Primary pure squamous cell carcinoma of the duodenum: a case report and review of literature

Primary pure squamous cell carcinomas(SCC) of the duodenum are very uncommon. To the best of our knowledge, only a few cases of SCC of the duodenum exist in the reported literature. Here, we report a case of SCC of the duodenum in northern China. A 45-year-old Chinese Han male patient presented with abdominal pain and weight loss. CT, endoscopic examinations, X-rays, and immunohistochemical markers were used to confirm this rare diagnosis of SCC. We performed a pancreaticoduodenectomy with a curative intention. However, histological examination revealed SCC of the duodenum. Postoperative chemotherapy was started after surgery. To the best of our knowledge, pancreaticoduodenectomy is the preferred form of treatment for carcinoma of the duodenum. This is supplemented with chemotherapy, which can further prolong survival.

Squamous cell carcinoma metastatic to cervical lymph nodes from unknown primary origin:the impact of chemoradiotherapy

The management of cervical lymph node metastases of squamous cell carcinoma from an unknown primary site is still a therapeutic challenge.We report here our experience in treating these patients with chemoradiotherapy as a curative approach.Data from 40 patients were reviewed.In total,20(50%) patients underwent excisional biopsy.All patients underwent radiotherapy,which was delivered to both sides of the neck and pharyngeal mucosa(extensive field),and concurrent chemotherapy consisting of weekly cisplatin at a dose of 40 mg/m2.The clinical stage of the cervical nodes at presentation was N1 in 25%,N2 in 60%,and N3 in 15%.Most patients(75%) developed at least grade 3 mucositis.Eight patients(20%) had grade 3 xerostomia and 18 patients(45%) required esophageal dilation for stricture.The 5-year overall survival(OS) rate of all patients was 67.5%.The 5-year OS rates of patients with N1,N2,and N3 lesions were 100%,67%,and 41%,respectively(P = 0.046).The 5-year progression-free survival rate was 62.5%.In multivariate analysis,only N stage significantly affected OS(P = 0.022).Emergence of the occult primary was very limited(1 patient only).Our results suggest that extensive irradiation of both sides of the neck and pharyngeal mucosa with concurrent chemotherapy results in a lower emergence of primary tumor.Because the survival of patients with unknown primary is comparable to that of patients with known primary,an attempt at cure should always be made.

Early Age of Onset, Multiple Primary Malignancies and Poor Prognosis Are Indicative of an Inherited Predisposition to Esophageal Squamous Cell Carcinoma in Familial Rather Than Sporadic Disease- An Update Based on 14- to 23-year Follow-up

OBJECTIVE To demonstrate the effects of an inherited predisposition to familial esophageal squamous cell carcinoma （ESCC） through the comparison and analysis of the clinicopathologic differences between familial and sporadic ESCC cases. METHODS Differences in age of onset, prevalence rates of double primary ESCC, and survival rates between familial ESCC （n = 476） and sporadic ESCC cases （n = 1226） were analyzed. RESULTS Overall, familial ESCC cases showed a significantly younger age of onset （51.9±8.2 vs. 53.4 ±8.0, Pt.test = 0.00）, a significantly higher prevalence rate for double ESCC （2.73 % vs. 1.22%, adjusted with TNM：χMH2 = 4.029, P = 0.045）, and a lower survival rate than in sporadic cases （Pwald = 0.04）. The familial cases showed both a younger age of onset and poorer survival in most subgroups, and the differences were more marked in early-stage rather than in the .late-stage disease groups. CONCLUSION Theses findings confirm the existence of familial as opposed to sporadic ESCC. By the theory of the ＂two-hit＂ origin of cancer, these findings also suggest that the ＂first hit＂, a genetic predisposition, can affect the age of onset, number of primary carcinomas, and the prognosis for familial ESCC patients.

