Adenosquamous pancreatic cancer producing parathyroid hormone-related protein

An autopsy case of adenosquamous pancreatic cancer in a 61-year-old male patient with an elevated serum level of parathyroid hormone-related protein (PTH-rP) is reported. He was admitted to our hospital with a 1-month-long history of abdominal discomfort and progressive abdominal fullness. A computed tomography (CT) scan of the abdomen showed a retroperitoneal mass, approximately 10cm in diameter, involving the pancreas, with round enhancement on contrast examination. Histological examination of a specimen taken by CT-guided needle biopsy suggested squamous cell carcinoma or transitional cell carcinoma. Laboratory data on admission revealed a high serum calcium level and high PTH-rP level. The calcium level initially responded to intravenous hydration, furosemide, calcitonin, and bisphosphonates, decreasing from 15.0 to 9.0mg/dl. However, the hypercalcemia recurred after 10 days. The patient developed carcinomatous peritonitis and acute renal failure, and died on the 25th hospital day. Autopsy revealed a mass in the pancreatic body to tail, invading the retroperitoneum, with progressive carcinomatous peritonitis. Histological examination of the mass revealed infiltrating carcinoma, showing squamous differentiation with focal intracytoplasmic lumina formation, consistent with pancreatic adenosquamous carcinoma. Immunohistological examination showed positive staining for PTH-rP. Adenosquamous carcinoma of the pancreas is relatively rare; only a few cases associated with hypercalcemia and for which PTH-rP has been identified as a causative factor have been reported. This is the first case in which immunohistochemistry proved localized PTH-rP in adenosquamous pancreatic cancer cells, associated with persistent hypercalcemia.     

Primary pulmonary squamous cell carcinoma associated with elevated IL-6, leukocytosis, hypercalcemia, phagocytosis, reactive lymphadenopathy and glomerular mesangial cell proliferation via the production of PTH-rP and G-CSF

We report an autopsied case of a 74-year-old man with primary pulmonary squamous cell carcinoma (SCC) associated with leukocytosis, hypercalcemia, phagocytosis in the bone marrow, reactive lymphadenopathy and mesangial cell proliferation in the glomerulus. Laboratory examination revealed increased serum levels of parathyroid hormone-related peptide (PTH-rP), granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6) and soluble interleukin 2 receptor (s-IL2R). An autopsy showed moderately differentiated SCC at the left lower lobe of the lung, of which tumor cells distinctly showed cytoplasmic immunoreactivity to anti-G-CSF and anti-PTH-rP antibodies. Thus, pulmonary SCC seemed to produce both G-CSF and PTH-rP, causing leukocytosis, hypercalcemia, and IL-6 production from the bone. IL-6 also might have stimulated the proliferation of SCC and glomerular mesangial cells, and induced phagocytosis, reactive lymphadenopathy and hepatosplenomegaly by interacting with the mononuclear phagocytic system.     

A case of parathyroid hormone-related peptide producing gallbladder carcinoma presenting humoral hypercalcemia of malignancy]

Humoral hypercalcemia of malignancy (HHM) in neoplastic syndrome has been most commonly reported in squamous cell carcinoma. Gallbladder carcinoma with HHM is uncommon. In this report, we describe a male case of gallbladder carcinoma with marked hypercalcemia and a high level of serum parathyroid hormone-related peptide (PTHrP). An immunohistochemical examination using PTHrP was also positive.     

Pancreatic adenosquamous carcinoma, 9 mm in size,diagnosed preoperatively by transpapillary biopsy. Report of a case

Adenosquamous carcinoma of the pancreas is a rare variant of pancreatic cancer, which is known to be difficult to diagnose. We herein report a case diagnosed by transpapillary biopsy of the pancreatic duct. A 73‐year‐old man was referred to our department with suspicion of pancreatic cancer. Ultrasound showed a hypoechoic mass, 9 mm in diameter, in the body of the pancreas. Endoscopic retrograde cholangiopancreatography demonstrated a stenosis of the main pancreatic duct in the body with upstream dilatation and a shift of the bile duct to the left. Histological examination of the specimens obtained by transpapillary biopsy of the pancreatic duct revealed both adenocarcinoma and squamous cell carcinoma. Pancreatoduodenectomy was performed and, histopathologically, the tumor was diagnosed as adenosquamous carcinoma of the pancreatic body, 9 mm in size. This is the first case of adenosquamous carcinoma of the pancreas preoperatively diagnosed by transpapillary biopsy of the pancreatic duct, and the smallest stage I (TNM classification) case of such carcinoma detected to date.     

