Thymic squamous cell carcinoma producing parathyroid hormone-related protein and CYFRA 21-1

A 54-year-old man was admitted to our hospital because of dyspnea. Radiographic examination showed an anterior mediastinal mass and pericardial effusion. Serum calcium and parathyroid hormone-related protein (PTHrP) levels were elevated, and serum CYFRA 21-1 level was extremely high. Results of percutaneous needle biopsy under computed tomography guidance led to a diagnosis of moderately differentiated squamous cell carcinoma. Immunohistological staining showed the tumor cells to be positive for PTHrP and cytokeratin monoclonal antibodies. Postmortem findings were considered to indicate thymic carcinoma. Thymic carcinoma is rare, but our case indicates that thymic squamous cell carcinoma can be identified in terms of paraneoplastic hypercalcemia.     

Parathyroid hormone-related peptide producing cholangiocellular carcinoma with a marked psammoma formation

Humoral hypercalcemia caused by parathyroid hormone-related peptide (PTHrP), associated with cholangiocellular carcinoma (CCC), has rarely been documented. There have been no reports of CCC associated with extensive calcification of the tumor with psammoma body formation. A 66-year-old man was admitted with a large calcified tumor in the liver detected on an abdominal X-ray. An ultrasound-guided fine needle biopsy specimen of the liver tumor showed evidence of adenocarcinoma. He had hypercalcemia with an elevated PTHrP level. The patient died because of disseminated intravascular coagulation and progressive hepatic failure. A postmortem examination revealed a large poorly differentiated CCC in the liver. Immunohistochemical examination showed the presence of PTHrP-positive tumor cells. The calcified lesion consisted of a number of accumulated psammoma bodies. We present a case of PTHrP producing CCC with a marked psammoma formation.     

Interleukin-6-producing thymic squamous cell carcinoma associated with Castleman's disease and nephrotic syndrome

When a 63-year-old man was hospitalized with nephrotic syndrome due to focal segmental glomerulosclerosis, a mediastinal mass was discovered. A biopsy specimen obtained by mediastinoscopy showed findings compatible with the plasma cell type of Castleman's disease. Fever, anemia, and anti-nuclear antibody were present. Serum concentrations of gamma globulin, acute phase proteins, and, most strikingly, interleukin-6 (IL-6) were elevated. Methylprednisolone pulse therapy resulted in no clinical improvement. Pathologic examination of the resected thymic tumor showed a squamous cell carcinoma immunoreactive for IL-6. To our knowledge, this case represents the first reported IL-6-producing thymic squamous cell carcinoma associated with Castleman's disease and nephrotic syndrome.     

Adenosquamous carcinoma of the liver.

A rare case of adenosquamous carcinoma of the liver is reported. An 85-year-old white man presented with a 6-month history of weight loss and an enlarged liver. A biopsy demonstrated a squamous cell carcinoma which was presumed to be metastatic with an occult primary. At autopsy, the liver was partially replaced by a focally cystic tumor. Histologically, the neoplasm demonstrated both malignant squamous and glandular contradistinctionmponents as well as foci of transition between the two. This is in co to the 5 previous reported cases of primary hepatic squamous cell carcinomas or tumors containing a squamous component. It is suggested that this neoplasm arose from malignant transformation of squamous metaplasia in a pre-existing cholangiocarcinoma.     

Syndrome paranéoplasique hypercalcémie–hyperleucocytose au cours des carcinomes épidermoïdes cutanés. À propos de deux observations

Introduction

We report two cases of hypercalcemia–hyperleucocytosis paraneoplastic syndrome complicating cutaneous squamous cell carcinoma.

