 15 cases of PD CRCs limited to the LP, 1 was a metastasis from a separate CRC and another had associated Paget disease of the anal skin. As such, even in the setting of PD carcinomas, no metastatic disease was seen arising from any of the cases that were confirmed as early primary lesions. These preliminary findings suggest that patients with isolated intramucosal PD CRCs may be managed endoscopically.

Inflammatory myofibroblastic tumors of the urinary tract: a clinicopathologic study of 46 cases, including a malignant example inflammatory fibrosarcoma and a subset associated with high-grade urothelial carcinoma.

Inflammatory myofibroblastic tumor (IMT) of the urinary tract, also termed postoperative spindle cell nodule, inflammatory pseudotumor, and pseudosarcomatous fibromyxoid tumor, is rare and in the past was believed to reflect diverse entities. We reviewed a series of 46 IMTs arising in the ureter, bladder, and prostate, derived primarily from a large consultation practice. There were 30 male and 16 females aged 3 to 89 years (mean 53.6). Lesions were 1.2 to 12 cm (mean 4.2). There was a history of recent prior instrumentation in 8 cases. Morphology was similar to that previously described for IMT occurring in this region, with the exception of 1 case that focally appeared sarcomatous. Polypoid cystitis coexisted in 5 patients (11%). Mitoses were typically scant (0 to 20/10 hpf, mean 1). Necrosis was seen in 14 (30%) cases. Invasion of the muscularis propria was documented in 19 (41%). By immunohistochemistry (IHC), lesions at least focally expressed anaplastic lymphoma kinase (ALK) (20/35, 57%), AE1/3 (25/34, 73%), CAM5.2 (10/15, 67%), CK18 (6/6, 100%), actin (23/25, 92%), desmin (15/19, 79%), calponin (6/7, 86%), caldesmon (4/7, 57%, rare cells), p53 (10/13, 77%), and most lacked S100 (0/14), CD34 (0/13), CD117 (2/13, 15%), CD21 (0/5), and CD23 (0/3). ALK gene alterations were detected by fluorescence in situ hybridization (FISH) in 13/18 (72%) tested cases, including 2 with prior instrumentation; 13/18 (72%) showed agreement between FISH ALK results and ALK protein results by IHC. Most bladder IMTs were managed locally, but partial cystectomy was performed as the initial management in 7 cases and cystectomy in 1 (1 IMT was initially misinterpreted as carcinoma, 1 IMT was found incidentally as a separate lesion in a cystectomy specimen performed for urothelial carcinoma). Follow-up was available in 32 cases (range 3 to 120 mo; mean 33; median 24). There were 10 patients with recurrences (2 with 2 recurrences). Recurrences were unassociated with muscle invasion or with ALK alterations. In 2 cases, tumors of the urinary tract (TURs) showing IMT preceded (1 and 2 mo, respectively) TURs showing sarcomatoid carcinoma with high-grade invasive urothelial carcinoma accompanied with separate fragments of IMT. Even on re-review the IMT in these 2 cases were morphologically indistinguishable from other cases of IMT, with FISH demonstrating ALK alterations in the IMT areas in one of them. Both these patients died of their carcinomas. Lastly, there was 1 tumor with many morphological features of IMT and an ALK rearrangement, yet overtly sarcomatous. This case arose postirradiation for prostate cancer 4 years before the development of the lesion, with tumor recurrence at 4 months and death from intra-abdominal metastatic disease at 9 months. In summary, urinary tract IMTs are rare and share many features with counterparts in other sites, displaying similar morphology and immunogenotypic features whether de novo or postinstrumentation. Typical IMTs can be locally aggressive, sometimes requiring radical surgical resection, but none of our typical cases metastasized, although they can rarely arise contemporaneously with sarcomatoid urothelial carcinomas. For these reasons, close follow-up is warranted.

Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions "caught in the act".

