We experienced a very rare case of occult breast lobular carcinoma with numerous circulating tumor cells in peripheral blood. The diagnosis was very difficult because there were no symptoms of breast cancer and the preceding chief complaints such as general fatigue and weight loss or abnormality of peripheral blood findings were suggestive of a hematological disease. We could make a correct diagnosis of this case by checking the findings of complete blood count and bone marrow biopsy at the same time using immunohistochemistry

Asumi Sakaguchi

Kanako Ogura

Kuniaki Kojima

Maki Amano

Taijiro Kosaka

Toshiaki Kitabatake

Toshiharu Matsumoto

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Case Reports in Pathology

Occult Breast Lobular Carcinoma with Numerous Circulating Tumor Cells in Peripheral Blood

We experienced a very rare case of occult breast lobular carcinoma with numerous circulating tumor cells in peripheral blood. The diagnosis was very difficult because there were no symptoms of breast cancer and the preceding chief complaints such as general fatigue and weight loss or abnormality of peripheral blood findings were suggestive of a hematological disease. We could make a correct diagnosis of this case by checking the findings of complete blood count and bone marrow biopsy at the same time using immunohistochemistry.</jats:p

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Case ReportOccult Breast Lobular Carcinoma with Numerous CirculatingTumor Cells in Peripheral BloodKanako Ogura,1 Maki Amano,2 Toshiharu Matsumoto,1 Asumi Sakaguchi,1Taijiro Kosaka,3 Toshiaki Kitabatake,3 and Kuniaki Kojima31Department of Diagnostic Pathology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan2Department of Radiology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan3Department of Breast Surgery, Juntendo University Nerima Hospital, Tokyo 177-8521, JapanCorrespondence should be addressed to Kanako Ogura; kanakogu@juntendo-nerima.jpReceived 2 April 2015; Revised 20 May 2015; Accepted 4 June 2015Academic Editor: Janina KulkaCopyright © 2015 Kanako Ogura et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We experienced a very rare case of occult breast lobular carcinoma with numerous circulating tumor cells in peripheral blood.Thediagnosis was very difficult because there were no symptoms of breast cancer and the preceding chief complaints such as generalfatigue and weight loss or abnormality of peripheral blood findings were suggestive of a hematological disease. We could make acorrect diagnosis of this case by checking the findings of complete blood count and bone marrow biopsy at the same time usingimmunohistochemistry.1. IntroductionInvasive lobular carcinoma (ILC) accounts for about 6% ofbreast cancer, which is the second most common type afterinvasive ductal carcinoma (IDC) [1, 2]. It is well known thatthe pattern of metastatic spread of ILC is different from thatof IDC, so scrupulous attention to metastasis to unusual focisuch as the gastrointestinal tract, uterus, ovary, andmeningesis required [3].There are some reports of breast cancers with bonemarrow metastases. Kopp et al. analyzed 22 of such cases, inwhich 7 cases were ILC [4]. Seventeen cases were diagnosedby bonemarrow histology and the other 5 cases were revealedbecause of leukoerythroblastic blood smear.On the other hand, occult breast carcinoma accounts for0.3 to 1% of breast cancer [5]. It is defined as breast carcinomawith an axillary lymph node metastasis as the first clinicalmanifestation of the disease. Recently, diagnostic imaginghas dramatically improved, so it has been recommended foroccult breast carcinoma to perform mammography repeat-edly or magnetic resonance imaging (MRI).The prognosis ofoccult breast cancer seemed to be similar to that of usual andovert breast cancer with lymph node metastasis.We experienced a unique case of occult invasive lobularcarcinoma with identification of circulating tumor cells inperipheral blood count.There have been very few reports thattumor cells themselves were identified in peripheral bloodcount, even if secondary change such as leukoerythroblasto-sis in peripheral blood smear was shown.2. Case PresentationThe patient was a 65-year-old woman, with chief com-plaints of general fatigue and weight loss. The findingsof peripheral blood test are summarized in Table 1. Thenumber of leukocytes was high (22,200/𝜇L) and atypicalunclassified cells were identified in her peripheral bloodcount. Those cells were counted as “other” at a level of 7.5%.The atypical cells were noncohesive and had round nucleiand cytoplasm with