Long-term survivor of metastatic squamous-cell head and neck carcinoma with occult primary after cetuximab-based chemotherapy:A case report

BACKGROUND Cancer of unknown primary(CUP)is a histological proven malignant tumor whose origin cannot be detected despite careful examination.Most cervical lymph node metastases in CUP(80%)will originate from head and neck sites,and 15%show infiltration of squamous carcinoma cells.The survival rates of CUP are poor:The 5-year-survival rate ranges from 10%to 15%.First-line treatment recommendation for advanced,inoperable squamous cell carcinoma of head/neck(HNSCC)was cetuximab plus platinum-fluorouracil chemotherapy until recently,when checkpoint inhibitors proved clinically beneficial therapies.CASE SUMMARY Here,we report a case of a 42-year-old female patient with cervical and abdominal lymph node and distant bone metastases of an occult primary of the head and neck(squamous cell carcinoma,human papillomavirus positive).The cancer was diagnosed during pregnancy 10 years ago,and after giving birth,the patient was treated with cetuximab plus platinum-fluorouracil chemotherapy achieving complete remission(CR).CR lasted 26 mo when new metastases(abdominal lymph node,lumbar vertebral body)emerged.Both manifestations were irradiated.From then on,the patient has not received any further treatment,and her disease has remained controlled.Ten years after the initial cancer diagnosis,the patient is still alive and in good health,representing an exceptional case of HNSCC.CONCLUSION This case illustrates the exceptional clinical course and benefits of combined therapy approaches in advanced metastatic HNSCC with occult primary.

Predictors of distant metastasis in acinic cell carcinoma of the parotid gland

BACKGROUND AiCC is a primarily indolent disease process.Our aim with this study is to determine characteristics consistent with rapidly progressive AiCC of the parotid gland.AIM To report on patients with metastatic lung disease from AiCC and potential correlative factors.METHODS Single-institution retrospective review of patients treated at the University of Michigan between 2000 and 2017.Univariate analyses were performed.RESULTS A total of 55 patients were identified.There were 6 patients(10.9%)with primary AiCC of the parotid gland who developed lung metastases.The mean age at diagnosis for patients with lung metastases was 57.8 years of age,in comparison to 40.2 years for those without metastases(P=0.064).All 6 of the patients with lung metastases demonstrated gross perineural invasion intraoperatively,in comparison to none of those in the non-lung metastases cohort.Worse diseasefree and overall survival were significantly associated with gross perineural invasion,high-grade differentiation,and T4 classification(P<0.001).CONCLUSION AiCC of the parotid gland is viewed as a low-grade neoplasm with good curative outcomes and low likelihood of metastasis.With metastasis,however,it does exhibit a tendency to spread to the lungs.These patients thereby comprise a unique and understudied patient population.In this retrospective study,factors that have been shown to be statistically significant in association with worse disease-free survival and overall survival include presence of gross facial nerve invasion,higher T-classification,and high-grade disease.

Metastasis of esophageal squamous cell carcinoma to the thyroid gland with widespread nodal involvement: A case report

BACKGROUND Esophageal cancer is one of the most common causes of cancer-related death.Some patients with esophageal cancer have distant metastases at the time of diagnosis,but metastasis to the thyroid gland(MTG)and multifocal thyroid lesions alone are extremely rare.CASE SUMMARY In this case report,we present a case of a 69-year-old male with esophageal MTG.The patient visited our hospital for a routine body check-up,which revealed multifocal nodules in his thyroid lobes and enlarged cervical lymph nodes.A fine needle aspiration biopsy showed malignancies in both thyroid lesions and lymph nodes.The patient was initially diagnosed with primary bilateral thyroid cancer that spread to his lymph nodes,and a total thyroidectomy was performed.The histology showed MTG and therefore,a diagnostic work-up was implemented to determine the primary tumor.A fluorine-18-deoxyglucose positron emission tomography scan showed that the lower part of the esophagus and the lymph nodes in the neck,chest,and abdomen were involved.An esophagogastroscopy and corresponding pathology revealed distal esophageal squamous cell carcinoma.The esophageal MTG diagnosis was confirmed with pathological immunohistochemistry.CONCLUSION This case report highlights the difficulty in diagnosing esophageal MTG.Patients may have no malignancy history and be asymptomatic.Further diagnostic procedures are necessary after MTG is confirmed by cytology or histology,and the final diagnosis should be made according to the identification of the primary malignancy combined with pathological immunohistochemistry findings.