Case reports

The first patient, a 50-year-old man, suffering for hidradenitis suppurativa for the past 20 years, was admitted for squamous cell carcinoma. Laboratory findings showed marked hypercalcemia and hyperleucocytosis. PTHrP serum level was increased. Bone scintigraphy was normal. There was evidence of pulmonary metastasis. Despite treatment the patient died of agranulocytosis. The second patient was a 60-year-old man who presented with several months enlarging left axillary tumour. He has been treated by surgery for a squamous cell carcinoma of the left hand, 6 months ago. Serum calcium and white cell bloods count were elevated. The diagnosis of metastatic lymph node of cutaneous squamous cell carcinoma was confirmed. There was evidence of pulmonary metastasis. Despite chemotherapy the patient died rapidly.

Conclusion

Hypercalcemia–hyperleucocytosis paraneoplastic syndrome is rarely described during the course of cutaneous squamous cell carcinoma. This syndrome seems to be related to hormones or cytokines secretion by the neoplasic cells including PTHrP and G-CSF. Some authors ascribe it a poor prognostic significance.     

食管鳞癌免疫相关基因鉴定及miR-6806-5p靶标预测

目的本研究基于GEO数据库综合数据分析,鉴定与食管鳞癌相关的免疫基因及miRNA。方法从GEO数据库下载GSE75241基因表达矩阵,通过差异分析对比食管鳞癌与正常食管组织基因表达数据,筛选鉴定出与免疫相关的差异基因,并进一步预测免疫相关基因的miRNA。结果分析得到130个上调和39个下调显著差异的免疫相关基因,最终确定关键免疫相关基因为IL-6、CXCL8(上调)和IL-18(下调)及其共同miRNA(miR-6806-5p)。结论IL-6、CXCL8和IL-18可能通过影响免疫细胞在肿瘤免疫逃逸过程中起作用,三者的共同靶标为miRNA(miR-6806-5p),其在食管鳞癌免疫治疗中的意义值得进一步研究。     

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.     

Elevation of circulating plasma cytokines in cancer patients with high plasma parathyroid hormone-related protein levels

Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.     

Messenger RNA stability of parathyroid hormone-related protein regulated by transforming growth factor-beta1

Humoral hypercalcemia of malignancy (HHM), a paraneoplastic syndrome associated with epithelial cancers, including squamous cell carcinoma (SCC), is due to expression and secretion of parathyroid hormone-related protein (PTHrP). Transforming growth factor-beta1 (TGFbeta1), expressed by many tumors, has been demonstrated in vitro to increase the half-life of PTHrP mRNA. In this study, oral squamous carcinoma cells (SCC2/88) had a two-fold increase in PTHrP mRNA stability (from 45 to 90 min) in response to treatment with TGFbeta1. In order to examine the mechanism of TGFbeta1-mediated PTHrP mRNA stability, a cell-free assay of mRNA degradation was utilized in which the degradation of in vitro-transcribed mRNA incubated with cytoplasmic protein extracts from SCC2/88 treated with vehicle or TGFbeta1 was measured. In this assay, full-length PTHrP mRNA was not significantly stabilized in TGFbeta1-treated samples when compared to vehicle treated samples. However, there was a striking (>5-fold) increase in PTHrP mRNA half-life in TGFbeta1-treated samples when PTHrP mRNA lacked the 3'-untranslated region (3'-UTR). In contrast, the degradation of 3'-UTR-truncated PTHrP mRNA using the cell-free assay was not altered in vehicle-treated samples. UV cross-linking of PTHrP mRNA and cytoplasmic proteins from cells treated with either vehicle or TGFbeta1 revealed numerous mRNA-binding proteins. TGFbeta1 treatment resulting in decreased binding of 33, 31, 27, 20 and 18 kDa binding proteins to the terminal coding region. These studies revealed that TGFbeta1-induced PTHrP mRNA stability might be, in part, the result of cis-acting sequences within the coding region of the PTHrP mRNA.     

