To the Editor,

I read with interest the report of Chakupurakal and colleagues on a patient who developed peripheral neuropathy during imatinib treatment.(1) Their report highlights the importance of vigilance for late, unexpected adverse events in patients receiving potentially lifelong maintenance chemotherapy.

The authors assert that neuropathy has not previously been reported as a side effect of imatinib. I would like to draw the authors' attention to a case of neuropathy during imatinib treatment, which I reported some years ago.(2) In that case there was a temporal association between the initiation of a concomitant medication (amlodipine) that may increase imatinib exposure and the acute onset of neuropathic symptoms. A search of Pubmed (accessed 28 April 2011) using the search terms 'imatinib' and 'neuropathy' identifies this paper, the paper of Chakupurakal and two less relevant papers. Since the publication of my case report I have twice been contacted by colleagues who had each observed a single case of neuropathy during imatinib treatment with no other explanation identified. It is difficult to know whether the frequency of neuropathy on imatinib is greater than the frequency of idiopathic neuropathy in an age-matched population.

The same caution applies to the interpretation of cases of left ventricular dysfunction during imatinib treatment. The authors include heart failure and left ventricular dysfunction in a list of 'commonly reported side effects of imatinib'. However, the average age of patients at diagnosis of chronic myeloid leukaemia coincides with the age at which cardiac problems start to rise in incidence in the general population. The experiments of Kerkela and colleagues (3) might lead us to predict many more cases of left ventricular failure with dasatinib, which is 300 times as potent as imatinib as an inhibitor of the ABL1 enzyme,(4) yet this is not a major clinical problem in experience to date. Whilst the absence of significant cardiac impairment in a prospective evaluation of imatinib- treated patients (5) is somewhat reassuring, it remains possible that late effects might emerge after many years of treatment, and ongoing pharmacovigilance is required.

References

1. Chakupurakal, G., Etti, R.J. & Murray, J.A. Peripheral neuropathy as an adverse effect of imatinib therapy. J Clin Pathol 2011; 64: 456.

2. Ross, D.M. Peripheral neuropathy on imatinib treatment for chronic myeloid leukaemia: suspected adverse drug interaction with amlodipine. Intern Med J 2009; 39: 708.

3. Kerkela, R., Grazette, L., Yacobi, R., Iliescu, C., Patten, R., Beahm, C., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12: 908-916.

4. O'Hare, T., Walters, D.K., Stoffregen, E.P., Jia, T., Manley, P.W., Mestan, J., et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005; 65: 4500-4505.

5. Estabragh, Z.R., Knight, K., Watmough, S.J., Lane, S., Vinjamuri, S., Hart, G., et al. A prospective evaluation of cardiac function in patients with chronic myeloid leukaemia treated with imatinib. Leuk Res 2011; 35: 49-51.

Conflict of Interest:

None declared

We thank Dr Naim for the interest in our paper. In our review of histiocytoid breast carcinoma (1), we have indicated that it is best categorized as a subtype of invasive lobular carcinoma, and this is stated in our title. The various terms mentioned in our review relate to historical descriptions that alluded to this unusual tumour, based on morphological evaluation and reports by authors who investigated this subject (2-6). The 'apocrine lobular' prefix is perhaps the most morphologically and immunophenotypically accurate among the terms, as histiocytoid breast carcinoma has been shown to express apocrine differentiation fairly consistently, and its underlying lobular origin is mostly well accepted. Eusebi et al used 'myoblastomatoid' to refer to its resemblance to granular cell tumour, which is a histologic differential diagnosis for histiocytoid breast carcinoma (6). The reference to 'pleomorphic' lobular breast carcinoma was because of the observation that histiocytoid carcinoma cells that mimicked 'foam' cells were noted in these aggressive pleomorphic tumours (2). While lipid-rich carcinoma was initially considered synonymous with histiocytoid breast cancer, lipid stains are generally negative in the latter (1, 3, 4). We are not suggesting that these myriad terms should be currently applied to histiocytoid lobular breast carcinoma. The purpose of their mention is to present a chronological sequence of how this entity was initially recognized and the subsequent work that led to our present understanding. We believe the term histiocytoid breast carcinoma is best applied to a tumour that consists of carcinoma cells that resemble benign histiocytes. Invariably, further workup usually establishes its lobular phenotype. 'Malignant histiocytoma', which implies a tumour of fibrohistiocytic origin, is not an appropriate term for histiocytoid lobular breast carcinoma which is epithelial and not fibrohistiocytic nature. When a breast tumour composed of histiocyte-like cells is established on immunohistochemistry to be epithelial in nature with lobular characteristics, the diagnosis of histiocytoid lobular breast carcinoma is firm. However, we acknowledge the potential challenges in making this diagnosis on needle core biopsy where limited sampling may pose diagnostic difficulty, and in such instances, further excision with more complete histological examination will allow a conclusive diagnosis. References 1.Tan PH, Harada O, Thike AA, Tse GM. Histiocytoid breast carcinoma: an enigmatic lobular entity. J Clin Pathol Mar 12.