Adenosquamous carcinoma of the pancreas: preoperative diagnosis and molecular alterations

Adenosquamous carcinoma of the pancreas is a rare tumor which has a less favorable prognosis than common ductal cell carcinoma of the pancreas, and a definite preoperative diagnosis of this tumor is quite difficult. We herein report two cases of this rare variant. The patients were a 41-year-old man (patient 1) and a 67-year-old woman (patient 2). Patient 1 had a hypoechoic mass measuring 3cm in the uncus of the pancreas, while patient 2 had a huge mass, measuring 8cm, in the tail of the pancreas. Patient 2 was successfully diagnosed preoperatively as having an adenosquamous carcinoma, by cytological examination of the pure pancreatic juice obtained by endoscopic retrograde pancreatic juice aspiration. A pylorus-preserving pancreatoduodenectomy was performed for patient 1, and a distal pancreatectomy with resection of the spleen and the left kidney was performed for patient 2. Subsequent pathological findings of these two tumors revealed adenosquamous carcinoma of the pancreas. K-ras point mutation, p53 overexpression, and telomerase activity in both tumor specimens were detected by the mutant allele specific amplification method, immunohistochemical staining, and telomeric repeat amplification protocol assay, respectively. The two patients died of recurrent disease 5 and 4 months, respectively, after surgery. Cytological examination of pure pancreatic juice is a useful modality for the preoperative diagnosis of this tumor, and frequent molecular alterations may be associated with the poor prognosis of adenosquamous carcinoma of the pancreas.     

Adenosquamous carcinoma of the pancreas

A 58-year-old Japanese man was admitted complaining of abdominal pain. An abdominal computed tomography examination demonstrated a tumor in the head of the pancreas and multiple calcifications. A laparotomy was performed and the tumor was removed by Whipple's operation. Histologically, the neoplasm that invaded the duodenal wall and the papilla of Vater was composed of nests of malignant squamous cells with intercellular bridges and showed the formation of keratinized pearls with a small area of concurrently neoplastic glandular and squamous elements. On the basis of these features, the diagnosis of adenosquamous carcinoma of the pancreas was made. The patient died 18 months after the operation. The neoplastic behavior of this rare primary pancreatic carcinoma is similar to that of duct cell carcinoma as well as pure squamous cell carcinoma of the pancreas. As the pancreas can be the target of metastases of squamous carcinomas from other organs it is wise to be aware of this rare entity.     

Parathyroid hormone-related protein (PTH-rP)-associated hypercalcemia in a patient with an atypical chronic lymphocytic leukemia

We describe a patient with an atypical chronic lymphocytic leukemia (CLL) of the mixed cell type with a hypercalcemia due to parathyroid hormone-related protein production by the malignant B cells. On regard of the elevated serum calcium level without overt lytic bone lesions we found elevated serum levels of PTH-rP and demonstrated the presence of PTH-rP on the malignant lymphocytes. PTH-rP-related hypercalcemia in CLL is very rare. The role in PTH-rP in humoral hypercalcemia of malignancy is discussed.     

Humoral hypercalcemia revealing a malignant non hodgkin lymphoma

INTRODUCTION: Hypercalcemia is a rare complication of non-Hodgkin lymphoma. Usually, hypercalcemia occurs late in the disease course, except for high-grade lymphoma. Most often hypercalcemia is related to excessive level of circulating PTH-rP or sometimes, 1,25(OH)2D3. Concomitant high plasmatic concentration of PTH-rP and 1,25(OH)2D3 is uncommon. EXEGESIS: We report the case of a 82-year-old man who presented with abdominal pain and weight loss, leading to the diagnosis of diffuse large-B-cell lymphoma (high-grade lymphoma) associated with symptomatic hypercalcemia (3.21mmol/l). PTH-rP and 1,25(OH)2D3 plasmatic levels were high. Calcium concentration was normalized with glucocorticoids and sequential chemotherapy. CONCLUSION: This case report confirms that hypercalcemia, as consequence of excessive plasmatic level of PTH-rP secreted by tumoral cells, can occur early in the course of high-grade lymphoma. Glucocorticoids and chemotherapy are the best treatment options.     

Primary adenosquamous carcinoma of the liver which produces granulocyte-colony-stimulating factor and parathyroid hormone related protein: association with leukocytosis and hypercalcemia

A 55-year-old man was admitted to our hospital with fever and vomiting. Abdominal computed tomography (CT) revealed multiple low density masses in the liver. A diagnosis of primary adenosquamous carcinoma of the liver was confirmed by histological examination of a necropsy specimen. The present case showed leukocytosis and hypercalcemia with high levels of serum granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone related protein (PTHrP). Recent studies have shown that G-CSF and PTHrP are responsible for the paraneoplastic syndromes with leukocytosis and hypercalcemia. The tumor cells demonstrated positive cytoplasmic immunohistochemistry staining with anti-G-CSF and anti-PTHrP antibodies. This result suggested that the tumor produced G-CSF and PTHrP.     