The increase of parathyroid hormone-related peptide and cytokine levels in synovial fluid of elderly rheumatoid arthritis and osteoarthritis

We simultaneously measured the concentrations of parathyroid hormone related peptide (PTHrP) and cytokines in synovial fluid (SF) to clarify the relationship between PTHrP and cytokine network in the SF of elderly patients with arthritis. SF was collected from knee joints of five RA patients aged 66+/-11 years old and nine osteoarthritis (OA) patients aged 80+/-9 years old. PTHrP in SF was measured by enzyme-linked immunosorbent assay (ELISA), whereas tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6) and interleukin-8 (IL-8) in SF were all measured by ELISA. The PTHrP levels in the SF of RA patients (2.56+/-0.89 pmol/l) were significantly (p<0.05) higher than those of OA patients (1.66+/-0.17 pmol/l). TNF-alpha, IL-1beta, IL-2 and IL-6 concentrations in SF of RA were also significantly higher than those in SF of OA (TNF-alpha 22.5+/-14.8 vs 4.8+/-3.0 pg/ml, p<0.01; IL-1beta 11.8+/-11.4 vs 1.4+/-1.3, p<0.05; IL-2 59.9+/-46.6 vs 12.5+/-8.0 pg/ml, p<0.05; IL-6 18424+/-8901 vs 3547+/-2948 pg/ml, p<0.01). The concentrations of IL-4 and IL-8 in SF of RA were similar to those of OA. Immunohistochemical studies revealed the presence of immunoreactive PTHrP in synovial fibroblasts from RA and OA. Among cytokines, only IL-6 was positively correlated with PTHrP levels in SF (r=0.685, p<0.01). In the culture of synovial cells from RA and OA, PTHrP was produced in RA more than OA after phorbol 12-mysistate 13-acetate (TPA) stimulation. These results indicate that PTHrP and cytokines, especially IL-6, might be involved in the inflammatory processes of elderly RA and OA. This is the first study in which PTHrP and cytokine levels were simultaneously examined in synovial fluid of elderly RA and OA.     

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.     

A novel mature B-cell line (DOBIL-6) producing both parathyroid hormone-related protein and interleukin-6 from a myeloma patient presenting with hypercalcaemia

A novel human EBV-negative B-cell line, designated DOBIL-6, was established from a patient with non-secretary myeloma. The DOBIL-6 cell has cytoplasmic γ protein and expresses CD19, 20, 38, 45RO, VLA-4 and PCA-1 antigens, but lacks CD10, 45RA and VLA5 antigens. Chromosome analysis showed that DOBIL-6 cells had many complex structural abnormalities, including t(11;14) (q13;q32), which were consistent with that of the fresh tumour cells. Interestingly, abundant interleukin-6 (IL-6) and parathyroid hormone-related protein (PTHrP) accumulated in the culture supernatant of DOBIL-6 cells. Hypercalcaemia and splenomegaly associated with plasma cell proliferations which resulted in the expansion of the light zones in the follicles were observed in DOBIL-6 transplanted nude mice. RT-PCR analysis detected mRNA for PTHrP, and IL-6 as well as its receptor (GP80) in DOBIL-6 cells. Treatment of the DOBIL-6 cells with neutralizing anti-IL-6 antibody inhibited their growth in a dose-dependent manner, whereas the addition of exogenous IL-6 stimulated it in serum-depleted conditions. These findings suggest that both IL-6 and PTHrP are produced in DOBIL-6 cells, and that IL-6 promotes its growth by an autocrine mechanism. Since IL-6 is known to stimulate not only the growth of B-cell neoplasms but also osteoclastic bone resorption by cooperating with PTHrP, this simultaneous production of IL-6 and PTHrP might be synergistically linked and play a role in the development of hypercalcaemia of the patient. The DOBIL-6 cell is a useful tool to clarify the mechanism of hypercalcaemia associated with mature B-cell neoplasms.     