microvilli resembling lymphocytes orplasma cells in form (Figure 1). The serum calcium level washigh (13.4mg/dL). Such findings leaded her physician intothe suspicion of hematological disease such as lymphomaor myeloma although the serum level of CEA was also high(621 ng/mL).Hindawi Publishing CorporationCase Reports in PathologyVolume 2015, Article ID 135684, 6 pageshttp://dx.doi.org/10.1155/2015/1356842 Case Reports in PathologyTable 1: The patient’s peripheral blood data.WBC 22200 /𝜇LNeutrophil 64.5 %Lymphocyte 20 %Monocyte 7.5 %Eosinophil 0 %Basophil 0 %Other 7.5 %Myelocyte 0.5 %Hb 13.7 g/dLHt 42.4 %Plt 315 × 104 /𝜇LTP 8.2 g/dLAlb 3.4 g/dLAST 57 IU/LALT 20 IU/LLDH 373 IU/LALP 973 IU/LBUN 29 mg/dLCre 1.2 mg/dLNa 135 mEq/LK 4.9 mEq/LCl 94 mEq/LCa 13.4 mg/dLCEA 621 ng/mLFigure 1: Tumor cells in peripheral blood smear. Noncohesiveround tumor cells resembling lymphocytes were identified.Her physician performed a bone marrow puncture. Thebone marrow specimen showed so-called “packed bonemarrow” and fibrosis was also shown, so aspiration failed (so-called “dry tap”). In the biopsy specimen, numerous smallround cells that were the same as the cells in the peripheralbloodhad grownwith proliferation of reticular fibers (Figures2(a) and 2(b)). We continued histological investigation usingimmunohistochemistry. These tumor cells were negative forLCA but positive for AE1/AE3. Furthermore, tumor cellswere also positive for GCDFP15, ER, and (Figure 2(c)) PgRbut negative for E-cadherin. On the basis of the resultof immunohistochemistry, we diagnosed the bone mar-row lesion as metastatic lobular carcinoma of the breast.Table 2: Immunohistochemical findings of this case.Bone marrow Axial lymph node StomachAE1/AE3 + + +ER + + +PR + + +HER2 Score 1+ Score 1+ Score 1+Mammaglobin − − −GCDFP15 + + +CK7 + + +CK20 − − −CDX2 − − −Subsequently, the patient underwent detailed examinationconcentrating on imaging study. However, no lesion ineither breast was identified by mammography (Figure 3(a)),ultrasonography, and even contrast-enhanced CT or MRI(Figure 3(b)). Enhanced CT images showed swelling of leftaxillary, right internal mammary, and perigastric lymphnodes and diffuse thickening of gastric wall like “Bormann4 tumor” (Figure 4). T1-weighted MRI revealed generalizedbone marrow metastasis. Fatty bone marrow was diffuselyoccupied by low-intensity lesion (Figure 5). Furthermore,bone scintigraphy also revealed generalized osseous metas-tasis by so-called “beautiful bone sign.” Biopsies from anenlarged left axillary lymph node and from gastric mucosawere performed, resulting in the finding of metastatic lobularcarcinoma that we confirmed by immunohistochemistryincluding ER, PgR, and GCDFP15 (Figures 6 and 7). Wesummarized the immunohistochemical findings of bonemarrow, axillary lymph node, and gastric biopsy specimensin Table 2. Carcinoma from accessory breast tissue in axillawas also ruled out.Finally, this case was diagnosed as occult breast lobularcarcinoma with multiple metastases to bone, bone marrow,left axillary lymph nodes, and stomach withmany circulatingtumor cells in peripheral blood.After the diagnosis, combination chemotherapy withdocetaxel, cyclophosphamide, and zoledronic acid hydratewas applied. During chemotherapy, diffuse thickening ofupper dermis of the left breast appeared. Since the patientrefused skin biopsy, the underlying cause of the skin swellingremains obscure. The symptoms such as swelling of axillarylymph nodes and thickening of dermis and gastric wall wereimproved by chemotherapy. Although enhanced CT has beenrepeatedly performed, there has been no lesion in eitherbreast. At the time of writing the paper, the patient is stillundergoing treatment.3. DiscussionThis case was difficult to diagnose because of an unusualclinical presentation, that is, identification ofmassive amountof nonhematological tumor cells in peripheral blood countand “occult” breast carcinoma.Pentheroudakis et al. recommended performing mam-mography repeatedly or magnetic resonance imaging (MRI)for occult breast carcinoma [6]. They documented thatCase Reports in Pathology 3(a) (b)(c)Figure 2: Bone marrow biopsy specimen. (a) H-E stain. Hypercellular bone marrow. (b) H-E stain. Monotonous tumor cells invaded bonemarrow space accompanied by fibrosis. (c) Immunohistochemical stain of estrogen receptor. Tumor cells were diffusely positive.Right Left(a) (b)Figure 3: (a) Mammography. There was no lesion in either breast. (b) Enhanced MRI. There was also no lesion in either breast.primary small foci in both breasts were identified in 59%of cases of occult breast cancer that they