2.Eusebi V, Magalhaes F, Azzopardi JG. Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol 1992 Jun; 23(6): 655-62.

3.Hood CI, Font RL, Zimmerman LE. Metastatic mammary carcinoma in the eyelid with histiocytoid appearance. Cancer 1973 Apr; 31(4): 793-800.

4.Ramos CV, Taylor HB. Lipid-rich carcinoma of the breast. A clinicopathologic analysis of 13 examples. Cancer 1974 Mar; 33(3): 812-9.

5.Eusebi V, Betts C, Haagensen DE, Jr., et al. Apocrine differentiation in lobular carcinoma of the breast: a morphologic, immunologic, and ultrastructural study. Hum Pathol 1984 Feb; 15(2): 134- 40.

6.Eusebi V, Foschini MP, Bussolati G, Rosen PP. Myoblastomatoid (histiocytoid) carcinoma of the breast. A type of apocrine carcinoma. Am J Surg Pathol 1995 May; 19(5): 553-62.

Conflict of Interest:

None declared

The Hematologists(Pathologists trained in hematology) of kolkata, West Bengal( in private setup tertiary care hospitals or in diagnostic laboratories or in Govt. set up secondary or tertiary care teaching hospitals) are being mostly trained with performing, interpretation, evaluation and diagnosis of common hematological problems, requiring Bone Marrow studies, by Bone Marrow aspiration(for diagnostic and follow up after any therapy) than by Bone Marrow Trephine biopsy, unless there is1) failed aspirate due to no marrow fragments in conditions when there is Marrow fibrosis or Marrow aplasia or 2) when there is suspected Pathology in Bone or 3) Marrow is cellular but poor aspiration happens due to tightly packed marrow. In Kolkata the interpretation and reporting of Bone Marrow aspiration is usually done by consultant pathologists trained specially in hematology division in a laboratory or in a teaching hospital Pathology dept set up. A very few centers[ one or two] are there in kolkata in the medical colleges where there are post doctoral trainees in hematology who also perform and report Bone marrow aspiration mainly and occasionally by trephine biopsy.