Conformal radiation therapy for liver metastasis of esophageal carcinoma

Recently, aggressive hepatectomies or hepatic arterial infusion chemotherapy for liver metastasis from gastric or colorectal carcinoma have been performed, and the number of successful studies of liver metastasis have increased. However, there have been few successful cases of liver metastasis from esophageal carcinoma by surgery or chemotherapy. Herein, we show the benefits of radiation therapy for the treatment of liver metastasis from esophageal carcinoma. A 60-year-old woman with a 5-cm solitary liver metastasis from esophageal squamous cell carcinoma was treated with radiation therapy. The treated volume was encompassed by the anteroposterior and right lateral opposing fields, shaped by a multileaf collimator. The daily fraction size was 1.8 Gy, 5 days per week, for a total dose of 54 Gy. During the course of treatment, the patient did not experience any complications. After radiotherapy, abdominal computed tomography showed that the enhanced solid tumor had changed to a very low-density mass lesion with a clear margin, and the size was decreasing gradually between the 6 months. Radiotherapy could be a treatment of choice in patients with liver metastasis from esophageal squamous cell carcinoma.     

Intractable hypercalcemia due to a metastatic carcinoid secreting parathyroid hormone-related peptide and interleukin-6: response to octreotide.

We describe a patient with a malignant carcinoid tumor who presented with severe, intractable hypercalcemia that would not respond to conventional therapy with fluids and pamidronate. His plasma concentrations of parathyroid-hormone-related peptide (PTHrP) and interleukin-6 (IL-6) were elevated. The patient was treated with subcutaneous injections of octreotide with a good response, resulting in normocalcemia. Plasma PTHrP and IL-6 fell with the octreotide but remained elevated above the upper limit of normal. We conclude that although rare, hypercalcemia may be associated with carcinoid tumors and may be mediated through the secretion of cytokines and or PTHrP. Treatment with octreotide may be effective in treating hypercalcemia in such patients.     

结肠肿瘤PTHrP的表达及其与P53蛋白表达关系的研究

目的 研究ＰＴＨｒＰ在肿瘤发生过程中的作用以及ＰＴＨｒＰ和Ｐ５３在结肠腺中表达的关系。方法 用免疫组织化学ＡＢＣ法对６８例结肠组织（３０例结肠腺癌,２０例腺瘤性息肉,１８例正常结肠组织）进行ＰＴＨｒＰ检测,并对其中３０例结肠腺癌进行Ｐ５３检测。结果 结肠癌组ＰＴＨｒＰ的阳性率明显高于腺瘤组（Ｐ〈０．０５）和正常组（Ｐ〈０．０５）。绫 ＰＴＨｒＰ的过度表达与细胞的恶性 经有关,与肿瘤分化程度无明显关     

Primary pulmonary combined scar carcinoma composed of adenocarcinoma,squamous cell carcinoma,and small cell carcinoma: An autopsy case and literature review

Primary pulmonary scar carcinoma with triplicate differentiation is very rare. A 66-year-old woman presented with cough, and consulted to a private hospital, where she was pointed out to have abnormal lung shadow by chest X-P. She was admitted to our hospital for scrutiny. Imaging modalities including chest X-P, CT, and MRI revealed a main tumor (35 mm in diameter) in the right lower lobe and multiple small metastases in both lungs. Biopsies and cytology revealed an adenocarcinoma. Metastasis to the liver, iliac bone and tibia bone were also detected. She was diagnosed as stage IV lung adenocarcinoma (T2N3M1), and received chemotherapy. Soon, she complained of right hemiparesis, and brain CT revealed multiple brain metastases. She died of respiratory failure due to bronchopneumonia 7 months after admission. An autopsy revealed a lung tumor (4 × 4 × 3 cm) in the right lower lobe. Miliary micrometastases were recognized in bilateral lungs, brain, bones, pleura, liver, brain, and systemic lymph nodes. The lungs showed bronchopneumonia. The liver was cirrhotic. Microscopically, the primary lung tumor consisted of adenocarcinoma element (70% in area), squamous cell carcinoma element (20%), and small cell carcinoma element (10%), all of which were embedded in a fibroelastic scar with calcification (scar carcinoma). There were gradual merges between the adenocarcinoma and squamous cell carcinoma elements, but the small cell carcinoma element was isolated. The liver metastases were composed only of small cell carcinoma, and other metastatic sites consisted of adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Other pathologic changes included pulmonary aspergilosis, bronchopneumonia, splenomegaly, emphysema, cardiac hypertrophy, and kidney congestion. The present case shows that a lung scar carcinoma can display triplicate differentiations.     