reviewed by MRIimaging. They also revealed that a small breast primaryfocus was identified histologically in 72% of cases treatedwith mastectomy. However, primary foci were sometimesnot identified. In our case, there was no lesion in eitherbreast regardless of performing various modalities suchas mammography, ultrasonography, CT, or MRI. Our casewas thought of as true occult breast carcinoma. Neal etal. reported occult breast carcinoma (ILC) presenting asgastrointestinal metastases without lesions in the breasts [7].Invasive lobular carcinoma has a tendency to metastasizeto gastrointestinal tract. Metastatic breast lobular carcinomacan easily be mistaken for a primary gastrointestinal cancer.Metastatic “occult” lobular carcinoma is even more difficultto identify. They documented that immunohistochemistrycould allow accurate diagnosis. In our case, tumor cellsmetastasized to stomach, axillary lymph node, and bonemarrow. We could perform immunohistochemistry to allsamples from stomach, lymph node, and bone marrowand compare the results. Immunohistochemistry was alsopowerful diagnostic tool in our case.Such a situation when circulating tumor cells are vis-ible in peripheral blood smear is extremely rare. In ourcase, hematological disease was suspected at the initial visitbecause of the many noncohesive tumor cells (7.5% of all4 Case Reports in Pathology(a) (b)Figure 4: (a) Upper endoscopy. Mucosal rugae were edematous and thickened. (b) Contrast-enhanced CT revealed diffuse thickening ofgastric wall.Figure 5: T1-weightedMRI revealed low-intensity lesion occupyinglumbar spine and iliac bone diffusely.blood cells) seen in the peripheral blood smear, suggestinghematological malignancy. There are reports of circulatingtumor cells in primary breast cancer. However, the methodsfor the identification of circulating tumor cells are almost allmolecular ones, such as RT-PCR. Fortunato et al. revealedthat RT-PCR of the BM is an independent prognostic factorfor disease-free survival of breast cancer patients [8]. Thisis the first case report of breast carcinoma with “countable”nonhematological tumor cells in a peripheral blood smear.In our case, bone marrow biopsy was also performed, so wecould compare the circulating atypical cells in both periph-eral blood smear and the biopsy sample with performingimmunohistochemistry. It contributed to prompt and correctdiagnosis of this difficult case.Kopp et al. warned that bone marrow involvement has tobe considered in breast cancer patients, in particular in thosewith bone metastases and otherwise unexplained cytopenia[4]. They also documented that full blood exam can serve asa simple diagnostic tool. Cotta et al. documented that lung,breast, and prostate cancers are prone to bone metastasisin adults [9]. If a carcinoma metastasises to bone marrow,leukoerythroblastic reaction can sometimes be found on fullblood exam.In our case, the patient was not suspected of havingbreast cancer at the first visit and bone marrow punctureproved to be the decisive tool in correct diagnosis. It maybe necessary for breast cancer patients to perform not onlycomplete blood count but also bonemarrow puncture if someabnormalities on full blood exam are identified. Cotta etal. also documented that circulating tumor cells sometimesmimic the clinical appearance of acute leukemia. In cases ofbreast cancer, lobular carcinomas do metastasize to skeletalsystem in higher frequency. The tumor cells can be difficultto identify because they can be small and scant, with anappearance that is difficult to distinguish from that of lym-phocytes or blast cells. Indeed, we also suspected lymphomaor plasmacytoma at first.Lyda et al. documented that keratin immunohistochem-istry (IHC) detected clinically significant metastases in bonemarrow biopsy specimens in women with lobular breastcarcinoma [10]. They divided the cases of ILC into threegroups based on hematoxylin and eosin (H-E) staining andkeratin IHC results.They showed that prognosis was worse inthe order of H-E-negative/IHC-negative, H-E-negative/IHC-positive, and H-E-positive/IHC-positive. They concludedthat routine morphologic examination without the aid ofkeratin IHC was unreliable in detecting clinically relevantmetastatic lobular carcinoma in bone marrow biopsies.According to Lyda et al., our case was categorized into H-Epositive/IHC positive case, so the patient’s prognosis was tobe expected as unfavorable. Immunohistochemistry in ourcase was not so much useful for prognostic prediction buthelped in accurate diagnosis. We could reconsider the originof the tumor cells by the immunohistochemical