PRIMARY SQUAMOUS CELL CARCINOMA OF THE BREAST-3 CASES REPORT

Primary squamous cell carcinoma of thebreast is very rare and 3 cases of this disease weredetected at our hospital.

Primary nonkeratinizing squamous cell carcinoma of the scapular bone:A case report

BACKGROUND Squamous cell carcinoma(SCC)of bone is usually caused by metastasis from the lungs,bladder,or other sites.Primary SCC of bone most frequently involves the skull bones,and primary involvement of other sites in the skeletal system is extremely rare.To date,only three such cases have been reported,which makes the diagnosis,treatment,and prognosis of this disease a challenge.CASE SUMMARY A 76-year-old Chinese man presented to our hospital with nonspecific pain and limited mobility in the right shoulder for 4 mo.He underwent three-dimensional computed tomography reconstruction and magnetic resonance imaging of the right shoulder,which revealed an osteolytic destructive lesion in the right scapula with invasion into the surrounding muscles and soft tissues.Ultrasound-guided core needle biopsy detected a malignant tumor,and immunohistochemical analysis revealed a poorly differentiated SCC.Wide excision of the right scapular bone was performed,and pathological examination of the surgical specimen confirmed the diagnosis.At the last follow-up examination within 2 years,the patient was doing well with the pain significantly relieved in the right shoulder.CONCLUSION Primary SCC of bone is extremely rare at sites other than the skull.Clinicians must exhaust all available means for the diagnosis of primary SCC of the bone,so greater attention can be paid to its timely and effective management.Regular and adequate follow-up is essential to help rule out metastasis and judge the prognosis.

Primary Pure Squamous Cell Carcinoma of the Gallbladder: Case Report

Squamous cell carcinoma of the gallbladder is rare and accounts for about 12.7% of all cases of gallbladder cancer. Pure squamous cell carcinoma is even less common with a reported incidence of 3.3%. We present a case of 72 year-old African-American woman with decreased appetite, fatigue, and weight loss associated with intermittent right upper quadrant pain for two months. Computed tomography of the abdomen revealed a mass in the gallbladder and the hepatic flexure of the colon with involvement of adjacent small bowel. On exploratory laparotomy, a mass at the dome of the gallbladder was found with local invasion of the hepatic flexure, and the proximal transverse colon. There was no obvious involvement of the duodenum, common bile duct, or the extra-hepatic biliary tree. An extended right hemicolectomy, distal small bowel resection, cholecystectomy, a wedge resection of the liver and a feeding jejunostomy, were performed. Pathologic evaluation demonstrated well to moderately differentiated squamous cell carcinoma of gallbladder without evidence of distant metastasis. The patient improved clinically and was discharged home in good condition.

Primary malignant melanoma of the esophagus combined with squamous cell carcinoma:A case report

BACKGROUND Primary malignant melanoma of the esophagus is a rare malignant tumor of the esophagus,and its combination with squamous cell carcinoma is also rare.Here,we report the diagnosis and treatment of a case of primary esophageal malignant melanoma combined with squamous cell carcinoma.CASE SUMMARY A middle-aged man underwent gastroscopy for dysphagia.Gastroscopy revealed multiple bulging esophageal lesions,and after pathologic and immunohistochemical analyses,the patient was finally diagnosed with"malignant melanoma with squamous cell carcinoma".This patient received comprehensive treatment.After one year of follow-up,the patient was in good condition,and the esophageal lesions seen on gastroscopy were controlled,but unfortunately,liver metastasis occurred.CONCLUSION When multiple esophageal lesions are present,the possibility of multiple pathological sources should be considered.This patient was diagnosed with primary esophageal malignant melanoma combined with squamous cell carcinoma.