Sessile serrated adenomas (SSAs) show serrations typical of hyperplastic polyps but display architectural differences and lack traditional dysplasia. SSAs with foci of low- (LGD) or high-grade dysplasia (HGD) or early invasive carcinoma are seldom biopsied and, thus, are not well studied. Immunohistochemical analysis for MLH1, MSH2, MSH6, and PMS2 (mismatch repair gene products) was performed on colon biopsy specimens from 11 patients (age range, 54-87 years; 4 men and 7 women) showing SSA with LGD (n = 1), HGD (n = 5), or focal invasive carcinoma (n = 5). All 11 cases showed intact nuclear staining for MSH2 and MSH6 in the SSA component; in foci of LGD, HGD, or carcinoma; and in background normal mucosa. In contrast, there was tandem loss of MLH1 and PMS2 in zones of LGD (1/1) or HGD (3/5) and early carcinoma (2/4; with concordant loss in associated HGD) but retention in SSA areas (11/11) and normal mucosa (11/11). No patient was known to have hereditary nonpolyposis colorectal cancer/Lynch syndrome. This study offers additional strong evidence that SSA is truly a precursor to at least a subset of sporadic microsatellite-unstable colorectal cancer.

Fibromatosis of the remnant pancreas after pylorus-preserving pancreaticoduodenectomy.

Intra-abdominal fibromatosis or desmoid tumors are rare forms of connective tissue cellular dysplasia characterized by proliferation of fibroblasts and abundant collagen. Most often these tumors associated with familial adenomatous polyposis or Gardner's syndrome. Those tumors not associated with polyposis are termed sporadic desmoids and tend to be locally aggressive in nature. Sporadic intra-abdominal desmoids involving the pancreas are quite rare, as only six previously reported cases exist. In this report we present a seventh case of a sporadic intraabdominal desmoid involving the pancreas. The patient, a 63-year-old white man, developed the desmoid tumor following a pylorus-preserving pancreaticoduodenectomy for an insulinoma. The patient was managed via further pancreatectomy, consisting of a distal pancreatectomy with en bloc splenectomy, sparing a 6-cm portion of pancreatic neck and proximal body. Finally, we present a complete review of the six previous cases of sporadic pancreatic fibromatosis.

Association between common variable immunodeficiency and collagenous infiltrative disorders of the gastrointestinal tract: A series of four patients.

Hypogammaglobulinemia/common variable immunodeficiency (CVID) may lead to disruption of the gut mucosal immune barrier. Collagenous infiltrative disorders of the intestinal tract (colitis, gastritis, sprue) constitute a relatively new spectrum of gastrointestinal disorders. Our aims were (1) to determine the association between immunoglobulin deficiency state like CVID and collagenous infiltrative disorders of the gut and (2) to study the clinic-pathologic characteristics and treatment outcomes in these patients. A retrospective search was conducted to identify cases with concurrence of these two conditions at an academic center from 2007 to 2013. Four such patients were identified from our database: three with collagenous colitis and one with collagenous gastritis. All patients with collagenous colitis had normal colonic mucosa while the patient with collagenous gastritis had nodular gastric mucosa. Only one patient out of four had decreased plasma cells in the submucosa as expected in low immunoglobulin states. All patients had improvement in their symptoms on immunoglobulin therapy with considerable remission on budesonide. Literature search revealed reporting of four similar patients. In conclusion, (1) the association between collagenous infiltrative disorders of the gut and CVID and its prompt response to immunoglobulins with effective maintenance with budesonide are novel findings. Our study also shows that the presence of plasma cells should not rule out the possibility of CVID. (2) In patients with chronic diarrhea, hypogammaglobulinemia and collagenous colitis/sprue should be considered for the available effective treatments such as immunoglobulins and budesonide.

ARID2, p110α, p53, and ß-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications.

ARID2 (ARID2), CTNNB1 (ß catenin), tumor protein 53 (p53), and PIK3CA (p110α) mutations are implicated in hepatocellular carcinoma (HCC); and previous work has contributed to thorough molecular characterization of these events. However, studies that assess the impact of these mutations on downstream protein expression, especially those that evaluate all 4 cancer markers simultaneously, are relatively lacking. Hence, the present study uses immunohistochemistry to assess protein expression patterns of ARID2, ß-catenin, p53, and p110α in HCCs and adjacent nonneoplastic cirrhotic tissues from 58 explanted livers. Notably, this study is the first to our knowledge to investigate ARID2 protein expression in the liver. The frequency of ARID2 mutations detected using our immunohistochemistry method was similar to that reported in previous molecular studies. Furthermore, we found that loss of ARID2 protein expression may be associated with recurrence, although further studies must be done to validate these findings in a larger population. We found that expression patterns of the 4 cancer markers were independent of each other, suggesting separate pathways of hepatocarcinogenesis. We also did not observe an association between viral etiology and protein expression. Consistent with previous studies, overexpression of p53 correlated with poor differentiation. Lastly, 17.5% of HCCs paradoxically had diffuse loss of the oncoprotein p110α compared with strong expression in background cirrhotic liver. The exact mechanism is unclear, but enigmatic loss of oncoprotein function has been described in other carcinomas and could potentially have significant implications for the use of mechanistic target of rapamycin (mTOR) drug therapies.

