automation in the histology lab make a histology lab more competitive given that medical practices...

Automation in the Histology Lab Investing in Cost Savings, Faster Turnaround Times, Reduced Contamination, and Standardization Meghan J. Cuddihy, Ph.D. Abigail G. Garrity, M.S.

In this white paper

Automation in the Histology Lab 2

Investing in Automation 2

Cost & Payback of Automated Equipment 4

Faster Turnaround Times 5

Reduced Contamination 6

Safety 8

Standardization 8

Microtomy: The Missing Link 9

Benefits of Automation 10

© 2014 Aquaro Biosystems www.aquarobio.com 2

Automation in the Histology Lab The demand for tissue-based diagnostic services, which account for over 90% of tests used for cancer diagnosis, is increasing due to rising cancer diagnoses and increased prevention efforts [1]. Research budgets are being cut and researchers are forced to choose the most cost-effective solutions and stretch each dollar as far as possible. New healthcare laws have resulted in reduced reimbursements, forcing labs to increase their output with less funds and staff. Additionally, a large portion of the histology workforce is nearing retirement age [2] and fewer histotechs are being trained than ever before. As a result, histology labs are under pressure to process increasing numbers of specimens with short turnaround times while maintaining high slide quality and eliminating contamination and mix-ups. In order to meet demand without increasing staff, automation and process improvements to streamline the histology workflow are needed. Table 1 summarizes the workflow steps for which automated technologies are available to histology labs. Automation allows for a continuous and efficient flow of specimens through the lab, yields a standard product, makes the lab safer for histotechs, and reduces contamination. Importantly, automation also decreases turnaround time, thereby improving patient quality of care. Furthermore, by decreasing hands-on time, automation reduces costs and allows labs to expand the services it offers, such as special stains, biomarkers, and digital pathology. Investing in Automation The cost of new equipment is a serious consideration for every histology lab. Automated equipment can cost anywhere from $15,000 for a microtome to $150,000 for an immunohistochemistry (IHC) stainer, not including service contracts. Integrated solutions such as the Kurabo Auto Slide Preparation System can cost much more. Lab managers need to be able to justify the cost of equipment within a reasonable payback period. Cost justification may be in terms of increased revenues from productivity and services offered, or decreased recurring costs, such as histotech time. Lab managers should decide where investments in automation will have the greatest impact on their workflow and margins. Figure 1 summarizes data on the average number of hours spent on manual histology workflow steps per 100 units [2]. Units are defined for each step and are indicated in the figure. Tissue processing was excluded from this data as the majority of labs utilize automated processors. Excluding grossing as it may be impossible to automate, all other steps occupy a

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Table 1. Summary of benefits of automating each step of the histology sample preparation work flow and examples of commercially available equipment.

Scale: ✓✓✓ = major improvement ✓✓ = some improvement ✓ = minor improvement - = N/A

Reduces

Hands-On Time

Standardizes Product

Improves Laboratory

Safety

Reduces Contamination Examples Capacity / Throughput

Processing ✓✓✓ ✓✓✓ ✓✓ ✓✓ Sakura Tissue-Tek® VIP® 6 300 cassettes per 110 minutes

Embedding ✓✓✓ ✓✓✓ ✓✓ ✓✓ Sakura Tissue-Tek® AutoTEC 120 cassettes per hour

Sectioning ✓-✓✓✓ ✓✓ ✓✓ - Leica RM2255 / RM2265 (Varies)

Kurabo AS-200 100 slides per hour

Mounting onto Slides ✓✓✓ ✓✓✓ ✓✓✓ ✓✓✓ Kurabo AS-400 100 slides per hour

Staining ✓✓✓ ✓✓✓ ✓✓✓ ✓-‐ ✓✓✓

Sakura Histo-Tek® SL Slide Stainer 100 slides per hour

Thermo Scientific™ Varistain™ Gemini Automatic Slide Stainer 300 slides per hour

Ventana® Symphony 160 - 200 slides per hour

Sakura Tissue-Tek® Prisma®/Film® 500 slides per hour

Coverslipping ✓✓✓ ✓✓ ✓✓ - Leica ST5010 Autostainer XL / CV5030 Coverslipper 600 slides per hour