Cetuximab combined with chemotherapy for simultaneous esophageal squamous cell carcinoma and colon adenocarcinoma:A case report

BACKGROUND Multiple primary carcinomas(MPCs)are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual.Synchronous MPCs are rarer than solitary cancers or metachronous MPCs.Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases.CASE SUMMARY A 64-year-old patient presented with dysphagia,without obvious cause.A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results.After multi-disciplinary consultations,combination chemotherapy(a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14)and esophageal cancer radiotherapy were initiated.Based on the results of genetic testing,we switched to a regimen of leucovorin+fluorouracil+oxaliplatin and cetuximab regimen for 8 cycles.Subsequently,capecitabine and bevacizumab were administered until the most recent follow-up,at which the tumor remained stable.CONCLUSION Successful cetuximab chemotherapy treatment provides a reference for the nonoperative and homogeneous treatment of different pathological types of synchronous MCPs.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas

Objective:Squamous cell carcinoma(SCC)represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma(OSCC),a tumor associated with different clinical outcomes and linked to human papilloma virus(HPV)status.Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs.The present study proposes a 3-dimensional(3 D)biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix(ECM)and cancer cells.Methods:We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds.We also explored cancer cell adaptation to the 3 D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures.Results:HPV-positive and HPV-negative cell lines were successfully grown in the 3 D model and displayed different collagen fiber organization.The 3 D cultures induced an increased expression of markers related to epithelial–mesenchymal transition(EMT)and to matrix interactions and showed different migration behavior,as confirmed by zebrafish embryo xenografts.The expression of hypoxia-inducible factor 1α(1α)and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area.Furthermore,the 3 D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures.Conclusions:Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs.Moreover,3 D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.

Primary rectal squamous cell carcinoma treated with surgery and radiotherapy

Primary squamous cell carcinoma of the rectum is a rare malignancy,and the discrete dual lesions of rectum are even rarer.There is currently no effective and satisfactory treatment for this disease.Here we report a case of an elderly female with bi-primary squamous cell carcinoma of the rectum treated with radical resection and radiotherapy.The patient is still alive 43mo after the initial curative resection of the tumor.We suggest that surgery as the primary treatment followed by concomitant radiotherapy may be an effective protocol for elderly patients with rectal squamous cell carcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma misdiagnosed as lung squamous cell carcinoma:A case report

BACKGROUND Primary pulmonary lymphoepithelioma-like carcinoma(PPLELC)is an uncommon subtype of squamous cell carcinoma(SCC)of the lung,closely associated with Epstein-Barr virus(EBV)infection.The pathological features of PPLELC closely resemble those of SCC,which makes it prone to misdiagnosis.Surgical intervention constitutes the primary treatment approach for PPLELC.CASE SUMMARY This report describes a 44-year-old woman who was hospitalized for 1 mo due to left chest pain.Computed tomography revealed a mass shadow in the anterior basal segment of the left lower lobe,and a subsequent needle biopsy suggested SCC.The patient underwent radical tumor resection in the lower left lobe of the lung,and postoperative pathological examination indicated lymphoepithelial carcinoma,and the test for EBV encoded small RNA was positive.Following surgery,the patient was scheduled to receive four cycles of adjuvant chemotherapy,using the paclitaxel+carboplatin regimen,but the patient refused further treatment.CONCLUSION PPLELC is an exceptionally rare subtype of lung SCC and is prone to misdiagnosis.

Comparison of biological behavior of lacrimal gland adenoid cystic carcinoma with high-grade transformation cells