Persistent and moderate hypercalcemia related to an ovarian clear cell adenocarcinoma: Pre- and postoperative parathyroid hormone related-peptide and 1,25-dihydroxyvitamin D3 levels

OBJECTIVE: To evaluate the role of PTH-related peptide (PTH-rP) and 1,25-dihyhydroxyvitamin D3 in a case of hypercalcemia related to an ovarian adenocarcinoma. DESIGN: We report a case of humoral hypercalcemia in a patient aged 74 yr with a clear cell adenocarcinoma of the right ovary at an early stage of its development (stage T1aN0M0) revealed by moderate and persistent hypercalcemia (variable level between 2.7 and 3.2 mmol/l without any treatment) over six months. METHODS: PTH-rP and 1,25-dihydroxyvitamin D3 were measured in blood samples taken before and after hysterectomy and bilateral salpingooophorectomy and in blood samples taken intraoperatively from the right ovarian vein and a peripheral vein. RESULTS: High levels of plasma PTH-rP and 1,25-dihydroxyvitamin D3 concomitant with high serum calcium and low PTH levels were found before surgery, which was followed by normalisation of all parameters studied. A concentration gradient was found regarding plasma PTHrP (right ovarian vein 60.4 pmol/l, peripheral vein 4.5 pmol/l), not 1,25-dihydroxyvitamin D3. CONCLUSION: 1) moderate and persistent hypercalcemia can be observed at an early stage of an ovarian carcinoma; 2) the gradient of PTH-rP concentration between the samples taken from the right ovarian vein and a peripheral vein provides evidence for a direct secretion of PTH-rP by the ovarian tumor; 3) the increased 1,25-dihydroxyvitamin D3 level is not related to a direct ovarian production, but is a consequence of PTH-rP secretion.     

Lung cancer associated with hypercalcemia induced by concurrently elevated parathyroid hormone and parathyroid hormone-related protein levels

In general, many cases of malignancy-associated hypercalcemia are due to HHM. In patients with humoral hypercalcemia of malignancy (HHM), it has been reported that plasma parathyroid hormone-related protein (PTHrP) and cyclic adenosine monophosphate (cAMP) levels were elevated, while plasma PTH and active vitamin D(3) levels were suppressed. Our patient showed hypercalcemia with a concurrent increase in plasma and tumor tissue PTHrP and PTH concentrations and also high cAMP and low 1-25(OH)(2)VD(3) levels in the plasma. These data suggest that the hypercalcemia exhibited by our patient was consistent with HHM due to lung cancer and its liver metastasis. Moreover, diagnostic imaging and autopsy findings showed no appreciable lesions of the parathyroid gland. In addition, histopathologic examination of the primary and metastatic tumors revealed the existence of PTH immunohistochemically stained with anti-PTH antibodies, suggesting an ectopic-PTH-producing lung tumor. From these data, our patient was diagnosed with a rare case of lung cancer, which produced both ectopic PTH and PTHrP.     

Diagnostic approach to hypercalcemia: relevance of parathyroid hormone and parathyroid hormone-related protein measurements

Background: Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTH-rP) are two potent hypercalcemic hormones that act on the same targets. Autonomous secretion of the former is involved in primary hyperparathyroidism (PHPT), whereas the latter is responsible for humoral hypercalcemia of malignancy (HHM). Methods: From 250 consecutive, hypercalcemic serum samples sent to our laboratory for assessment of intact PTH, we were able to obtain clinical information, as well as an additional plasma sample for PTH-rP measurement, in 134 patients. At the time of sampling, patients could be classified into seven groups: cancer without known bone metastases (CaNoMeta, n=36), cancer with bone metastases (CaMeta, n=9), no evidence of cancer (noEvCa, n=71), sarcoidosis (Sarc, n=3), end-stage renal disease (ESRD, n=12), vitamin D overdose (VIT-D, n=2), and hyperthyroidism (Thyr, n=1). Results: In the CaNoMeta group, 29/36 patients had elevated PTH-rP levels, 9/36 patients had inappropriately elevated PTH levels, and 5/36 had elevated levels of both hormones. In the CaMeta group, three of the nine patients had inappropriately elevated PTH levels, two of them with concomitantly elevated PTH-rP levels. In the NoEvCa group, 63/71 patients had an inappropriate elevation of PTH levels and were diagnosed as having PHPT. Four of the 71 patients had elevated levels of both PTH and PTH-rP; three of them were in poor health and died within a short period of time. All of the ESRD patients had very high PTH and normal PTH-rP levels, except for one woman with high PTH-rP and undetectable PTH levels; she died from what later turned out to be a recurrent bladder carcinoma. In the Sarc, Vit-D, and Thyr groups, both PTH and PTH-rP levels were normal. Conclusions: (1) Elevated PTH-rP levels are a common finding in cancer patients without bone metastases. Intact PTH, however, should always be measured in hypercalcemic patients with malignancy because concurrent primary hyperparathyroidism is not rare. (2) Primary hyperparathyroidism accounts for hypercalcemia in 90% of patients without evidence of cancer whose PTH-rP levels may also be found to be elevated in a few cases, even some with surgically demonstrated parathyroid adenoma.     