Sakura Tissue-Tek® GlasTM g2 400 slides per hour


significant portion of the workflow. Thus, introducing automation at any of these steps can have a positive impact. It is notable that microtomy takes twice as much time as the other steps, but has the least amount of associated automation (see the Microtomy section, page 9). As procedures vary from lab to lab, the impact of automation at each step will vary as well. For example, if three slides per block are required, a histotech will spend three times as long staining and coverslipping than a when only making one slide per block. Thus, the benefits of automating staining and coverslipping increase as more slides are needed. Before deciding where to add automated technologies, lab managers should identify bottlenecks and examine where histotech hours are spent to determine which equipment will have the greatest impact on their workflow. Cost & Payback of Automated Equipment Automated equipment can perform routine tasks faster and with a higher throughput (number processed per batch) than can be performed manually. Table 2 estimates the approximate time saved by using an automated embedder, stainer, or stainer and coverslipper to process 100 units. These numbers translate into a shift in the hours required to perform the work step shown in Figure 1. For example, by employing both an embedder and an integrated stainer and coverslipper, a lab can decrease their workflow time by over 20%. These calculations do not take into account the how histotech time could be reallocated, as discussed below. A major quantifiable savings from automation is in histotech time. Table 3 estimates the approximate time saved by employing an automated embedder, stainer, or integrated stainer and coverslipper to process 100 units. These estimates were calculated utilizing the number of manual hours spent on each step (Figure 1) and representative throughputs for common automated equipment (examples in Table 1).

Figure 1. Average hours spent on manual histology workflow tasks per 100 units. Units for each step are defined as follows: grossing: surgical case (i.e., patient); cassetting: surgical case; embedding: block; sectioning: block; staining: slide; coverslipping: slide. Data from [2].


Table 2. Approximate time saved by automating selected steps of the histology workflow when compared to the time taken to perform the step manually.

Workflow Step Time Saved by Automation (Hours Per 100 Units)

Percentage Reduction in Workflow by Automation (100 Units)

Embedding 1.17 6.3% Staining (H&E) 1 5.4% Staining (H&E) & Coverslipping

3.09 16.8%

Approximating the saved histotech time in cost savings for the lab, Table 3 also calculates representative cost savings in histotech salary, excluding overhead. For example, in a lab that processes 500 blocks each day, utilizing an automated hematoxylin and eosin (H&E) stainer can save over $5,500 each month in salary, or $66,000 annually. This means that the payback period for a $40,000 stainer would be approximately eight months. The payback period would be significantly shorter when overhead and additional profits due to increased throughput are considered. A similar calculation for a more time-consuming step, such as IHC staining, reveals the payback period would be even shorter. This calculation assumes that all slides produced by the lab are IHC stained, which is unlikely, but it demonstrates that even a higher-priced instrument can return its investment if relieving a manual step. The estimates in Table 3 also assume that one instrument can handle the day’s workload of the lab, which may not be ideal for continuous processing. For example, for a lab that processes 1000 blocks per day and stains one slide per block, the automated stainer, which processes 100 blocks per hour, would need to run 10 hours per day. This may not be adequate or may create a bottleneck at the staining step. Each lab should determine whether one or more of each device is necessary to preserve a continuous workflow. Lastly, the estimates do not take into account where existing histotechs could spend their time after implementing automation. For example, automated slide stainers, especially those for special stains, have transformed the daily work of histotechs. Where histotechs used to spend a whole workday staining slides, now it takes only minutes per day [3]. Histotechs can now manage several workflow steps and/or focus on more manual steps, such as grossing and microtomy. As such, the lab can optimize histotech operations to maintain the flow of specimens and reduce bottlenecks, further improving lab capacity and turnaround times. Faster Turnaround Times Shorter turnaround times are a large benefit of automation. Turnaround times affect how quickly a patient is diagnosed and can start treatment. Faster turnaround times


Table 3. Estimated hours and US dollars saved per month by automating selected steps of the histology workflow.

Throughput: 1000 Blocks/Day 500 Blocks/Day 100 Blocks/Day

Histotech Hours Saved*

Embedding 20 10 2 Staining (H&E) 20.4 10.2 2 Staining (H&E) & Coverslipping 32.9 16.5 3.3

Staining (IHC) 233 116.5 23.3

Amount Saved/ Month (US $ )**

Embedding $10,833 $5,416 $1,083 Staining (H&E) $11,050 $5,525 $1,105 Staining (H&E)/ Coverslipping $17,820 $8,910 $1,782

Staining (IHC) $126,208 $64,104 $12,620 Payback period for $25K embedder (months)*** 2 5 23

Payback period for $40K Stainer (H&E) (months)*** 4 8 37

Payback period for $90K Stainer (H&E) / Coverslipper (months)*** 6 11 51

Payback period for $150K Stainer (IHC) (months)*** 2 3 12

*Assumes (1) One slide per block, (2) all slides stained with indicated instrument (when applicable), (3) one instrument can handle necessary throughput, and (4) time to set up automated equipment negligible. ** Assumes pay rate of $25 / hour. *** Accounts for saved histotech time only; does not include increased throughput.