AIM:To evaluate the differences between human lacrimal gland adenoid cystic carcinoma with high-grade transformation(LACC-HGT)primar y cells cultured by high-grade transformation tissue and non-high-grade transformation(non-HGT)primary cells cultured by non-highgrade transformation tissue in proliferation,metastasis,drug susceptibility,and genes.METHODS:LACC-HGT primary cells were established by tissue block culture,and the 4^(th)to 10^(th)generation primary cells were selected as research objects.The cells were preliminarily identified by immunofluorescent staining.The differences between non-HGT and LACC-HGT primary cells in terms of proliferation,metastasis,and drug susceptibility were compared by cell counting kit-8(CCK-8)assay,wound healing,and drug sensitivity experiments.Differentially expressed genes were screened using mRNA array.Gene expression was analyzed using real-time quantitative polymerase chain reaction(RT-qPCR).RESULTS:LACC-HGT primary cells were successfully cultured by tissue block culture.Immunofluorescence staining results showed that cytokeratin(CK)and CK7 expression levels were positive in LACC-HGT primary cells.CCK-8 results showed that the proliferation ability of LACCHGT cells was significantly higher than that of non-HGT cells.Wound healing experiment showed that the migration ability of LACC-HGT cells was significantly higher than that of non-HGT cells.LACC-HGT cells were also less sensitive to cisplatin and paclitaxel than non-HGT cells.Compared with non-HGT cells,9566 differentially expressed genes were found in LACC-HGT primary cells,of which 5162 were upregulated and 4404 were down-regulated.The expression of N-acetylneuraminate pyruvate lyase(NPL),MARVEL domain containing 3(MARVELD3),syntabulin(SYBU),and allograft inflammatory factor 1(AIF1)was higher in LACCHGT cells than in non-HGT cells,whereas that of periostin(POSTN)was lower.CONCLUSION:LACC-HGT primary cells have faster proliferation,stronger migration ability,and poorer sensitivity to chemotherapy drugs than non-HGT primary cells.The expression of mRNAs in non-HGT and LACC-HGT primary cells are significantly different.These features are speculated to be the reasons why high-grade transformation tissues exhibit higher malignant degree and poorer prognosis than their counterparts.

Pleomorphic Adenoma with Exuberant Squamous Metaplasia and Keratin Cysts Mimicking Squamous Cell Carcinoma in Minor Salivary Gland

Salivary gland tumors, the second most common neoplasm of the mouth after squamous cell carcinoma, account for a significant proportion of tumors of the oral and perioral regions. An unusual case of adenoma presented as a solitary intraoral palatine mass in a 32-year-old woman is reported here. The tumor was interpreted as an unusual pleomorphic adenoma because of the presence of exuberant squamous metaplasia, clinically mimicking squamous cell carcinoma. Moreover, the presence of cystic structures filled with keratinized material was also salient feature. Pleomorphic adenomas may occasionally display focal squamous metaplastic changes;when extensive, it presents the potential for misinterpretation of the histology as indicative of well-differentiated squamous cell carcinoma.

Atypical Cystic Parotid Gland Acinic Cell Carcinoma in a Child

Purpose: To describe the extremely rare occurrence of acinic cell carcinoma of the parotid in a young child. Materials & Methods: A 14-year-old boy presented with a left sided facial mass. It was initially thought to be a bug bite or perhaps a wrestling injury. However, it progressed rapidly overall several weeks. CT revealed a well-circumscribed, cystic, 3.9 × 2.8 × 3.2 cmmass centered in the deep lobe of the left parotid gland, also involving the superficial lobe and extending medially through the stylomandibular tunnel with a component extending to the stylomastoid foramen. There was no solid enhancing portion. There were several enlarged level II lymph nodes suspicious for nodal metastases. Results: The mass was biopsied and pathology was consistent with acinic cell carcinoma. Complete left parotidectomy and left selective neck dissection was performed, confirming the diagnosis. Conclusions: Salivary gland neoplasms are rare in children. Less than 5% of salivary gland tumors occur in children. Salivary gland neoplasms account for less than 8% of pediatric head and neck tumors. Approximately 1/3 of salivary gland tumors arising in childhood are malignant;most being mucoepidermoid. Acinic cell carcinoma of the parotid gland in children is extremely rare, especially in those under age 16, with only a few available case reports. This case was also unusual in that the lesion was predominantly cystic.