We authors consider however that there are till many advantages of performing and reporting Bone Marrow aspiration then reporting Bone Marrow Trephine biopsy, some of them can be summarized as follows • The Marrow aspiration needles are less costly, supplied and easily available in the kolkata market, in each &every laboratories and can be easily sterilized then islam or Jamshedi needles for marrow trephine biopsy ** the procedure can be repeated if and when necessary *** Multiple numbers of slides can be drawn from a single aspirate and may be used thus for special stain, cyto-chemistry and immuno histochemistry when necessary **** Report can be handed over to patient by 24 hours in most cases unless special stains or immunostains are asked for.***** Cytogenetic studies including flow cytometry can be performed with aspirated materials******The technique and interpretation can be percolated even at secondary health care level where there is a trained pathologists(at district and sub divisional level hospitals or diagnostic laboratories) and thus necessary treatment can be given earlier by General physicians or primary care physicians. • However there remain recognized problems with Bone Marrow aspiration studies 1) That the aspirated material often becomes diluted with much aspirated blood and in that case it is wiser to suck off blood before making smears with a blotting paper edge 2) the smear drawn by the trainee Post doctorals may not be equally enough thin and spreaded and clumping of many cells at some patchy areas of the slide 3) Marrow material may be drawn inadequate for interpretation 4) while Interpretation of cases and diagnosis are given erythriod hyperplasia particularly in children-the underlying diseases is not well described and many reports realy are such 5) When there is suspected focal lesion –in the bone marrow itself marrow aspiration can miss diagnosis 6) suspected &focal bone marrow fibrosis 7) when there is need to study the bone marrow architecture or bone structure or bone marrow blood vessels, Bone marrow aspiration may not be adequate study • Besides there may be many indications for performing Bone marrow Trephine biopsy like in Aplastic anemia; Myelofibrosis; MDS; Hairy cell leukemia; smoldering Multiple Myeloma; Early Multiple Myeloma Granulomatous lesions in Marrow [ may be from bacterial, viral, rickettsial, fungi, parasitic and sarcoidosis]; Osteopatheis. hypocellular MDS and investigation of suspected MDS or MDS with fibrosis; investigation for suspected amylodosis in cases of Multiple Myeloma ; Hypoplastic acute leukemia; AML M7; After Bone marrow transplant assessments; in CML for sub-typing the disease or to detect early blast crisis and to assess marrow fibrosis; for staging of Hodgkin disease(Bone marrow involvement is(2-32%) diagnosis and staging of small cell tumors of childhood; investigations for unexplained luekoerythroblastic blood picture and trephine biopsy can diagnose occult or micro metastasis if any or necrosis of bone marrow when there is infraction of bone which are missed or become difficult to diagnose by Bone Marrow aspiration studies. • The problem of trephine biopsy is that needles( Islam or jamshidi or westermann-jensen) needles are not available in every laboratories even at tertiary care teaching hospitals Pathology department and disposable needles are very costly for patient* it is always necessary to carry out aspiration at same time** Requires tissue processing set up with fixation facility {microwave fixation is better then10% buffered formalin or zinker fixative as often requires immuno stain as style] and decalcification fluid and making paraffin or resin blocks *** Training for interpretation and evaluation of Trephine biopsy is not adequate; Adequacy of length of Marrow tissues often not obtained (25% shrinkage is natural for fixation and at least 5-6 trabecular space is required for interpretation as per authors] and there remains also word of cautions for patients with coagulation disorders, liver failure and in patients with thrombocytopenia{< 1.5 lack/cumm] • Finally Bone Marrow aspiration and Bone Marrow trephine biopsy are complementary to each other as per authors at least if aspirations are not done then bone marrow imprint should be seen before evaluating Trephine biopsy.

Conflict of Interest:

None declared

This study by Prof Abbas et al of German Pathology Institute is in the very important domain of transitional medicine, requiring molecular definition and designation for the lesions or morbid entities previously held diagnosable on the histopathological basis with or without special staining. Molecular basis of defining disease as in the case under consideration of IgG-4 related systemic disease, is to take into account the molecule(s), like IgG-4 here, so varied histopathological inflammatory, sclerotic, fibrotic, and phlebitic entities in bone, joint, pancreas, salivary glands, skin, lymph nodes or else, if present with serum IgG-4 elevation/ presence of IgG-4 plasma cells, such lesions/morbidities are being by the researchers labelled as IgG-4 associated inflammatory expression diseases (Kim HJ 2000, Fragoulis GE 2010, Stone JR 2011). As evident in the present study, there may be IgG-4 plasmoinflammatory (mean 55/hpf) Rheumatoid (RF+ve) Synovitis, and IgG-4 plasmoinflammatory Rheumatoid factor negative (RF-ve) Synovitis as also reported by previous studies above. Likewise in oral including neoplastic lesions, skin diseases previously defined as allergies like pemphigus, Salivary sclerotic inflammations; where ever lesion is accompanied by tumifective inflammatory component and shows serum IgG-4 above normal levels and/or IgG-4 plasma cells infiltration 5-50 or more cells/hpf, the diagnostician is bound to tag diagnosis as IgG-4 associate say Rheumatoid arthritis. As such any anti nuclear, anti cytoplasm or anti membranous features could not be demonstrated in the IgG-4 or related plasma cells, which also appeared to be consequence of (B lymphocyte irritation) disease rather than cause. Hence designations like IgG-4 associated disease may not be proper in view of the consequent confusion. Better it may be identified as a common feature in several varied inflammation manifesting diseases requiring treatment for IgG-4 plasmoinflammation, besides for the cause and symptoms of the disease. What the authors concluded in this study appeared to constitute IgG-4 related transition defect (TD) or transition ambiguity (TA).

Conflict of Interest:

None declared