AT-rich interactive domain 2, p110α, p53, and ß-catenin protein expression in hepatocellular carcinoma and clinicopathologic implications.

AT-rich interactive domain 2 (ARID2), catenin (cadherin-associated protein), beta 1, 88kDa (ß-catenin), tumor protein 53 (p53), and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α) mutations are implicated in hepatocellular carcinoma (HCC); and previous work has contributed to thorough molecular characterization of these events. However, studies that assess the impact of these mutations on downstream protein expression, especially those that evaluate all 4 cancer markers simultaneously, are relatively lacking. Hence, the present study uses immunohistochemistry to assess protein expression patterns of ARID2, ß-catenin, p53, and p110α in HCCs and adjacent nonneoplastic cirrhotic tissues from 58 explanted livers. Notably, this study is the first to our knowledge to investigate ARID2 protein expression in the liver. The frequency of ARID2 mutations detected using our immunohistochemistry method was similar to that reported in previous molecular studies. Furthermore, we found that loss of ARID2 protein expression may be associated with recurrence, although further studies must be done to validate these findings in a larger population. We found that expression patterns of the 4 cancer markers were independent of each other, suggesting separate pathways of hepatocarcinogenesis. We also did not observe an association between viral etiology and protein expression. Consistent with previous studies, overexpression of p53 correlated with poor differentiation. Lastly, 17.5% of HCCs paradoxically had diffuse loss of the oncoprotein p110α compared with strong expression in background cirrhotic liver. The exact mechanism is unclear, but enigmatic loss of oncoprotein function has been described in other carcinomas and could potentially have significant implications for the use of targeted mechanistic target of rapamycin (serine/threonine kinase) drug therapies.

Preoperative platelet count associates with survival and distant metastasis in surgically resected colorectal cancer patients.

OBJECTIVE: Platelets have been implicated in cancer metastasis and prognosis. No population-based study has been reported as to whether preoperative platelet count directly predicts metastatic recurrence of colorectal cancer (CRC) patients. DESIGN: Using a well-characterized cohort of 1,513 surgically resected CRC patients, we assessed the predictive roles of preoperative platelet count in overall survival, overall recurrence, as well as locoregional and distant metastatic recurrences. RESULTS: Patients with clinically high platelet count (≥400 × 10(9)/L) measured within 1 month before surgery had a significantly unfavorable survival (hazard ratio [HR] = 1.66, 95 % confidence interval [CI] 1.34-2.05, P = 2.6 × 10(-6), P(log rank) = 1.1 × 10(-11)) and recurrence (HR = 1.90, 1.24-2.93, P = 0.003, P(log rank) = 0.003). The association of platelet count with recurrence was evident only in patients with metastatic (HR = 2.81, 1.67-4.74, P = 1.1 × 10(-4), P(log rank) = 2.6 × 10(-6)) but not locoregional recurrence (HR = 0.59, 95 % CI 0.21-1.68, P = 0.325, P(log rank) = 0.152). The findings were internally validated through bootstrap resampling (P < 0.01 at 98.6 % of resampling). Consistently, platelet count was significantly higher in deceased than living patients (P < 0.0001) and in patients with metastatic recurrence than locoregional (P = 0.004) or nonrecurrent patients (P < 0.0001). Time-dependent modeling indicated that the increased risks for death and metastasis associated with elevated preoperative platelet counts persisted up to 5 years after surgery. CONCLUSION: Our data demonstrated that clinically high level of preoperative platelets was an independent predictor of CRC survival and metastasis. As an important component of the routinely tested complete blood count panel, platelet count may be a cost-effective and noninvasive marker for CRC prognosis and a potential intervention target to prevent metastatic recurrence.