Clear cell carcinoma of salivary gland type presenting as an endotracheal polypoid tumor

A 66-year-old woman presented with a 2-year history of asthma has progression of dyspnea within a week, and a computed tomography (CT) revealed an endotracheal tumor at level of aortic arch. The resected tumor, measured by 18 × 12 × 10 mm, has histologically malignant features including frank invasion with desmoplastic stroma and foci of necrosis. Presence of glycogen and mucin was confirmed by periodic acid-Schiff (PAS) and diastase PAS staining. Immunohistochemically, the tumor cells were diffusely positive for cytokeratin (CK) 7 and AE1/3, focally positive for CK5/6 and CK14, but negative for CK20. Thyroid transcription factor-1 (TTF-1), Napsin A, and SP-A, indicating lung parenchymal origin were all negative. Other muscular markers, neuroendocrine markers, renal cell carcinoma markers, and markers related to perivascular epithelioid cell tumors were all negative. Postoperative systemic examination suggests no primary tumor outside the lung. The follow up was excellent being recurrence free for 14 months in spite of the positive surgical margin by the tumor cells. This is a first report ?of rare neoplasm, clear cell carcinoma of salivary gland type, presenting as an endotracheal mass.

Hydroxyurea-induced cutaneous squamous cell carcinoma: A case report

BACKGROUND Hydroxyurea(HU)is a non-alkylating antineoplastic agent that is active in the Sphase of the cell cycle and inhibits the enzyme ribonucleoside reductase.HU is currently used to treat leukemia,sickle cell anemia,psoriasis,and chronic myeloproliferative disorders.Although HU is easy to use and effective and has high tolerance,there have been numerous reports of cutaneous complications during long-term therapy with HU.CASE SUMMARY We report a 67-year-old woman on long-term HU therapy for primary myelofibrosis who developed concurrent skin lesions during treatment.The first skin lesion appeared on the dorsum of her right hand in 2015.Despite continuous use of HU,her cutaneous changes were neglected.Approximately 3 years ago,she had multiple nodular and keratotic lesions on both hands with sharp margins,branny desquamation,and dotted hyperpigmentation.Furthermore,she developed acutely numerous ulcerative lesions on her hands and legs.Topical wound therapy with dressing changes and parenteral antibiotics was applied for management of the lesions.Most of the wounds healed after HU withdrawal.Lesions on both hands were replaced by scabs.Nevertheless,the wound on her left ankle reached 9 cm×7 cm in size in January 2018.Pathology confirmed welldifferentiated squamous cell carcinoma at the ulcer area.In addition,her left foot was severely affected and radical surgery with a below-the-knee amputation was suggested followed by preventive right groin nodal dissection.CONCLUSION In patients receiving continuous HU therapy,close dermatologic follow-up is critical for the early diagnosis and selection of appropriate treatment for cutaneous lesions.

Younger age of onset and multiple primary lesions associated with esophageal squamous cell carcinoma cases with a positive family history of the cancer suggests genetic predisposition

Background Previous epidemiological studies have consistently found a positive family history of esophageal cancer is associated with a significantly increased risk of the cancer.However,whether the elevated risk could be attributed to common household exposure or inherited susceptibility is uncertain.This study aimed to highlight the effect of genetic predisposition by noting the significant differences in onset age and multiple primary cancers between esophageal squamous cell carcinoma （ESCC） cases with or without a positive family history of the cancer.Methods Age at onset and the percentage of multiple primary cancers were compared between ESCCs with （n=766） or without （n=1 776） a positive family history of the cancer in a consecutive surgery cohort at the Department of Thoracic Surgery of Hebei Tumor Hospital and the Fourth Hospital of Hebei Medical University.Results Overall,ESCCs with a positive family history of the cancer featured both a significantly younger age of onset and significantly more multiple primary cancers than those with a negative family history （onset age 51.83 vs.53.49 years old,P 〈0.01; percent of multiple primary cancers 5.50% vs.1.70%,x2=25.42,P 〈0.01）.Both the differences were evident in subgroup analyses,but did not correlate.While age at onset differed significantly by family history among the male,smoking,and drinking groups,the difference of multiple primary cancers was significant among the otherwise nonsmoking,nondrinking,and younger onset age groups.Conclusions Younger age of onset and multiple primary cancers associated with ESCCs with a positive,as opposed to a negative family history of the cancer,suggest a genetic predisposition.The results of subgroup analyses indicate a younger age of ESCC development results from the interaction of environmental and genetic risk factors,but multiple primary cancers may be related only to genetic predisposition.