Superficial undifferentiated small cell carcinoma of the esophagus showing an interesting growing pattern in histology

We report a case of superficial undifferentiated small cell carcinoma of the esophagus. The histology of the tumor was interesting; there was squamous cell differentiation within the epithelial layer and undifferentiated small cells growing within the submucosal layer. The tumor had a negative Grimelius reaction, suggesting no differentiation into a hormone-producing carcinoma known as an apudoma (Amine Precursor Uptake and Decarboxylation (APUD)). The serum levels of ACTH and calcitonin were within normal limits. As the patient was elderly and had a history of pleural tuberculosis causing poor pulmonary function, and owing to the fulminant nature of this carcinoma, he underwent blunt dissection of the esophagus by posterior mediastinal gastric pull-up. The patient recovered quickly and was able to be discharged with a good quality of life until the tumor recurred as a liver metastasis 6 months later.     

An elderly case of non-Hodgkin's lymphoma (NHL) with hypercalcemia]

A 93 year-old woman was admitted due to anorexia and unconsciousness. Biochemical examination of serum showed hypercalcemia (corrected Ca; 16.6 mg/dl). The level of intact parathyroid hormone (i-PTH) was suppressed, whereas parathyroid hormone-related peptide (PTHrp) was to 5.0 pM (normal range: below 0.6 pM). IL-6 and renal cAMP were also elevated. We started to ameliorate hypercalcemia by saline infusion, furosemide and calcitonin. However, hypercalcemia was not improved and the patient died of DIC and renal failure. Autopsy revealed primary lesion of NHL (diffuse large B cell type) to be in the stomach with infiltration of lymphoma into the liver, pancreas, spleen, adrenal glands, jejunum, and lumbar vertebrae. The results of immunohistochemical examination demonstrated the expression of PTHrP in lymphoma cells. PTHrP was also found in lymphoma cells of the spleen by the RT-PCR technique. These findings indicated that hypercalcemia was caused by overexpression of PTHrP from lymphoma cells.     

Alternative splicing of parathyroid hormone-related protein mRNA: expression and stability

Parathyroid hormone-related protein (PTHrP) is a multifunctional protein that is often dysregulated in cancer. The human PTHrP gene is alternatively spliced into three isoforms, each with a unique 3'-untranslated region (3'-UTR), encoding 139, 173 and 141 amino acid proteins. The regulation of PTHrP mRNA isoform expression has not been completely elucidated, but it may be affected by transforming growth factor-beta1 (TGF-beta1). In this study, we examined differences in the PTHrP mRNA isoform expression in two squamous carcinoma cell lines (SCC2/88 and HARA), an immortalized keratinocyte cell line (HaCaT), and spontaneous human lung cancer with adjacent normal tissue. In addition, the effect of TGF-beta1 on PTHrP mRNA isoform expression and stability was examined. Cell-type specific expression of PTHrP mRNA isoforms occurred between the various cell lines, normal human lung, and immortalized human keratinocytes (HaCaT). PTHrP isoform expression pattern was significantly altered between normal lung tissue and the adjacent lung cancer. In vitro studies revealed that TGF-beta1 differentially altered the mRNA steady-state levels and mRNA stability of the PTHrP isoforms. Protein-RNA binding studies identified different proteins binding to the 3'-UTR of the PTHrP isoforms (139) and (141), which may be important in the differential mRNA stability and response to cytokines between the PTHrP isoforms. The data demonstrate that there is cell-type specific expression of PTHrP mRNA isoforms, and disruption of the normal regulation during cancer progression may in part be associated with TGF-beta1-induced changes in PTHrP mRNA isoform expression and stability.