reactions:LCA was negative and ER, PR, and GCDFP15 were positivein the atypical cells in bonemarrow, axillary lymph node, andgastric biopsy specimens. It was also important to check thefindings of complete blood count and bone marrow biopsyspecimen at the same time.Misdiagnosis or delay of diagnosismight have occurred if the diagnosis based on complete bloodcount preceded bone marrow biopsy.Case Reports in Pathology 5(a) (b)(c)Figure 6: Axillary lymph node specimen. (a) H-E stain. Low power field. Tumor cells invaded lymph node parenchyma. (b) H-E stain.High power field. Monotonous tumor cells and fibrotic area. (c) Immunohistochemical stain of estrogen receptor. Tumor cells were diffuselypositive.(a) (b)(c)Figure 7: Gastric biopsy specimen. (a) H-E stain. Low power field. Tumor cells infiltrated the lamina propria. (b) H-E stain. High powerfield. Monotonous round tumor cells resembling the tumor cells seen in bone marrow and axillary lymph nodes. (c) Immunohistochemicalstain of estrogen receptor. Tumor cells were diffusely positive.6 Case Reports in PathologyIn conclusion, we experienced a case of occult breastlobular carcinoma with numerous circulating tumor cells inperipheral blood count. Although the diagnosis was difficultbecause circulating tumor cells were abundant andmimickedlymphocytes or blast cells, immunohistochemistry was veryuseful for the correct diagnosis. We could also make adiagnosis quickly because we checked the patient’s peripheralblood smear and bone marrow biopsy specimen at the sametime.Conflict of InterestsThe authors declare that there is no conflict of interestsregarding the publication of this paper.AcknowledgmentThe authors thank Mr. Daniel Mrozek (Medical EnglishService, Kyoto, Japan) for organizing the English revision ofthis paper.References[1] B. C. Pestalozzi, D. Zahrieh, E. Mallon et al., “Distinct clinicaland prognostic features of infiltrating lobular carcinoma of thebreast: combined results of 15 International Breast Cancer StudyGroup clinical trials,” Journal of ClinicalOncology, vol. 26, no. 18,pp. 3006–3014, 2008.[2] M. S. Moran, Q. Yang, and B. G. Haffty, “The yale universityexperience of early-stage invasive lobular carcinoma (ILC) andinvasive ductal carcinoma (IDC) treated with breast conserva-tion treatment (BCT): analysis of clinical-pathologic features,long-term outcomes, and molecular expression of COX-2, Bcl-2, and p53 as a function of histology,”The Breast Journal, vol. 15,no. 6, pp. 571–578, 2009.[3] S. R. Lakhani, E. Rakha, and P. T. Simpson, “Invasive lobularcarcinoma,” in WHO Classification of Tumours of the Breast, S.R. Lakhani, I. O. Ellis, S. J. Schnitt, P. H. Tan, and M. J. van deVijver, Eds., pp. 40–42, IARC, 4th edition, 2012.[4] H. G. Kopp, K. Krauss, T. Fehm et al., “Symptomatic bonemarrow involvement in breast cancer—clinical presentation,treatment and prognosis: a single institution review of 22 cases,”Anticancer Research, vol. 24, pp. 1593–1599, 2009.[5] S. Lanitis, K. A. Behranwala, R. Al-Mufti, and D. Hadjiminas,“Axillary metastatic disease as presentation of occult or con-tralateral breast cancer,” Breast, vol. 18, no. 4, pp. 225–227, 2009.[6] G. Pentheroudakis, G. Lazaridis, and N. Pavlidis, “Axil-lary nodal metastases from carcinoma of unknown primary(CUPAx): a systematic review of published evidence,” BreastCancer Research and Treatment, vol. 119, no. 1, pp. 1–11, 2010.[7] L. Neal, N. Sookhan, andC. Reynolds, “Occult breast carcinomapresenting as gastrointestinal metastases,” Case Reports inMedicine, vol. 2009, Article ID 564756, 3 pages, 2009.[8] L. Fortunato, A. Mascaro, A. Baldi et al., “Positive bone marrowbiopsy is associated with a decreased disease-free survivalin patients with operable breast cancer,” Annals of SurgicalOncology, vol. 16, no. 11, pp. 3010–3019, 2009.[9] C. V. Cotta, S. Konoplev, L. J. Medeiros, and C. E. Bueso-Ramos, “Metastatic tumors in bone marrow: histopathologyand advances in the biology of the tumor cells and bonemarrowenvironment,” Annals of Diagnostic Pathology, vol. 10, no. 3, pp.169–192, 2006.[10] M. H. Lyda, M. Tetef, N. H. Carter, D. Ikle, L. M. Weiss, andD. A. Arber, “Keratin immunohistochemistry detects clinicallysignificant metastases in bone marrow biopsy specimens inwomen with lobular breast carcinoma,” American Journal ofSurgical Pathology, vol. 24, no. 12, pp. 1593–1599, 2000.Submit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

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Occult Breast Lobular Carcinoma with Numerous Circulating Tumor Cells in Peripheral Blood

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