Humoral hypercalcemia complicating adenosquamous carcinoma of the proximal colon

Summary Hypercalcemia as a complication of carcinoma of the colon is uncommon (1). It usually occurs in the presence of anorectal or rectal carcinoma that metastasizes to the lumbosacral vertebrae (2–4). Hypercalcemia complicating colon carcinoma in the absence of bone metastases—so-called humoral hypercalcemia of malignancy or paraneoplastic hypercalcemia—is rare. Only two such cases associated with adenocarcinoma of the colon (5, 6) and two cases associated with adenosquamous carcinoma of the distal colon (rectum and sigmoid) (7) have been reported. We describe the first reported case of an adenosquamous carcinoma of the cecum and ascending colon that was accompanied by severe humoral hypercalcemia. The hypercalcemia was associated with a parathyroid hormone (PTH) -like substance.     

Esophageal carcinoma with humoral hypercalcemia and leukocytosis successfully treated by a two-stage operation: report of a case

We herein report a patient demonstrating esophageal carcinoma with humoral hypercalcemia and leukocytosis. A 56-year-old Japanese man complained of a 2-month history of pyrexia. The radiological and endoscopic findings showed advanced esophageal carcinoma with a giant intraabdominal lymph node metastasis. Preoperative examination suggested that the tumor, consisting of squamous cell carcinoma, produced both parathyroid hormone-related protein and granulocyte colony-stimulating factor. We first performed an extirpation of the giant metastatic tumor to reduce the degree of humoral secretion and to improve his general condition. Thereafter, the hypercalcemia, leukocytosis, and other associated symptoms all improved. As a result, we were then able to safely perform an esophagectomy 2 months later. The patient has been doing well during the 10-month follow-up period, and is presently alive more than 1 year since hypercalcemia and leukocytosis were first observed. This is the first report of esophageal carcinoma with humoral hypercalcemia and leukocytosis that was successfully treated by an operation.     

Parathyroid hormone-related protein as a cause of hypercalcemia in a B-cell type malignant lymphoma.

Hypercalcemia occurred in a patient with non-Hodgkin's (B-cell type) lymphoma when generalized lymphadenopathy developed. Despite low normal plasma parathyroid hormone (PTH), nephrogenous cAMP (NcAMP) was not suppressed, and serum and urine PTH-related protein (PTH-rP) levels were elevated. The plasma level of 1,25(OH)2D was within normal range. The combined chemotherapies successfully reduced the tumor size, serum Ca, PTH-rP, and lactic dehydrogenase. Serum osteocalcin was suppressed while the patient was hypercalcemic, and increased after chemotherapy. In the extract of the tumor tissue obtained post mortem, bioactivity stimulating the production of cAMP in osteoblasts was demonstrated along with the immunoreactive PTH-rP. This is the first report of a B-cell lymphoma producing PTH-rP and its association with humoral hypercalcemia of malignancy.     

Gallbladder carcinoma with osteoclast-like giant cells

Extraskeletal tumors containing multinucleated, osteoclast-like giant cells (OGCs) are uncommon. These neoplasms are most frequently reported in the breast and pancreas. Recently, some authors have suggested that carcinomas containing OGCs may represent a distinct clinicopathological entity with a more favorable prognosis. Occurrence in the gallbladder is extremely rare, with only one previous case. We report here on an additional case of gallbladder carcinoma with an infiltrate of OGCs. A 72-year-old woman presented with postprandial abdominal pain and was found to have a mass in the body of the gallbladder with direct liver invasion. Histological examination showed an adenosquamous carcinoma with an infiltrate of benign OGCs. Immunohistochemical analysis demonstrated that the giant cells were of histiocytic origin. The patient survived for 6 years without evidence of recurrence. This case adds to a small body of literature on gallbladder carcinoma with OGCs. Further studies are required to clearly define the prognostic significance of these giant cells in gallbladder cancer and the differences between adenosquamous carcinoma with OGCs and other gallbladder carcinomas (such as adenocarcinoma and squamous cell carcinoma) with those cells.     