can make a histology lab more competitive given that medical practices and researchers often have many choices for where to send their samples, and make a hospital or medical practice more patient friendly with faster times to diagnosis. Automation can therefore have a major impact on the way in which a lab serves the pathologist, clinician, hospital, and patient. For example, prior to rapid tissue processors, tissues were processed in large batches that took hours at a time. Tissues were often processed overnight, with these batches moving to embedding, microtomy, and staining the next day [4]. Rapid tissue processors that allowed for large batches to be changed every 20 minutes eliminated a bottleneck at the start of the workflow and allowed for a steady flow of fixed and embedded tissues downstream, reducing turnaround times from more than two days to less than one [5]. Reduced Contamination Contamination of histology specimens, in which tissue fragments from one specimen are found on the slide of another, can require the re-processing and re-


Table 4. Most common histology lab workflow steps where contamination occurs [6, 8].

Step Contamination Evidence

Cause Possible Solution(s)

Grossing & embedding

Occurs in block. Extraneous tissue often found in periphery of block.

May be due to “unclean” tongs or workspace.

Improved standard procedures for cleaning workspace and instruments. Instrumentation and consumables to reduce human interaction with tissues.

Section mounting (water bath)

Occurs on slide. Extraneous tissue often seen far from primary specimen.

Tissue fragments separate from embedded sections and can stick to other embedded sections or slides.

Improved standard procedures for cleaning water bath. Possible continuous flow/filtration system.

Staining (solution baths)

Occurs on slide. Extraneous tissue can be found close to primary specimen.

When slides are dipped into staining solutions, tissue fragments can separate and stick to other slides.

Improved standard procedures for changing staining bath solutions. Implementation of discrete automated stainer.

examination of tissue sections. This can result in many hours lost, and in the worst cases, contamination can result in misdiagnosis. One study found 1.5% of samples had contamination, and upon re-examination this number increased to 6.2% [6]. This is particularly a problem in anatomic pathology labs that specialize in a specific discipline, such as gastrointestinal pathology, as many of the tissues will be the same type [7]. Table 4 summarizes the causes and possible solutions for contamination in the histology lab. In some cases, automation of the workflow steps in Table 4 can reduce the risk of contamination. Sakura’s Tissue-Tek® Paraform® cassettes, designed for use with the Tissue-Tek® AutoTEC Embedder, reduce potential contamination by having the grossing tech place the tissue in the embedding cassette. This reduces the amount of human interaction with the tissue and therefore the possibility of losing or damaging tissue. Discrete stainers that place staining solutions directly onto a slide lying flat in a tray, such as the Ventana Symphony, reduce contamination by eliminating the need to dip multiple slides into the same solution bath. As the water bath for section mounting to slides is a source of contamination, a system that filters and recycles the water will both reduce risk of cross contamination and prevent the need to sweep or change the bath. The reduction in contamination from automation can impact both patient safety, by reducing misdiagnoses, and lab costs, by reducing the need to re-process tissues.


Safety Histotechnicans are exposed to a variety of workplace hazards; in 2013, the position was ranked the most unhealthy in the U.S. [9]. The most dangerous hazards are exposure to solvents like xylene, which can irritate the skin, eyes, nose, throat, and lungs, and can have long-term effects on the kidneys, lungs, heart, and nervous system. Automated instruments, such as automated tissue processors and slide stainers have significantly decreased exposure to the solvents used in tissue processing and paraffin removal. Histology lab managers are often concerned with repetitive motion injuries among their staff. When using rotary microtomes, where histotechs repeatedly turn a handwheel, histotechnicians become prone to repetitive motion injuries such as carpal tunnel syndrome. One paper estimated that a histotech cutting 50 blocks per day with a manual microtome will turn the handwheel half a million times a year [10]. Another small study found that more than 70% of female histotechs reported symptoms of musculoskeletal disorders [11]. Repetitive motion injuries can also occur during manual staining and coverslipping. Throughout the histology workflow, neck, back, shoulder, and arm injuries are common from examining specimens. Injuries are becoming more common as the histotech workforce ages. Automated instrumentation in each of these workflow steps can reduce or eliminate repetitive motion and other injuries, extending the health and productivity of histology lab staff. Lastly, with increasing demands on histology labs to maximize throughput and decrease turnaround times with decreasing staff, the histology lab can become a stressful workplace [10]. When automation relieves this pressure, the can become safer and lead to fewer near misses and injuries. Standardization Automation not only streamlines workflow steps but also creates uniformity of techniques across histotechs in the same lab and between labs. Standardization thereby improves patient diagnoses and allows for increased digital collaboration. Standardization also makes it possible to assess productivity and compare metrics to other similarly-sized labs. As documentation and validation become required at more institutions, standardization of all laboratory processes will be necessary. The future of anatomic pathology will involve digital scanning of slides for fluorescence microscopy, data sharing, and for 3D reconstruction of tissues. To achieve optimal image quality, the histology workflow steps of specimen preparation, sectioning, mounting sections onto slides, and staining will have to be standardized [12]. Automation at each of these steps will help labs adhere to


defined standards, and labs that are able to follow the standards required for digital pathology will gain a significant market advantage. Lastly, the standardization of section preparation on slides can reduce the cost of diagnosis. For example, having every tissue section placed uniformly on each slide reduces the time spent by pathologists scanning slides for the region of interest. Whether in a clinical setting or a contract research organization, decreased pathologist time can translate to lower cost of diagnosis or treatment for the patient. Microtomy: The Missing Link Figure 2 summarizes the average amount of time spent per day on each histology task, excluding tissue processing, when all are performed manually. Unlike Figure 1, this data is not normalized to a number of units, but represents the actual time spent on manual tasks. From this information, it is clear that microtomy consumes the majority of histotech time, as it includes trimming the block, sectioning, and mounting sections to slides. Despite being incredibly time-consuming, automated microtomes remain widely underutilized. Many histotechs can operate the microtome manually at the same rate as an automated microtome. Histotechs are currently required for trimming the block to the appropriate depth. After sectioning, histotechs move sections to the water bath and float mount the sections onto slides. Microtomy can be automated with appropriate developments in technology and programming. This would be especially useful in cases where sections cannot be lost and the full block is sectioned and mounted to slides. Importantly, fully automated microtomy would allow histotechs to pay attention to several microtomes at once, doubling or tripling their output. Better standardization of specimen and block preparation will make automated microtomy even easier, removing the need

Grossing(

Casse,ng(

Embedding(

Microtomy(

Staining((H&E)(

Coverslipping(

Grossing(

Casse,ng( Microtomy(

Staining((H&E)(

Coverslipping(

Embedding(

Average'Hours'Per'Day'Spent'on'Manual'Histology'Workflow'Steps'

Average'Hours'Spent'on'Manual'Histology'Workflow'Steps'Per'100'Units'

Hours(/(day(

Hours(/(day(0( 2( 4( 6( 8( 10( 12( 14( 16( 18( 20(

0( 5( 10( 15( 20( 25( 30( 35( 40(

Figure 2. Average hours per day spent on histology workflow tasks in U.S. labs. Data from [2].


for histotech involvement in trimming in some cases. Kurabo has developed its Auto Slide Preparation Systems, which can trim, section, and mount sections onto slides. The system is revolutionary in its auto-trimming and section placement capabilities, and also because it is an integrated system that combines several workflow steps into a single walkaway instrument. Unfortunately, the systems are cost-prohibitive, not widely available, and almost double turnaround time [13]. Ideally, automation around the microtome should begin with something that allows histotechs to interact closely with the tissue blocks for trimming, and be easily added and removed from the microtome. This will make the transition to automation easier for labs. It should replicate the job of the histotech as much as possible, but allow for hands-free operation to increase throughput and make microtomes safer and easier to use. Automation at the microtome will also make histology more accessible to those with less training, especially in settings where histotechs are scarce or researchers do not have the availability of a well-trained histotech. Automated microtomy is becoming increasingly necessary as more sections per block are needed for things like special stains. In research, the rise of 3D pathology will require many sections per block. The properly automated lab will be prepared for increases in workload when facing decreasing staff. With the final step in automation – automated sectioning and mounting to slides – the histology lab will have significant leaps in its efficiency, safety, and standardization. Benefits of Automation The benefits of automation span all parties touched by tissue-based diagnostics: the histology lab manager, the histotech, the clinician, the pathologist, and most importantly, the patient (Figure 3). For the lab manager, automation can not only lower costs through greater efficiency, but it can make accessible new sources of revenue. With proper adoption of automated equipment and optimized workflow, staff time can be freed up, increasing lab margins and allowing for the lab to expand its offerings of special stains, biomarkers, and digital pathology. Histotechs

Figure 3. Automation in the histology lab benefits the lab manager, histotech, clinician, pathologist, and most importantly, the patient.