Surgical outcome of adenosquamous carcinoma of the pancreas

Adenosquamous carcinoma is rare, accounting for 3%-4% of all pancreatic carcinoma cases. These tumors are characterized by the presence of variable proportions of mucin-producing glandular elements and squamous components, the latter of which should account for at least 30% of the tumor tissue. Recently, several reports have described cases of adenosquamous carcinoma of the pancreas. However, as the number of patients who undergo resection at a single institute is limited, large studies describing the clinicopathological features, therapeutic management, and surgical outcome for adenosquamous carcinoma of the pancreas are lacking. We performed a literature review of English articles retrieved from Medline using the keywords ＇pancreas＇ and ＇adenosquamous carcinoma＇. Additional articles were obtained from references within the papers identified by the Medline search. Our subsequent review of the literature revealed that optimal adjuvant chemotherapy and/or radiotherapy regimens for adenosquamous carcinoma of the pancreas have not been established, and that curative surgical resection offers the only chance for long-term survival. Unfortunately, the prognosis of the 39 patients who underwent pancreatic resection for adenosquamous carcinoma was very poor, with a 3-year overall survival rate of 14.0% and a median survival time of 6.8 mo. Since the postoperative prognosis of adenosquamous carcinoma of the pancreas is currently worse than that of pancreatic adenocarcinoma, new adjuvant chemotherapies and/or radiation techniques should be investigated as they may prove indispensible to the improvement of surgical outcomes.     

Treatment of squamous cell carcinoma of the pancreas with gemcitabine

Primary squamous cell carcinoma of the pancreas is a rare tumor. We report a case of a 49 years old patient with a metastatic squamous cell carcinoma of the pancreas. Histological diagnosis was established by echoguided biopsy of the liver. Due to that, we cannot be sure that this tumor was not adenosquamous with a metastatic component from only the squamous part of the lesion. Two types of chemotherapy have been performed. The first one was radiochemotherapy with an association of 5FU and cisplatinum. Gemcitabin was the second one. An objective response was obtained with gemcitabin and the patient's health improved. To our knowledge, this has never had been reported beforehand. However the prognosis of this cancer remains poor. Overall survival was 8 months.     

胰腺腺鳞癌的临床诊治分析

目的 总结胰腺腺鳞癌临床诊治经验,以提高对该病的认识和诊治水平.方法 对2002年7月至2008年6月我院收治的5例胰腺腺鳞癌患者的临床资料进行回顾性分析,并结合文献讨论.结果 本组5例胰腺腺鳞癌患者,其中男3例,女2例,平均年龄(64±18)岁.肿瘤位于胰头部者2例,位于胰体尾部者3例;行胰头十二指肠切除术1例,行胰体尾、脾脏切除术3例,行胆肠+胃肠双旁路内引流术并~(125)Ⅰ粒子植入1例.肿瘤平均长径4.5 em,1例侵犯胃后壁、十二指肠降部、门静脉,2例侵犯脾门处包膜,2例合并有神经、血管侵犯,1例伴有淋巴结转移.组织学特征为腺癌和鳞癌成分混杂在一起,呈浸润性生长.5例均获随访,3例死于肿瘤复发和肝转移,术后生存8.5～13.5个月,平均11.2个月,2例已生存6个月和56个月.结论 胰腺腺鳞癌好发年龄60岁左右,临床确诊较困难,恶性程度高,预后差,手术切除结合放、化疗的综合治疗可提高疗效.     

Pancreatic neuroendocrine tumor with extensive vascularisation and parathyroid hormone-related protein (PTHrP)--associated hypercalcemia of malignancy.

We report the case of a 34 year old male presenting with symptomatic hypercalcemia due to excessive PTHrP secretion from a pancreatic neuroendocrine carcinoma with extensive hypervascularization and without any evidence for metastatic disease. In the early phase of the disease conventional chemotherapy with streptozocin and doxorubicin was able to control functional activity as well as tumor growth. However, after 2 years tumor escape was indicated by severe therapy-resistant hypercalcemia. Therapeutic options were reduced due to the excessive tumor vascularization and the patient died from his disease after a short period of intensified therapy. The role of PTHrP in hypercalcemia of malignancy (HHM) and its association with neuroendocrine pancreatic tumors as well as possible therapeutic options are reviewed.