Clinician'•  Faster'diagnosis'and'treatment'decisions'

•  Be0er'treatment'

decisions'from'availability'

of'more'informa6ve'

stains''

Pa)ent'•  Fast'diagnosis'•  More'accurate'

•  Be0er,'more'

personalized'treatment'

•  Lower'cost'

Lab'Manager'•  Increased'efficiency'

•  Lower'cost'per'specimen'

•  Ability'to'expand'stains'and'services'

porBolio'

•  Fewer'errors'

Histotech'•  Improved'work'environment''

•  Freedom'to'focus'on'

challenging'samples'and'new'

technologies'

•  Sa6sfac6on'of'helping''more'pa6ents'

•  Improved'safety'

Pathologist'•  Easier'to'read,'

standardized'slides'

•  Availability'of'new'clinical'and'research'technologies'

(e.g.,'digital'or'3D'

pathology,'biomarkers)'

Benefits'of'Automa)on'


experience reduced stress and greater safety with more walkaway instrumentation. This enables them to concentrate on difficult specimens and highly technical tasks. Outside of the histology lab, the pathologist benefits from slides that are easier to read as automation standardizes their preparation. Faster sample preparation and examination also allows the pathologist to increase their clinical throughput. Automation benefits the clinician by decreasing turnaround time and allowing for a faster diagnosis and the possibility to request more special stains or biomarkers. Above all, the patient benefits from automation, which allows them to spend less time worrying and begin treatment faster. References

1. International Agency for Research on Cancer. Global Battle against Cancer Won’t Be Won with Treatment Alone. Effective Prevention Measures Urgently Needed to Prevent Cancer Crisis. Available at: http://www.iarc.fr/en/media-centre/pr/2014/pdfs/pr224_E.pdf. Accessed June 1, 2014.

2. Buesa RJ. Histology aging workforce and what to do about it. Ann Diagn Pathol. 2009;13:176-184. 3. Ford A. For productivity gains, histology labs press on. CAP Today [serial online]. September 2012.

Available at: http://www.cap.org/apps//cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=cap_today%2F0912%2F0912b_productivity.html&_state=maximized&_pageLabel=cntvwr. Accessed June 1, 2014.

4. Cutts S. The age of automation finally dawns for histopathology. Laboratory News [serial online]. May 3, 2005. Available at: http://www.labnews.co.uk/features/the-age-of-automation-finally-dawns-for-histopathology/. Accessed June 1, 2014.

5. Morales AR, et al. Experience With an Automated Microwave-Assisted Rapid Tissue Processing Method. Am J Clin Pathol. 2004;121:528-536.

6. Gephart GN and Zarbo RJ. Extraneous Tissue in Surgical Pathology. Arch Pathol Lab Med. 1996;120: 1009-14.

7. Carpenter, JB. Risk of Misdiagnosis Due to Tissue Contamination May be Higher for Certain Specimen Types. Dark Daily [serial online]. 2011. Ventana Medical Systems. Available at: http://www.darkdaily.com/white-papers/risk-of-misdiagnosis-due-to-tissue-contamination-may-be-higher-for-certain-specimen-types-changes-to-laboratory-staining-techniques-offer-opportunity-to-reduce-contamination-events-31411. Accessed May 15, 2014.

8. Platt E. et al., Tissue Floaters and Contaminants in the Histology Laboratory. Arch Pathol Lab Med. 2009;113:973-8.

9. Kiersz A and Nisen M. The 15 Jobs that are Most Damaging to your Health. Business Insider [serial online]. 1 Dec. 2013. Available at: http://www.businessinsider.com/the-most-unhealthy-jobs-in-america-2013-11?op=1. Accessed June 1, 2014.

10. Herman GE et al., Histologists, Microtomy, Chronic Repetitive Trauma, and Techniques to Avoid Injury: Comparison of Performance Characteristics of a Motorized Microtome to Conventional Rotary Microtomes. The Journal of Histotechnology. 1996;19(1):55-63.

11. Mishew J. Histology Lab Ergonomics and Occupational Risk Factors. Micro-graf [serial online]. 2013; 42(3). Available at: http://www.mihisto.org/Resources/Documents/tp.4204%5Bfall13%5Dergonomics.pdf. Accessed June 1, 2014.

12. Yagi Y and Gilbertson JR. Digital imaging in pathology: the case for standardization. J Telemed Telecare. 2005;11(3):109-116.

13. Onozato ML et al. Evaluation of a completely automated tissue-sectioning machine for paraffin blocks. J Clin Pathol 2013;66:151-154.


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